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Abstract 1223: Somatic mutations in collagens impact patient outcomes in cancer

Stomach cancer remains among the most lethal diseases around the world demanding improved treatments. The tumor microenvironment (TME) is a critical driver of tumor progression and response to therapy and mediates many of the cancer hallmarks. Collagens are major components of the TME that controls disease progression and mediate therapeutic response. Collagens have been associated with stiffening of the tumor stroma, malignancy and therapeutic resistance. Collagenopathies are caused by loss of function collagen mutations that disrupt tissue formation and are dominant negative variants. We have found somatic tumor variants in collagens that are similar loss-of-function mutations as the germline variants observed in collagenopathies, providing guidance to interpret these cancer mutations. Indeed, the role of somatic mutations in collagens has not been addressed. Remarkably, we found multiple independent lines of evidence that collagen variants impact stomach adenocarcinoma tumors, consistent with a model that collagen variants disrupt the extracellular matrix (ECM) leading to improved therapeutic responses. 1) We find that loss-of-function collagen missense and nonsense mutations are associated with improved survival and disease-free progression times in gastric tumors in the TCGA dataset. 2) The same type of mutations observed in cancer are known to cause rare human diseases and therefore have the potential to impact cell function. 3) Independent of the patient outcome data, collagen variants were associated with significant changes in expression of tumor environment factors including ECM glycoproteins and EMT expression signatures. 4) Remapping RNA-seq reads reveals that single nucleotide variants of the collagens, matching the exome sequencing data are expressed. We will present computational and functional data supporting the hypothesis that somatic variants impact gastric tumors as well as analysis of the impact of collagens somatic mutations PanCancer. Somatic mutations in collagens represent a new paradigm for how cancer cells mediate the TME providing new biomarker and therapeutic opportunities to disrupt the ECM and improve outcomes for cancer patients. Citation Format: Alexander S. Brodsky, Jay Khurana, Dongfang Yang, Ece Gamsiz, Ian Wong, Murray Resnick. Somatic mutations in collagens impact patient outcomes in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1223.