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TEAD2, a Hippo pathway gene, is somatically mutated in gastric and colorectal cancers with high microsatellite instability

To the Editor Hippo signaling pathway (also known as the Salvador/Warts pathway) controls organ size in animals through the regulation of cell proliferation and apoptosis that are central to tumorigenesis as well (1). Perturbation of the Hippo pathway can trigger tumorigenesis in mice and flies, and altered Hippo pathway activity has been observed in human cancers (2). However, most Hippo pathway genes are not commonly mutated in human cancers except for neurofibromin 2 (NF2) that is mutationally inactivated in cancer and is considered a tumor suppressor gene (TSG) (3). In Hippo pathway, TEA domain family member 2 (TEAD-2) is a major transcription factor that interacts with YAP to form heterodimeric transcription factors that activate proliferative and anti-apoptotic gene expressions (1). In a public genome database (http://genome.cse. ucsc.edu/), we found that human TEAD2 gene had a mononucleotide repeat in its coding sequences that could be targets for frameshift mutation in cancers with microsatellite instability (MSI). Frameshift mutation of genes containing mononucleotide repeats is a feature of gastric (GC) and colorectal cancers (CRC) with MSI (4). To date, however, it is not known whether TEAD2 gene is mutationally altered in GC and CRC with MSI. To see whether the mononucleotide repeat in TEAD2 gene is mutated in GC and CRC, we analyzed a C8 repeat in the exon 9 by polymerase chain reaction (PCR)-based single strand conformation polymorphism (SSCP) assay. For this, we used methacarn-fixed tissues of 34 GC with high MSI (MSI-H), 45 GC with stable MSI (MSS), 99 CRC with MSI-H and 45 CRC with MSS. In cancer tissues, malignant cells and normal cells were selectively procured from hematoxylin and eosin-stained slides by microdissection (5). Radioisotope [(P) dCTP] was incorporated into the PCR products for detection by autoradiogram. The PCR products were subsequently displayed in SSCP gels. After SSCP, direct DNA sequencing reactions were performed in the cancer cells with mobility shifts in the SSCP as described previously (5, 6). On the SSCP, we observed aberrant bands of the TEAD2 gene in nine cancers. DNA from normal tissue showed no shifts in SSCP, indicating the aberrant bands had risen somatically (Fig. 1). DNA sequencing analysis confirmed that aberrant bands represented TEAD2 somatic mutations. All of the mutations were a type of heterozygous frameshift mutation (deletion of one base) in the C8 repeat (c.883delC) that would result in a frame shifting change with histidine 295 as the first affected amino acid, changing to a methionine and cresting a new reading frame ending in a stop at