Genetic epidemiological approaches to identify predisposition to human cancers, especially pancreatic cance

Background Various study designs can be applied for the detection of chronic disease genetic susceptibility loci and variants, including candidate gene/variant association studies, genome wide association studies (GWAS), familial linkage studies, etc. A large proportion of complex disease heritability has not yet been explained by family-based linkage studies that aim to identify highly penetrant genes containing very rare mutations, nor by GWAS aimed at identifying common variants conferring modest risk effects. It has been proposed that rare variants in the moderate portion of the penetrance spectrum may be able to explain the "missing heritability". Next generation sequencing, including the use of whole exome sequencing (WES) and whole genome sequencing (WGS) study designs, has been proposed to be an effective strategy to determine etiologic roles of rare, functional variants in complex diseases. Recently, with very large-scale national and international collaborations in human diseases, especially cancer, extensive datasets from germline WES/WGS have become available on affected patients. If carefully considered approaches were used, they may be valuable resources for identifying new disease susceptibility genes. Pancreatic cancer is a representative complex disease for which genetic factors are known to influence risk although the majority of genetic susceptibility remains unexplained by published linkage or GWAS studies. Several large-scale WES sets focusing on PC patients have been available from the International Cancer Genome Consortium (ICGC) and the Cancer Genome Atlas (TCGA). New approaches to analyze the WES/WGS data may help to identify novel susceptibility genes containing rare variants for pancreatic cancer. Besides the efforts for detecting genetic susceptibility loci focusing on more general disease cases, strategies based on disease specific patterns can be potentially useful in determining novel susceptibility factors as well. Research has shown that melanoma cases may exist in pancreatic cancer kindreds, also there is increased risk of pancreatic cancer in familial melanoma. Furthermore, type 2 diabetes mellitus (T2DM) is a known risk factor for pancreatic cancer, and first-degree relative history of T2DM is associated with increased risk of pancreatic cancer. Based on these evidence, we hypothesize that pancreatic cancer and melanoma, as well as pancreatic cancer and T2DM may share genetic susceptibility variants in common. (Abstract shortened by ProQuest.).