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Alamance County Recreation and Parks Commission
The Recreation and Parks Commission serve as the advisory body for the Department of Recreation and Parks. The Commission suggests policies to the Department, the Manager and the Alamance County Board of Commissioners. The Commission serves as a liaison between the Department, the Manager, the Alamance County Board of Commissioners and the citizens of Alamance County. The Commission consults with and advises the Department, the Manager and the Alamance County Board of Commissioners in matters affecting recreation policies, program, personnel, finances, and the acquisition of lands and properties related to the total County recreation and parks needs.


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I highly recommend this Ayurvedic Retreat, from the expert consultation in Ayurvedic lifestyle by Richard to the fun staff to the excellent vegetarian cuisine (chef prepared) and the expert Ayurvedic treatments provided by the therapists nothing short of outstanding. A must do for anyone wishing to gain insight and inner peace. Namaste. Karen
- Also Known As:
- Ayurveda Health Retreat Hotel
- Ayurveda Health Retreat Hotel Alachua
- Official Description (provided by the hotel):
- The Ayurveda Health Retreat (AHR) is one of the premier retreat centers in Florida that offers traditional Ayurvedic medicine and Panchakarma treatments. The AHR was established by Richard Masla, ND, in 2001 and is located in the small historic town of Alachua, in north central Florida. The Retreat initially had only one treatment room and an office space. From these humble beginnings, it now encompasses three buildings: a beautiful yoga studio, a retreat center and a yoga ashram. Annually we serve hundreds of guests who visit us from all over the world. We are a group of dedicated health professionals who have created an authentic Ayurvedic retreat offering traditional Kerala Ayurvedic therapies. We have an Ayurvedic Practitioner, a Doctor of Naturopathy, psychologist, massage therapists, Reiki healers, and yoga & meditation teachers. Richard Masla, our Ayurvedic Practitioner, studied traditional Ayurveda under Dr. Vasant Lad, Dr. Pankaj Naram and Dr. Syama. Richard has mastered the ancient art of Kerala Ayurvedic Panchakarma and has trained all of our massage therapists. We're here to accommodate you, whether you need a weekend refresher or a full 21-day retreat. We look forward to being of service! ... more less

subset: commoncrawl


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BlackHawk Shotgun Sling with 15-Round Shell Holder Nylon Black
Product #: 633374
BlackHawk #:
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Lisa Hanna Movies
Here is a partial list of Lisa Hanna movies.
Movie Title | Year | Grade |
How Stella Got Her Groove Back | 1998 |
This list may not include all of Lisa Hanna's movies. Why? Our database only goes back to 1995. Lame, we know.
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Russia's President Vladimir Putin speaks during a media conference at the conclusion of the G8 summit at the Lough Erne resort near Enniskillen in Northern Ireland on June 18, 2013. World leaders were close to striking a deal on pushing for peace in Syria at the G8 summit as they also tried to reach agreement on cracking down on tax evasion. AFP PHOTO / POOL / MATT DUNHAMMATT DUNHAM/AFP/Getty Images
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hands full in
snaky' landing
CHARLESTON, W.Va. (AP)
Monty Coles was 3,000 feet in
the air when he discovered a
stowaway peeking out at him
from the plane's instrument
panel: a 4 -foot snake.
Coles was taking a leisurely
flight over the West Virginia
countryside in his Piper
Cherokee last weekend and was
preparing to land in Ohio when
the snake revealed itself.
Nothing in any of the manuals
ever described anything like
this,'' said the 62-year-old Cross
Lanes resident.
But advice given 25 years earlier
from his flight instructor
sprung to mind: No matter
what happens, fly the plane.''
Coles attempted to swat the
snake but it fell to the pilot's
feet, then darted to the other side
of the cockpit.
While maintaining control of
the single-engine plane with one
hand, Coles grabbed the reptile
behind its head with his other.
There was no way I was letting
that thing go,'' he said. It
coiled all around my arm, and its
tail grabbed hold of a lever on
the floor and started pulling.''
The next step was to radio for
emergency landing clearance.
They came back and asked
what my problem was,'' he said.
I told them I had one hand full
of snake and the other hand full
of plane. They cleared me in.''
After a smooth landing, Coles
posed for pictures with the
snake, then let it loose.
That snake resides in Ohio
now,'' he said.


text:
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Pathe have rights to clips in Time to Remember programmes but not to commentary or whole programme as screened.
Reel 1.
01:27:32 Various shots pianist possibly Morton Downey singing Stormy Weather.
01:27:56 Opening Titles - "Time to remember - a programme to take you back,...
We always welcome comments and more information about our films.
All posts are reactively checked. Libellous and abusive comments are forbidden.


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8 items from 2013
6 May 2013 3:43 PM, PDT | ShockYa | See recent ShockYa news »
The studio just sent us this exclusive clip from the upcoming horror-thriller, 'Aftershock,' from Radius-twc. The film directed by Nicholas Lopez stars Eli Roth, Andrea Osvárt, Ariel Levy and Selena Gomez (Rudderless, Getaway, Spring Breakers). Synopsis: 'Aftershock' follows a hapless American tourist, Gringo (Eli Roth), who's busy partying with his two Chilean friends, Ariel (Ariel Levy) and Pollo (Nicolas Martinez). The three pals are having the times of their lives, except for the fact that they can't find women to hook up with. But their luck changes when they meet Russian model Irina (Natasha Yarovenko), non-stop party girl Kylie (Lorenza Izzo) and her serious sister Monica (Andrea Osvart), who agree [ Read More ]
The post Exclusive: Crazy New Clip from Eli Roth's Aftershock appeared first on Shockya.com. »
- Brian Corder
29 April 2013 9:54 AM, PDT | Rope of Silicon | See recent Rope Of Silicon news »
Today I have quite the double-bill. It begins at noon with a screening of Noah Baumbach's much-talked-about Frances Ha, which premiered at the Toronto Film Festival last year and, along with playing the Seattle Film Festival, will hit limited theaters on May 17. Then, this evening my Summer Movie Season begins with Iron Man 3, which half the world has already seen to the tune of $195.3 million and reviews have been through the roof. My 2013 Summer Movie Season continues tomorrow night with Star Trek Into Darkness (5/17) and next Monday I'll be screening The Great Gatsby (5/10). I've already seen Before Midnight (5/24) and while in Cannes I'll see The Bling Ring (7/14), Only God Forgives (7/19), Ain't Them Bodies Saints (8/16) and Fruitvale Station (7/26). I mention all of this because I was considering writing up a Top Ten Most Anticipated 2013 Summer Movies feature, or even a Too 15, but when I will have seen nearly my »
- Brad Brevet
1 April 2013 12:09 PM, PDT | Filmofilia | See recent Filmofilia news »
Rudderless – make sure you remember this title! It's an upcoming musical drama that already has an awesome cast on board! Check this out – Selena Gomez, Anton Yelchin, Laurence Fishburne and Billy Crudup are all set to star in William H. Macy's directorial debut! Sounds promising, don't you think? Not much is known about Rudderless project at this moment, except that Macy will direct the whole thing from a script he co-wrote with Casey Twenter and Jeff Robison. According to Deadline, this musical drama will revolve around a grieving father who forms a band after finding his deceased son's songs. Still nothing about the...
Click to continue reading Selena Gomez, Anton Yelchin, Laurence Fishburne, and Billy Crudup Set For Musical Drama Rudderless! on | FilmoFilia
Related posts: Laurence Fishburne to Join NBC's Hannibal Laurence Fishburne To Star In Soderbergh's Contagion Selena Gomez to Produce/Star in »
- Jeanne Standal
26 March 2013 7:08 PM, PDT | MovieWeb | See recent MovieWeb news »
Warner Bros. has released their 2013 Summer preview, which showcases their slate of movies from May to August. The studio's new releases include The Great Gatsby, The Hangover Part III, Man of Steel, Pacific Rim, The Conjuring, 300: Rise of an Empire, We're the Millers and Getaway.
The Great Gatsby - May 10th
The Great Gatsby follows Fitzgerald-like, would-be writer Nick Carraway (Tobey Maguire) as he leaves the Midwest and comes to New York City in the spring of 1922, an era of loosening morals, glittering jazz, bootleg kings, and sky-rocketing stocks. Chasing his own American Dream, Nick lands next door to a mysterious, party-giving millionaire, Jay Gatsby (Leonardo DiCaprio), and across the bay from his cousin, Daisy (Carey Mulligan), and her philandering, blue-blooded husband, Tom Buchanan (Joel Edgerton). It is thus that Nick is drawn into the captivating world of the super rich, their illusions, loves and deceits. As Nick bears witness, »
- MovieWeb
25 March 2013 10:46 AM, PDT | Rope of Silicon | See recent Rope Of Silicon news »
Photo: Warner Bros. Warner Bros. is the first studio to lift the lid on their crop of 2013 summer films beginning with The Great Gatsby, which will not only hit theaters on May 10, but will also open the 2013 Cannes Film Festival. From there films include Insidious director James Wan's new film The Conjuring, the Selena Gomez and Ethan Hawke thriller Getaway, the return of the Wolf Pack in The Hangover Part III, Zack Snyder's take on the Superman origin produced by Christopher Nolan Man of Steel, Guillermo del Toro's monster movie Pacific Rim and the Jennifer Aniston-led comedy We're the Millers. Finally, and the only movie that does not yet have any accompanying images for you to check out, 300: Rise of an Empire, which appears to still be on track for an August 2 release, but we'll see. I have included a preview image and information on »
- Brad Brevet
18 March 2013 8:28 PM, PDT | Alt Film Guide | See recent Alt Film Guide news »
Gomez, Hudgens, Franco, guns and bikinis: Outstanding domestic debut Harmony Korine's crime flick Spring Breakers currently boasts the year's highest per-theater average. That's no small feat. As per final Us/Canada weekend box-office numbers published on the web site Box Office Mojo, this past weekend (March 15-17) the film raked in $263,002 at three locations (two in New York City, one in Los Angeles). That's down slightly from the studio's $270,000 estimate released on Sunday, but still enough to average a fantastic $87,667 per venue. (Pictured above: Gomez [scroll down for more on Gomez's box-office performance to date; pictured below: bad girls in bikinis in court.) One of the highest opening weekend per-theater averages ever Spring Breakers was down one spot on Box Office Mojo's post-1982 chart of opening-weekend per-theater averages. At #23, the movie is sandwiched between two Academy Award winners: Tom Hooper / Colin Firth's The King's Speech with $88,863 and Steven Spielberg / Daniel Day-Lewis' Lincoln with $85,846. Once inflation is factored in, Spring Breakers drops to the 52nd spot (down nine spots from yesterday's estimates), landing between Daniel Myrick »
- Zac Gille
13 March 2013 10:39 AM, PDT | DailyDead | See recent DailyDead news »
Horror typically equates "coming of age" with survival – prevailing over a would-be killer – but in Stoker, director Park Chan-wook turns that struggle, and transformation, into an origin story.
The tale of a young woman whose 18th birthday unleashes a mysteriously seductive sort of hell on a grieving family, Park deconstructs nature, nurture and everything in between. A visual feast whose psychosexual boilerplate proves intriguingly complex, Stoker is a born classic – a brilliant English-language crossover effort for Park that doubles as a genre-transcending triumph.
Mia Wasikowska (Alice in Wonderland) plays India Stoker, a young woman whose 18th birthday coincides with the death of her father Richard (Dermot Mulroney). Mourning the loss quietly as her mother Evelyn (Nicole Kidman) attempts to forge the sort of connection India once shared with her father, their efforts to move on are interrupted by the arrival of Charlie (Matthew Goode), Richard's long-absent brother. Charlie agrees »
- Todd Gilchrist
1 January 2013 12:49 PM, PST | MovieWeb | See recent MovieWeb news »
2012 was a nearly perfect year in cinema. Every month saw a new, interesting movie that captivated audiences, and brought plenty of money streaming into the box office. It was a year where top ten lists meant little to nothing, because there were at least twenty other films on any given list not accounted for. Will 2013 prove to be such a heavyweight? Or will it suffer in the shadow of its predecessor? Right now, there are 109 planned major releases that could be included on any best of 2013 list. We're whittling those down to the 13 most anticipated movies in the coming year, according to both our community here at Movieweb as well as past box office records. If anything can be said about 2013, its that some great movies are coming our way over the course of the next twelve months. The following list is in order by release date.
Identity Thief - »
- MovieWeb
8 items from 2013
IMDb.com, Inc. takes no responsibility for the content or accuracy of the above news articles, Tweets, or blog posts. This content is published for the entertainment of our users only. The news articles, Tweets, and blog posts do not represent IMDb's opinions nor can we guarantee that the reporting therein is completely factual. Please visit the source responsible for the item in question to report any concerns you may have regarding content or accuracy.
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text:
- Material: Polyester Peach Skin
- Size 1: 120 x 20cm/47.2 x 78.7in(Hx L)
- Size 2: 160 x 20cm/63.0 X 78.7in(H x L)
- The mosquito netting is ger net style with king size in light blue
- Both beautiful and functional, the ger mosquito netting will bring you high quality life
- This king mosquito netting is the least possible money you can spend to dramatically change a room
- Sweet dreams are assured as your little princess slumbers beneath this dreamy canopies mosquito netting
Size Reference Table:
N. America
UK / Ireland
Europe / Latin America
39in x 75in
36in x 75in
90cm x 190cm
90cm x 200cm
Single / Twin
99cm x 191cm
91cm x 191cm
35.5in x 75in
35.4in x 79in
54in x 75in
135cm x 190cm
140cm x 200cm
Full / Double
137 cm x 191cm
53in x 75in
55in x 79in
60in x 80in
150cm x 200cm
160cm x 200cm
152cm x 203cm
60 in x 78in
(63in x 79in)
76in x 80in
198cm x 203cm
72in x 80in
180cm x 200cm
(US/Aus) King
(California King 72in x 84in
183cm x 203cm
72in x 78in
180cm x 210cm)
NOTE:- Size may differ because of the different measure methods
Package Included:- 2 x Bed Curtains
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Welcome to Mrs. Schiemer's class
RoseMary Schiemer
Welcome to 8th grade Language Arts! I look forward to a great year together. I hope to pass on some invaluable knowledge to each of my students, as well as learn from each of you.
Classroom Mission
Our class will become better readers and writers. The best way to accomplish this is by reading, reading, reading and writing, writing, writing.
About Me
Eighth grade is my absolute favorite grade to teach! There is never a boring moment when working with 13 and 14 year olds! This is my 10th year teaching. I have a B.S. from the University of Maryland and a Master's Degree from the University of North Carolina at Charlotte. I enjoy teaching about other languages and cultures and will incorporate that into my classroom.
I live in Mooresville with my husband Chris and four children, CJ, RoseAnna, Fischer and RosaLee. They attend Lakeshore Middle, Lake Norman High School and the University of South Carolina. We are a very busy family with sports and school activities, and I'm sure I will see you all outside the classroom.
loose leaf notebook paper
colored pencils
one three ring binder (you don't need a big one, but it doesn't matter really what size. I'd rather you use one you already have.)
lots of post it notes (sticky notes, doesn't matter what color or size)
3X5 index cards
Last Modified on June 10, 2013
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Study: Teen marijuana use on the rise
CBS News
(AP) WASHINGTON - More teens are smoking dope, with nearly 1 in 10 lighting up at least 20 or more times a month, according to a new survey of young people.
The report by The Partnership at Drugfree.org, being released Wednesday, also said abuse of prescription medicine may be easing a bit among young people in grades 9 through 12, but still remains high.
Partnership President Steve Pasierb says the mindset among parents is that it's just a little weed or a few pills no biggie.
"Parents are talking about cocaine and heroin, things that scare them," said Pasierb. "Parents are not talking about prescription drugs and marijuana. They can't wink and nod. They need to be stressing the message that this behavior is unhealthy."
Use of harder drugs cocaine and methamphetamine has stabilized in recent years, the group's survey showed. But past-month usage of marijuana grew from 19 percent in 2008 to 27 percent last year. Also alarming, says Pasierb, is the percentage of teens smoking pot 20 or more times a month. That rate went from 5 percent in 2008 to 9 percent last year, or about 1.5 million teens toking up that frequently.
Alex, 17, in Houston, says he started smoking pot at age 13, mostly on the weekends with friends.
"I just liked being high," said Alex, who is in a recovery program and asked that his last name not be used. "I always felt happier. Everything was funnier and my life was just brighter."
Alex then started abusing prescription drugs at 14. He blacked out one day at school, got arrested and ended up in rehab. After being sober for two years, Alex slipped and smoked pot last month. Still, he says he hopes to work toward a more sober life.
The findings on marijuana track closely with those in a recent University of Michigan study sponsored by the National Institute on Drug Abuse, part of the National Institutes of Health. That study also found marijuana use rising among teens the past few years, reversing a long decline in the previous decade.
The partnership study suggests a link between teens who smoke pot more regularly and the use of other drugs. Teens who smoked 20 times or more a month were almost twice as likely as kids who smoked pot less frequently to use ecstasy, cocaine or crack.
Other findings:
-One in 10 teens reports using prescription pain medication Vicodin or OxyContin in the past year. That's down from a peak of 15 percent in 2009 and 14 percent in 2010.
-Just over half of Hispanic teens say they have used an illicit drug, such as Ecstasy or cocaine, in the past year. That compares to 39 percent for Caucasian teens and 42 percent for African American teens.
The Marijuana Policy Project, which advocates legalization, says making pot legal for adults might help cut teen usage.
"We definitely don't think that minors should be using marijuana any more than they should be drinking or using tobacco, but arresting people for doing that never stops minors," said Morgan Fox, a spokesman for the group. "If we remove marijuana from the criminal market and have the market run by responsible business people that have an incentive to check IDs and not sell to minors, then we might see those rates drop again."
The Partnership's study was sponsored by the MetLife Foundation. Researchers surveyed 3,322 teens in grades 9-12 with anonymous questionnaires that the youngsters filled out at school from March to June 2011. The study has a margin of error of plus or minus 3 percentage points.
Based in New York, The Partnership at Drugfree.org is formerly The Partnership for a Drug-Free America perhaps best known for the "this is your brain on drugs" ads of the 1980s and 1990s. The nonprofit group launched its new name in 2010 to position itself as more of a resource to parents and to avoid the misperception the partnership is a government organization.
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- linkicon reporticon emailicon
- "nearly 1 in 10 lighting up at least 20 or more times a month,... One in 10 teens reports using prescription pain medication" Yea, right-no correlation there. Gateway drug my bohukus. Wake up dumassesss.
- reply
- linkicon reporticon emailicon
- Legalize it already and quit feeding into gov propaganda!!!
- reply
- linkicon reporticon emailicon
- "Hemp for Victory!" - WWII poster and book
- reply
- linkicon reporticon emailicon
- If they legalize pot how will all those people who cant pass drug tests get a job? After all if it is in your system who is to say you didn't spark a bowl while driving yourself to work and not last night?
- reply
- linkicon reporticon emailicon
- they will pass the test the same way they do now
- linkicon reporticon emailicon
- Just don't make the deadly mistake of smoking cigarets.
- reply
- linkicon reporticon emailicon
- Yup, because this country sets suuuch a good example for it's youth. Only after decades-long legal and public opinion battles did the U.S. government acknowledge that tobacco companies produce what is basically a genetically and chemically enhanced poisonous, addictive drug. Major televised sports events advertise alcohol to be what it's not, an enhancer of courtship, recreational and socialization skills, and the media promotes materialistic, misogynous, narcissistic, semi-criminal behavior as "fly" while a block down the road there's a gun show on the county carnival grounds featuring a ferris wheel, Freddie the Clown and automatic firearms. This is the U.S., home of the sociopathic urban werewolf that's addicted to everything that makes money for the rich and pays taxes, and the government has it's drawers in a bunch because some stressed-out kids get a buzz on a little hemp????
- reply
- linkicon reporticon emailicon
- I agree with you on all but one point. As long as Liberals refrain from buying guns, the crooked scumbags who own America know they can continue turning this place into an absolute plutocracy with total impunity. Don't expect the government to hold them back. Our laws were not designed to protect us from America's crooked rich. They were designed to protect them from us.
- linkicon reporticon emailicon
- To all those vacuuous adults out there that think pot and pills are "no big deal." You don't deserve to parents and your kids should be in foster homes with adults playing with full decks.
- reply
- linkicon reporticon emailicon
- i am speaking of pot, not pills
- linkicon reporticon emailicon
- @verrz...Have to agree w/honestabe8...get your head out of your a&&.
- linkicon reporticon emailicon
- The USA has the highest percentage of prisoners per population in the world, higher than in the USSR gulags under Stalin. Half of them are there for drug offenses, 80% of those for simple possession.
Gulags for profit - the American way. - reply
- linkicon reporticon emailicon
- Is it just me or should we get Steppenwolf to do a comeback special?
Speaking of high,
Now note the lead singer wearing specs while his cohorts, with their close-ups, definitely look like they're in la-la-land...
And anybody with a few free minutes can look up the lyrics to some of the songs on any given compilation/best of album. There's one where they glorify weed - it's almost funny.
("noble weed", indeed...) - reply
- linkicon reporticon emailicon
- New moniker suggestion: hypnoterd
- linkicon reporticon emailicon
- @hypnotoad72...Your point?
- linkicon reporticon emailicon
- [Teens who smoked 20 times or more a month were almost twice as likely as kids who smoked pot less frequently to use ecstasy, cocaine or crack.]
is that the correlation ... or is it ... teens who used ecstasy, cocaine, or crack tend to smoke more weed? - reply


text:
Hairstyle Ideas, Tips & Photos
If you have been wearing the same hairstyle for years, it's time to get out of your beauty rut and find a whole new look. The SheKnows Beauty & Style Experts have assembled an array of hairstyle ideas for every hair length, color and texture. From dramatic updos to simple wash-and-wear styles, you're sure to find the hairstyle that fits you perfectly.
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text:
Holes of Oblivion Open Up in China
One central feature of totalitarianism is the desire of those at the top of the movement to retain full—that is, total—control of their people. Total control requires, at times, the ability to lie, especially when facts on the ground fail to conform with past and present pronouncements. The strength of any totalitarian system can, in part, be measured by how successfully lies can be maintained and how effectively the movement can lie in spite of the facts.
A story out of China this week offers great insight into the totalitarian ambitions of some in China's government, but also the fissures in that façade. As is now well known, Chinese President Hu Jintao is resigning, leaving office voluntarily when he had been expected to seek another term in power. Moreover, Hu is not maintaining any significant position of power in the new Chinese leadership, something quite unusual. And now the reasons have surfaced.
It seems that Hu was brought down by the emergence of a cover-up orchestrated by his most trusted deputy, Ling Jihua. The facts are such:
Mr. Ling's son crashed his black Ferrari, killing himself and injuring two young women he was driving with. One of the women later died. Even though the crash and the son's death were reported in the press, Mr. Ling set about erasing that news and denying it. He admitted the crash, but insisted his son was still alive, even creating false social media posts from his son to "prove" that he had survived. In addition, a major Chinese bank with connections to President Hu paid hush money to the families of the two women.
What is surprising is not so much the cover-up, but that it failed. As the New York Times reports,
Under normal circumstances, party insiders said, suppressing such news to protect the image of the party would be a routine matter. But Ling Jihua went further, they said, maneuvering to hide his son's death even from the leadership.
Against Ling's heavy-handed efforts, Chinese bureaucrats fought back. Intentionally or not, the police recorded the name of Ling's son as Jia, a word that sounds like the word in Chinese for fake, and also a word similar to a retired party leader. That leader was furious about reports of his ignoble death. This and other accidents led to increasing pressure on Ling, and eventually the cover-up unraveled, leaving Hu embarrassed and eventually allowing him to be pushed out of power.
The fascinating story is yet another reminder of one of the most optimistic of Hannah Arendt's repeated claims, that "The holes of oblivion do not exist." In other words, no totalitarian system is perfect and no matter how sophisticated the lie, if the lie is big and important enough, the truth will eventually come out. As Arendt writes:
Nothing human is that perfect, and there are simply too many people in the world to make oblivion possible. One man will always be left alive to tell the story.
It is always good to be reminded of this basic fact of the human world, that as artful as humans may be at lying, truth is stronger than the lie.
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Justices Rule Vaccine Firms Protected From Suits
The Wall Street Journal
Date Published:
February 23, 2011
The Supreme Court handed a victory to vaccine makers Tuesday, ruling 6-2 that U.S. law shields them from product-liability suits alleging defects in a vaccine's design. The high court ruled in the case of a Pennsylvania couple who alleged that their daughter suffered profound impairments after receiving a diphtheria, tetanus and pertussis vaccine made by Wyeth, now part of Pfizer Inc. The result takes a key legal tool out of the hands of those who contend their children's autism was caused by vaccines.


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Colon Cancer Genes
Major Genes
Adenomatous Polyposis Coli (APC)
Mut Y Homolog
DNA MMR Genes
Peutz-Jeghers Gene(s)
Juvenile Polyposis Gene(s)
Cowden Syndrome/Bannayan-Riley-Ruvalcaba Syndrome Gene(s)
De novo mutation rate
Genetic Polymorphisms and CRC Risk
Polymorphism-modifying risk in average-risk populations
Major Genes
Major genes are defined as those that are necessary and sufficient for disease causation, with important mutations (e.g., nonsense, missense, frameshift) of the gene as causal mechanisms. Major genes are typically considered those that are involved in single-gene disorders, and the diseases caused by major genes are often relatively rare. Most pathogenic mutations in major genes lead to a very high risk of disease, and environmental contributions are often difficult to recognize.[1] Historically, most major colon cancer susceptibility genes have been identified by linkage analysis using high-risk families; thus, these criteria were fulfilled by definition, as a consequence of the study design.
The functions of the major colon cancer genes have been reasonably well characterized over the past decade. Three proposed classes of colon cancer genes are tumor suppressor genes, oncogenes, and DNA repair genes.[2] Tumor suppressor genes constitute the most important class of genes responsible for hereditary cancer syndromes and represent the class of genes responsible for both familial adenomatous polyposis (FAP) and juvenile polyposis, among others. Germline mutations of oncogenes are not an important cause of inherited susceptibility to colorectal cancer (CRC), even though somatic mutations in oncogenes are ubiquitous in virtually all forms of gastrointestinal cancers. Stability genes, especially the mismatch repair (MMR) genes responsible for Lynch syndrome (LS) (also called hereditary nonpolyposis colorectal cancer [HNPCC]), account for a substantial fraction of hereditary CRC, as noted below. (Refer to the Lynch syndrome (LS) section in the Major Genetic Syndromes section of this summary for more information). MYH is another important example of a stability gene that confers risk of CRC based on defective base excision repair. Table 2 summarizes the genes that confer a substantial risk of CRC, with their corresponding diseases.
Table 2. Major Genes Associated with Risk of Colorectal CancerGene | Syndrome | Hereditary Pattern | Predominant Cancer |
FAP = familial adenomatous polyposis; GI = gastrointestinal; OMIM = Online Mendelian Inheritance in Man database. | |||
Tumor suppressor genes | |||
APC (OMIM) | FAP (OMIM) | Dominant | Colon, intestine, etc. |
AXIN2 (OMIM) | Attenuated polyposis (OMIM) | Dominant | Colon |
TP53 (p53) (OMIM) | Li-Fraumeni (OMIM) | Dominant | Multiple (including colon) |
STK11 (OMIM) | Peutz-Jeghers (OMIM) | Dominant | Multiple (including intestine) |
PTEN (OMIM) | Cowden (OMIM) | Dominant | Multiple (including intestine) |
BMPR1A (OMIM) | Juvenile polyposis (OMIM) | Dominant | Gastrointestinal |
SMAD4 (DPC4) (OMIM) | Juvenile polyposis (OMIM) | Dominant | Gastrointestinal |
Repair/stability genes | |||
MLH1 (OMIM), MSH2 (OMIM), MSH6 (OMIM), PMS2 (OMIM) | Lynch (OMIM) | Dominant | Multiple (including colon, uterus, and others) |
EPCAM (TACSTD1) (OMIM) | Lynch (OMIM) | Dominant | Multiple (including colon, uterus, and others) |
MYH (MUTYH) (OMIM) | Attenuated polyposis (OMIM) | Recessive | Colon |
BLM (OMIM) | Bloom (OMIM) | Recessive | Multiple (including colon) |
Oncogenes | |||
KIT (OMIM) | Familial GI stromal tumor (OMIM) | GI stromal tumors | |
PDGFRA (OMIM) | Familial GI stromal tumor (OMIM) | GI stromal tumors |
Adenomatous Polyposis Coli (APC)
The APC gene on chromosome 5q21 encodes a 2,843-amino acid protein that is important in cell adhesion and signal transduction; beta-catenin is its major downstream target. APC is a tumor suppressor gene, and the loss of APC is among the earliest events in the chromosomal instability colorectal tumor pathway. The important role of APC in predisposition to colorectal tumors is supported by the association of APC germline mutations with FAP and attenuated FAP (AFAP). Both conditions can be diagnosed genetically by testing for germline mutations in the APC gene in DNA from peripheral blood leukocytes. Most FAP pedigrees have APC alterations that produce truncating mutations, primarily in the first half of the gene.[3,4] AFAP is associated with truncating mutations primarily in the 5' and 3' ends of the gene and possibly missense mutations elsewhere.[5-8]
More than 300 different disease-associated mutations of the APC gene have been reported.[4] The vast majority of these changes are insertions, deletions, and nonsense mutations that lead to frameshifts and/or premature stop codons in the resulting transcript of the gene. The most common APC mutation (10% of FAP patients) is a deletion of AAAAG in codon 1309; no other mutations appear to predominate. Mutations that reduce rather than eliminate production of the APC protein may also lead to FAP.[9]
Most APC mutations that occur between codon 169 and codon 1393 result in the classic FAP phenotype.[5-7] There has been much interest in correlating the location of the mutation within the gene with the clinical phenotype, including the distribution of extracolonic tumors, polyposis severity, and congenital hypertrophy of the retinal pigment epithelium. The most consistent observations are that attenuated polyposis and the less classic forms of FAP are associated with mutations that occur in or before exon 4 and in the latter two-thirds of exon 15,[6] and that retinal lesions are rarely associated with mutations that occur before exon 9.[7,10] Exon 9 mutations have also been associated with attenuated polyposis. Additionally, individuals with exon 9 mutations tend not to have duodenal adenomas.[11]
Mut Y HomologThe Mut Y homolog gene, which is also known as MUTYH and MYH, is located on chromosome 1p34.3-32.1.[12] The protein encoded by MYH is a base excision repair glycosylase. It repairs one of the most common forms of oxidative damage. Over 100 unique sequence variants of MYH have been reported (Leiden Open Variation Database). A founder mutation with ethnic differentiation is assumed for MYH mutations. In Caucasian populations, two major variants (Y165C and/or G382D) account for 70% of biallelic mutations in MYH-associated polyposis patients, and 90% of these patients carry at least one of these mutations.[13] Biallelic MYH mutations are associated with a 93-fold excess risk of CRC with near complete penetrance by age 60 years.[14]
DNA MMR GenesLS is caused by mutation of one of several DNA MMR genes.[15-21] The function of these genes is to maintain the fidelity of DNA during replication. The genes that have been implicated in LS include MSH2 (mutS homolog 2) on chromosome 2p22-21;[18,19] MLH1 (mutL homolog 1) on chromosome 3p21;[17] PMS2 (postmeiotic segregation 2) on chromosome 7p22;[21,22] and MSH6 on chromosome 2p16. The genes MSH2 and MLH1 are thought to account for most mutations of the MMR genes found in LS families.[23,24]
A variety of LS-associated mutations in MSH2 and MLH1 have been identified. These include founder mutations in the Ashkenazi Jewish, Finnish, Portuguese, and German American populations.[24-29] The wide distribution of the mutations in the two genes preclude simple gene testing assays (i.e., assays that would identify only a few mutations). Commercial testing is available to search for mutations in MSH2, MLH1, MSH6, and most recently for PMS2. Clinical and cost considerations may guide testing strategies. Most commercial genetic testing for MSH2 and MLH1 is done by gene sequencing. Because sequencing fails to detect genomic deletions that are relatively common in LS, methods such as Southern blot or multiplex ligation-dependent probe amplification (MLPA),[30] for detection of large deletions, are being used.[31] (Refer to the Genetic/Molecular testing for LS section of this summary for more information about issues to be considered in testing for these mutations.)
Peutz-Jeghers Gene(s)Peutz-Jeghers syndrome (PJS) is characterized by mucocutaneous pigmentation and gastrointestinal polyposis and is caused by mutations in the STK11 (also named LKB1) tumor suppressor gene located on chromosome 19p13.[32,33] Unlike the adenomas seen in FAP, the polyps arising in PJS are hamartomas. Studies of the hamartomatous polyps and cancers of PJS show allelic imbalance (loss of heterozygosity [LOH]) consistent with the two-hit hypothesis, demonstrating that STK11 is a tumor suppressor gene.[34,35] However, heterozygous STK11 knockout mice develop hamartomas without inactivation of the remaining wild-type allele, suggesting that haploinsufficiency is sufficient for initial tumor development in PJS.[36] Subsequently, the cancers that develop in STK11 +/- mice do show LOH;[37] indeed, compound mutant mice heterozygous for mutations in STK11 +/- and homozygous for mutations in TP53 -/- have accelerated development of both hamartomas and cancers.[38]
Germline mutations of the STK11 gene represent a spectrum of nonsense, frameshift, and missense mutations, and splice-site variants and large deletions.[39,40] Approximately 85% of mutations are localized to regions of the kinase domain of the expressed protein, and no germline mutations have been reported in exon 9. No strong genotype-phenotype correlations have been identified.[39]
One gene (STK11) has been unequivocally demonstrated to cause PJS. Although earlier estimates using direct DNA sequencing showed a 50% mutation detection rate in STK11, studies adding techniques to detect large deletions have found mutations in up to 94% of individuals meeting clinical criteria for PJS.[40-42] Given the results of these studies, it is unlikely that other major genes cause PJS.
(Refer to the Peutz-Jeghers syndrome (PJS) section in the Rare Colon Cancer Syndromes section of this summary for more information.)
Juvenile Polyposis Gene(s)Juvenile polyposis is defined by the presence of a specific type of hamartomatous polyp called a juvenile polyp, usually in the setting of a family history. The diagnosis of a juvenile polyp is based on its histologic appearance rather than age of onset, and the familial form is caused by mutations in the BMPR1A gene in 20% of cases and by mutations in the SMAD4 gene in another 20%.[43,44]
SMAD4 encodes a protein that is a mediator of the transforming growth factor (TGF)-beta signaling pathway, which mediates growth inhibitory signals from the cell surface to the nucleus. Germline mutations in SMAD4 predispose individuals to forming juvenile polyps and cancer,[45] and germline mutations have been found in 6 of 11 exons. Most mutations are unique, but several recurrent mutations have been identified in multiple independent families.
BMPR1A is a serine-threonine kinase type I receptor of the TGF-beta superfamily that, when activated, leads to phosphorylation of SMAD4. The BMPR1A gene was first identified by linkage analysis in families with juvenile polyposis who did not have identifiable mutations in SMAD4. Mutations in BMPR1A include nonsense, frameshift, missense, and splice-site mutations.[46] Large genomic deletions detected by MLPA have been reported in both BMPR1A and SMAD4 in patients with juvenile polyposis syndrome.[47,48] It was reported that two individuals with mutations in both PTEN and BMPR1A also had phenotypic features of juvenile polyposis syndrome (JPS) and Cowden syndrome (see below).[49] Rare JPS families have demonstrated mutations in the ENG and PTEN genes but these have not been confirmed in other studies.[49,50]
JPS of infancy is often caused by microdeletions of chromosome 10q22-23, a region that includes BMPR1A and PTEN.[51]
Cowden Syndrome/Bannayan-Riley-Ruvalcaba Syndrome Gene(s)Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome (BRRS) are part of a spectrum of conditions known collectively as PTEN hamartoma tumor syndromes. Approximately 85% of patients diagnosed with Cowden syndrome and approximately 60% of patients with BRRS have an identifiable mutation of PTEN.[52]
PTEN functions as a dual-specificity phosphatase that removes phosphate groups from tyrosine and serine and threonine. Mutations of PTEN are diverse, including nonsense, missense, frameshift, and splice-variant mutations. Approximately 40% of mutations are found in exon 5, which represents the phosphate core motif, and several recurrent mutations have been observed.[53] Individuals with mutations in the 5' end or within the phosphatase core of PTEN tend to have more organ systems involved.[54]
(Refer to the Cowden Syndrome section in the PDQ summary on the Genetics of Breast and Ovarian Cancer for more information.)
De novo mutation rateUntil the 1990s, the diagnosis of genetically inherited polyposis syndromes was based on clinical manifestations and family history. Now that some of the genes involved in these syndromes have been identified, a few studies have attempted to estimate the spontaneous mutation rate (de novo mutation rate) in these populations. Interestingly, FAP, JPS, PJS, Cowden syndrome, and BRRS are all thought to have high rates of spontaneous mutations, in the 25% to 30% range,[55-57] while estimates of de novo mutations in the MMR genes associated with LS are thought to be low, in the 0.9% to 5% range.[58-60] These estimates of spontaneous mutation rates in LS seem to overlap with the estimates of nonpaternity rates in various populations (0.6% to 3.3%),[61-63] making the de novo mutation rate for LS seem quite low in contrast to the relatively high rates in the other polyposis syndromes.
Genetic Polymorphisms and CRC RiskIt is widely acknowledged that the familial clustering of colon cancer also occurs outside of the setting of well-characterized colon cancer family syndromes.[64] Based on epidemiological studies, the risk of colon cancer in a first-degree relative of an affected individual can increase an individual's lifetime risk of colon cancer 2-fold to 4.3-fold.[65] The relative risk (RR) and absolute risk of CRC for different family history categories is estimated in Table 1. In addition, the lifetime risk of colon cancer also increases in first-degree relatives of individuals with colon adenomas.[66] The magnitude of risk depends on the age at diagnosis of the index case, the degree of relatedness of the index case to the at-risk case, and the number of affected relatives. It is currently believed that many of the moderate- and low-risk cases are influenced by low-penetrance genes or gene combinations. Given the public health impact of identifying the etiology of this increased risk, an intense search for the responsible genes is under way.
Each locus would be expected to have a relatively small effect on CRC risk and would not produce the dramatic familial aggregation seen in LS or FAP. However, in combination with other common genetic loci and/or environmental factors, variants of this kind might significantly alter CRC risk. These types of genetic variations are often referred to as polymorphisms. Most loci that are polymorphic have no influence on disease risk or human traits (benign polymorphisms), while those that are associated with a difference in risk of disease or a human trait (however subtle) are sometimes termed disease-associated polymorphisms or functionally relevant polymorphisms. When such variation involves changes in single nucleotides of DNA they are referred to as single nucleotide polymorphisms (SNPs).
Polymorphisms underlying polygenic susceptibility to CRC are considered low penetrance, a term often applied to sequence variants associated with a minimal to moderate risk. This is in contrast to high-penetrance variants or alleles that are typically associated with more severe phenotypes, for example those APC or MMR gene mutations leading to an autosomal dominant inheritance pattern in a family. The definition of a moderate risk of cancer is arbitrary, but it is usually considered to be in the range of an RR of 1.5 to 2.0. Because these types of sequence variants are relatively common in the population, their contribution to total cancer risk is estimated to be much higher than the attributable risk in the population from the relatively rare syndromes such as FAP or LS. Additionally, polymorphisms in genes distinct from the MMR genes can modify phenotype (for example average age of CRC) in individuals with LS.
In general, low-penetrance variants have been identified in one of two manners. Earlier studies focused on candidates genes chosen because of biologic relevance to colon cancer pathogenesis. More recently, genome-wide association studies (GWAS) have been used much more extensively to identify potential CRC susceptibility genes. (Refer to the Genome-wide searches section of this summary for more information.)
Polymorphism-modifying risk in average-risk populationsLow-penetrance candidate genes
Several candidate genes have been identified and their potential use for clinical genetic testing is being determined. Candidate alleles that have been shown to associate with modest increased frequencies of colon cancer include heterozygous BLMAsh (the allele that is a founder mutation in Ashkenazi Jewish individuals with Bloom syndrome), the GH1 1663 T→A polymorphism (a polymorphism of the growth hormone gene associated with low levels of growth hormone and IGF-1), and the APC I1307K polymorphism.[67-69]
Of these, the variant that has been most extensively studied is APC I1307K. Yet, neither it nor any of the other variants mentioned above are routinely used in clinical practice. (Refer to the APC I1307K section of this summary for more information.)
Genome-wide searchesAlthough the major genes for polyposis and nonpolyposis inherited CRC syndromes have been identified, between 20% and 50% of cases from any given series of suspected FAP or LS cases fail to have a mutation detected by currently available technologies. It is estimated that heredity is responsible for approximately one-third of our susceptibility to CRC,[70] and causative germline mutations account for less than 6% of all CRC cases.[71] This has led to suspicions that there may be other major genes that, when mutated, predispose to CRC with or without polyposis. A few such genes have been detected (e.g., MYH, EPCAM) but the probability for discovery of other such genes is fairly low. More recent measures for new gene discovery have taken a genome-wide approach. Several GWAS have been conducted with relatively large, unselected series of CRC patients that have been evaluated for patterns of polymorphisms in candidate and anonymous genes spread throughout the genome. These SNPs are chosen to capture a large portion of common variation within the genome, based on the International HapMap Project.[72,73] The goal is to identify alleles that, while not pathologically mutated, may confer an increase (or potential decrease) in CRC risk. Identification of yet unknown aberrant CRC alleles would permit further stratification of at-risk individuals on a genetic basis. Such risk stratification would potentially enhance CRC screening. The use of genome-wide scans has led to the discovery of multiple common low-risk CRC susceptibility alleles. (Refer to Table 3 for more information.)
A large GWAS was performed using tagSNPs in a total of 10,731 CRC cases and 10,961 controls from eight centers to identify and enrich for CRC susceptibility alleles.[74] In addition to the previously reported 8q24, 15q13, and 18q21 CRC risk loci, two previously unreported associations at 10p14 (P = 2.5 × 10-13) and 8q23.3 (P = 3.3 × 10-8) were identified. The 8q23.3 locus tags a plausible causative gene, EIF3H (OMIM). The authors of this study estimated that the loci identified account for approximately 3% to 4% of the excess familial CRC risk, but that a high proportion of the population would be carriers of at-risk genotypes. They estimated that 3% of individuals may carry seven or more deleterious alleles. The authors concluded that their data are compatible with a polygenic model in which individual alleles, each exerting a small effect, combine either additively or multiplicatively to produce much larger risks in carriers of multiple risk alleles.
A GWAS using 555,510 SNPs in 14,500 cases of CRC and 13,294 controls from seven different centers revealed a previously unreported association on 11q23 (odds ratio [OR], 1.1; P = 5.8 × 10-10) and replicated susceptibility loci at 8q24 (OR, 1.19; P = 8.6 × 10-26) and 18q21 (OR, 1.2; P = 7.8 × 10-28).[75] Furthermore, the authors were unable to identify causative coding sequence variants in any of the candidate genes at 8q24 (POU5F1P1, HsG57825, and DQ515897) or 18q21 (SMAD7). The variants identified are common in the general population, with risk-allele frequencies in populations of European ancestry of 0.29, 0.37, and 0.52, respectively. It was estimated that carrying all six possible risk alleles yielded an OR of 2.6 (95% confidence interval [CI], 1.75–3.89) for CRC.
A meta-analysis of GWAS data obtained from the two studies above (the combined dataset analyzed contained 38,710 polymorphic SNPs in 2,024 cases and 2,092 controls) revealed four additional susceptibility loci.[76] In addition to six loci identified in previous GWAS (8q23, 8q24, 10p14, 11q23, 15q13, and18q21), the following four new loci were identified:
- Two SNPs linked to a 38 kilobase (kb) region on 20p12.3 [two SNPs: (i) combined OR, 1.12; 95% CI, 1.08–1.16; P = 2.0 × 10-10 and (ii) combined OR, 1.12; 95% CI, 1.08–1.17; P = 2.1 × 10-10] lacking genes or predicted protein-encoding transcripts;
- 14q22.2 (combined OR, 1.11; 95% CI, 1.08–1.15; P = 8.1 × 10-10) in a region 9.4kb from the transcription start site of the BMP4 gene;
- 19q13.1 [two SNPs: (i) combined OR, 0.87; 95% CI, 0.83–0.91; P = 4.6 × 10-9 and (ii) combined OR, 0.89; 95% CI, 0.85–0.93; P = 2.2 , 10-7], which lies within the Rho GTPase binding protein 2 (RHPN2) gene; and
- 16q22.1 (combined OR, 0.91; 95% CI, 0.89–0.94; P = 1.2 × 10-8), which lies within intron 1 of the E-cadherin (CDH1) gene.
No interactions between the loci were associated with an increased risk of CRC and the loci identified were estimated to collectively account for approximately 6% of the excess familial risk of CRC. The data analyses led the authors to conclude the following:
- The loci readily detectable through current GWAS are associated with modest effects (genotypic risks of approximately 1.2).
- The number of common variants explaining more than 1% of inherited risk is very low.
- Only a small proportion of heritability of any cancer can be explained by the currently identified loci.
- Of the common risk loci identified thus far, no significant epistatic effects were observed.
Because few of the observed associations seem to be due to correlation with common coding variants and many of the loci map to regions lacking genes of protein-coding transcripts, it seems likely that much of the common variation in cancer risk is mediated through sequence changes influencing gene expression.
A genome-wide linkage analysis was performed in 30 Swedish non-FAP/non-LS families with a strong family history of CRC.[77] Several loci on chromosomes 2q, 3q, 6q, and 7q with suggestive linkage were detected by parametric and nonparametric analysis.
A GWAS of affected, unaffected, and discordant sibling pairs in 194 kindreds utilized clinical information (histopathology, size and number of polyps, and other primary cancers) in conjunction with age at onset and family history to define five phenotypic subgroups (severe histopathology, oligopolyposis, young, colon/breast, and multiple cancers) prior to analysis.[78] 1p31.1 strongly linked to the multiple-cancer subgroup (P < .00007). 15q14-q22 linked to the full-sample (P < .018), oligopolyposis (P < .003), and young (P < .0009) phenotypes. This region includes the HMPS/CRAC1 locus associated with hereditary mixed polyposis syndrome in families of Ashkenazi descent. BRCA2 linked with the colon/breast phenotypic subgroup. Linkage to 17p13.3 in the breast/colon subgroup identified HIC1 (hypermethylated in colon cancer 1) as a candidate gene.
Nonparametric analysis revealed three loci at 3q29 (logarithm of the odds [LOD] score = 2.61; P = .0003), 4q31.3 (LOD = 2.13; P = .0009), and 7q31.31 (LOD = 3.08; P = .00008) in a GWAS performed in 70 kindreds with at least two siblings affected with colorectal adenocarcinoma or colorectal polyps with high-grade dysplasia.[79] Linkage to 8q24, 9q22, and 11q23 was not obtained in these kindreds. Minor linkage to 3q21-q24 was present in this study population.
Table 3. Colorectal Cancer Susceptibility Loci Identified Through Genome-Wide Association StudiesChromosome | Logarithm of the Odds (LOD) Score/Odds Ratio (OR) | P Value | Single Nucleotide Polymorphism (SNP) | Marker |
3q29 | LOD = 2.61 [79] | .0003 | D3S240 | |
4q31.3 | LOD = 2.13 [79] | .0009 | D4S2999 | |
7q31.31 | LOD = 3.08 [79] | .00008 | D7S643 | |
8q23.3 | Combined OR = 1.29 [76] | 1.1 × 10-10 | rs11986063 | |
8q23.3 | ORallelic = 1.25, ORhet = 1.27, ORhom = 1.43 [74] | 3.3 × 10-18 | rs16892766 | |
Combined OR = 1.32 [76] | 1.1 × 10-10 | |||
8q24 | ORallelic = 1.24, ORhet = 1.35, ORhom = 1.57 [74] | 7.0 × 10-11 | rs6983267 | |
Combined OR = 0.83 [76] | 2.1 × 10-14 | |||
8q24 | OR = 1.19 [75] | 8.6 × 10-26 | rs7014346 | |
Combined OR = 1.21 [76] | 3.0 × 10-13 | |||
8q24 | Combined OR = 1.17 [76] | 1.2 × 10-10 | rs7837328 | |
8q24 | Combined OR = 1.14 [76] | 1.5 × 10-7 | rs10808555 | |
10p14 | ORallelic = 0.89, ORhet = 0.87, ORhom = 0.80 [74] | 2.5 × 10-13 | rs10795668 | |
Combined OR = 0.91 [76] | 3.1 × 10-4 | |||
11q23 | OR = 1.11 [75] | 5.8 × 10-10 | rs3802842 | |
Combined OR = 1.21 [76] | 5.2 × 10-13 | |||
14q22.2 | Combined OR = 1.11 [76] | 8.1 × 10-10 | rs4444235 | |
15q13 | ORallelic = 1.23, ORhet = 1.17, ORhom = 1.70 [74] | 4.7 × 10-7 | rs4779584 | |
Combined OR = 1.19 [76] | 1.7 × 10-8 | |||
16q22.1 | Combined OR = 0.91 [76] | 1.2 × 10-8 | rs9929218 | |
17p13.3a | Not available [78] | .0364 | D17S1308 | |
18q21 | ORallelic = 0.85, ORhet = 0.84, ORhom = 0.73 [74] | 1.7 × 10-6 | rs4939827 | |
Combined OR = 0.85 [76] | 2.2 × 10-11 | |||
19q13.1 | Combined OR = 0.89 [76] | 2.2 × 10-7 | rs7259371 | |
19q13.1 | Combined OR = 0.87 [76] | 4.6 × 10-9 | rs10411210 | |
20p12.3 | Combined OR = 1.12 [76] | 2.0 × 10-10 | rs355527 | |
20p12.3 | Combined OR = 1.12 [76] | 2.1 10-10 | rs961253 |
ORhet = odds ratio among heterozygotes; ORhom = odds ratio among homozygotes. | ||
aIdentified in a breast/colon cohort. |
It is important to note the limitations of the tagged SNP approach in GWAS in identifying SNPs with minor allele frequencies of 5% to 10%, low-frequency variants with potentially stronger effects, and copy number variants. It is yet unclear how the identification of these new susceptibility alleles in individuals will apply to CRC screening and how comprehensive panels of low-penetrance cancer associated alleles may be applied in the clinical setting.
Genetic Variation in 8q24 and SMAD7Three separate studies showed that genetic variation at 8q24.21 is associated with increased risk of colon cancer, with RR ranging from 1.17 to 1.27.[80-82] Although the RR is modest for the risk alleles in 8q24, the prevalence (and population-attributable fraction) of these risk alleles is high. The genes responsible for this association have not yet been identified. In addition, common alleles of SMAD7 have also been shown to be associated with an approximately 35% increase in risk of colon cancer.[83]
Other candidate alleles that have been identified on multiple (>3) genetic association studies include the GSTM1 null allele and the NAT2 G/G allele.[84] None of these alleles has been characterized enough to currently support its routine use in a clinical setting. Family history remains the most valuable tool for establishing risk of colon cancer in these families. Similar to what has been reported in prostate cancer, a combination of susceptibility loci may yet hold promise in profiling individual risk.[85,86]
Variants of Uncertain Significance in Major Cancer Susceptibility GenesAPC I1307K
Polymorphisms in APC are the most extensively studied polymorphisms with regard to cancer association. The APC I1307K polymorphism is associated with an increased risk of colon cancer but does not cause colonic polyposis. The I1307K polymorphism occurs almost exclusively in people of Ashkenazi Jewish descent and results in a twofold increased risk of colonic adenomas and adenocarcinomas compared with the general population.[69,87] The I1307K polymorphism results from a transition from T→A at nucleotide 3920 in the APC gene and appears to create a region of hypermutability.[69] Although clinical assays to assess for the APC I1307K polymorphism are currently available, the associated colon cancer risk is not high enough to support routine use. On the basis of currently available data, it is not yet known whether the I1307K carrier state should guide decisions regarding the age to initiate screening, the frequency of screening, or the choice of screening strategy.
Clinical implications of low-penetrance allelesAlthough the statistical evidence for an association between genetic variation at these loci and CRC risk is convincing, the biologically relevant variants and the mechanism by which they lead to increased risk are unknown and will require further genetic and functional characterization. Additionally, these loci are associated with very modest risk, with ORs for developing CRC in heterozygous carriers usually from 1.1 to 1.3. More risk variants will likely be identified. Risks in this range do not appear to confer enough increase in age-specific risk as to warrant modification of otherwise clinically prudent screening. Until their collective influence is prospectively evaluated, their use cannot be recommended in clinical practice.
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Members of the White Collar Crime Group have vast experience in cases prosecuted by HMRC, including Missing Trader Intra-Community fraud and carousel fraud cases, and have successfully defended in some of the largest prosecutions of these types to come to trial. Our attention to detail in cases sometimes involving many hundreds of thousands of documents, our case management skills and our cross-examination and advocacy techniques are unrivalled and have led to notable success over the years.
Our members further utilise their unrivalled experience by acting for both individual and corporate respondents in regulatory proceedings brought by HMRC. We are frequently instructed to act for appellants in proceedings in the VAT & Duties Tribunal (First-tier Tribunal (Tax)) in cases of significant value and complexity.
We are often instructed as part of multi-disciplinary teams with accountants and tax advisers and by working closely with clients, we ensure we minimise the risks and penalties to their businesses in both the short and long term.


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White dust on an intoxicated man gave police the clue that he was responsible for a burglary and theft incident at an apartment in western Garapan.
Danny T. Daniel, 25, was served with an arrest warrant last week for burglary and theft.
Detective Israel De Leon stated in his report that Police Officer Rudy Sablan suspected Daniel for committing a burglary and theft because of the white dusts around his body and scratches.
De Leon said that, on Sept. 15, 2012 at 12:21am, two police officers entertained a complainant's report at Koban Police Station that his friend's apartment was burglarized.
According to preliminary investigation, a woman came home from work at Fiesta Resort & Spa at 12am when she discovered her belongings in the bedroom were scattered.
The victim learned that her two laptops, a cell phone, a wireless router/modem, and assorted jewelry were missing.
The sliding window in the kitchen area was open. The screen for the window was damaged. The window bar was pried open on the top right corner about a foot and a half.
As Officers Sablan and Flora Aguon were heading back to the second floor on the stairway of the apartment building, Sablan spotted two males walking along Ginger Avenue.
Officer Sablan recognized one male as Daniel, a suspect from an earlier incident of disturbing the peace at a poker arcade.
When the two officers approached Daniel on the roadway, Daniel was observed to be intoxicated.
Sablan then noticed that Daniel had white dust on his arms, clothing, and leg portions and his arms and fingers had scratches.
The officers escorted Daniel to Koban Station for further investigation.
The officers escorted Daniel to the victim's apartment, but on their way, they spotted Daniel's earlier companion.
The companion told the officers that he received some items from Daniel. The companion reached inside the backpack and took a foot lotion cream, AA batteries, and perfume.
Sablan also found a knife, pair of clothes, and a toothbrush inside the backpack.
Sablan showed the items to the victim, who immediately identified the foot lotion and AA batteries as hers and that the perfume belonged to her roommates.
The victim's cellphone was also found in Daniel's bag.
De Leon said Daniel later confessed how he broke into the victim's apartment.
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I am in need of someone who knows a lot about pension credit, tax and other benefits. If anyone can help or knows of someone who could help. I am happy to make an appointment to see them and of course pay for their services.
many thanks
Hi, I am no expert but as a single parent and being self employed I have applied for a range of benefits to help me in my first year or so, though hadn't thought about pension credits (oops). Feel free to give me a call on 0161 222 8421 or 07828 788 618.
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