Kristen Piteck

Genome-wide association study of survival in patients with pancreatic adenocarcinoma The pancreas is an organ hidden behind other organs such as the stomach, small intestine, liver, gallbladder, spleen, and bile ducts. The pancreas is the main source of enzymes for digesting lipids and proteins. It also produces several important hormones, including insulin, glucagon, and pancreatic polypeptide which circulate in the blood. Pancreatic adenocarcinoma is a major cause of cancer-related deaths worldwide. Pancreatic cancer is difficult to detect and diagnose. There arent any noticeable signs or symptoms in the early stages of pancreatic cancer and the symptoms, when present, are similar to the symptoms of many other illnesses. The five- year overall survival rate is approximately 5%. Patient survival times vary and have not been fully explained by traditional clinical and pathological features. Evidence indicates that germline genetic variability may impact patient survival rates. A defining feature of pancreatic adenocarcinoma is the recruitment of host cells which surround the tumor. This layer of tissue, stroma, plays a critical role in promoting the tumor development and progression. Laboratory studies suggest that treatments that modify the interaction of pancreatic cancer cells with their surrounding stroma can impact survival in genetically engineered mouse models. Prior studies of germline variants have relied on an incomplete understanding of tumor and host biology. Recent genome-wide association studies (GWAS) have identified several genetic variants associated with the development of pancreatic adenocarcinoma in European and Chinese populations. In this study, the data from the GWAS studies was used to evaluate the

association of germline variants with overall survival in more than 1000 cases of pancreatic adenocarcinoma. Two studies were used. PanScan included cases and controls from 11 prospective cohort studies from European populations in the USA and Europe. ChinaPC included cases and controls from Cancer Hospital, Chinese Academy of Medical Sciences and Fudan University in China. Survival time was measured as the time from diagnosis to death or date of last known contact. Staging data were organized into three categories. (1) local disease amenable to resection (surgery) (2) local disease with extra-pancreatic extersion rendering it unresectable but without distant metastases (3) distant metastatic disease. An evaluation of the top two SNPs (singlenucleotide polymorphism) already associated with survival time with specific chromosomes and genes was done. Two SNPs , rs100500715 and rs7106914, were identified on chromosome 11p15.4 located on SBF2 gene. The median overall survival rate was 4.1 months for cases with the TT genotype and 7.0 months for those with TG or GG genotype. A two stage analytical approach was used that took advantage of two large GWAS of pancreatic cancer in two different populations. In both studies, PanScan and ChinaPC, two SNPs were highly associated with pancreatic survival rates. The gene code (SBF2) the SNPS were located intronic (share common regulatory mechanisms and expression patterns with their host gene) to have encodes for a protein in the myotubularin family of lipid phosphatases and is also known as myotybularin-related protein-13 (MYMR13) which is similar to the known tumor

suppressor gene (PTEN)29. Germline genetic variations in the SBF2 locus were associated with an average increase in pancreatic survival rate of three months. This study has some limitations. Treatment programs varied and could not be used in a control for this study. However chemotherapy and radiation have only a moderate effect on patient survival. Treatment in both studies was unlikely to be different for germline genotypes. Additional studies with large databases are needed to further evaluate germline genetic variants and survival in patients with pancreas adenocarcinoma.

Wu C, Kraft P, Stolzenberg-Solomon R, et al. Gut 2014:63:152-160