| Primary gastrointestinal malignancies have among the highest incidence, morbidity and mortality rates. We hypothesized that improved understanding of predisposing germline variation and acquired somatic variation would inform novel prevention and treatment strategies. We generated germline and somatic DNA and RNA sequence data from colorectal and pancreatic cancer patients.;For the germline, we identified non-silent variation occurring at allele frequencies of less than 1% in the general population in a gene, FAT1, which co-segregates with colorectal adenocarcinoma by exome sequencing of affecteds in pedigrees that meet Familial Colorectal Cancer Type X criteria obtained from Canadian and Australian databases. This observation was not validated by targeted sequencing of affected probands or by a genetically modified mouse model.;For the somatic, we identified genomic signatures that describe mutational processes acting on pancreatic ductal adenocarcinomas and transcriptomic signatures that describe the immune component of the tumour-associated stroma by whole genome and transcriptome sequencing of a retrospective cohort of surgically resected specimens. We integrated the two signature types, demonstrating that pancreatic cancers with deficiencies in DNA repair, namely mismatch repair and homologous recombination, were associated with high expression of transcripts representative of active adaptive immunity and co-regulatory pathways.;We also studied three separate pancreatic ductal adenocarcinomas that presented in one patient, two of which arose following resection of the primary cancer. By whole genome sequencing, we demonstrated that these secondary lesions were in fact intra-parenchymal metastases sharing a common ancestor with the primary, rather than distinct metachronous lesions arising from separate tumour lineages. The degrees of genomic concordance between the primary and two secondary samples were characterised to determine the molecular phylogeny of the three lesions. Clinically, this informs patient management, as resection of metastatic pancreas cancer is unlikely to result in meaningful disease control. Scientifically, this allows the study of primaries and metastases in a system independent of external selective pressures.;Overall, we have identified novel somatic findings in pancreas cancer that will hopefully inform patient management, and we have created germline and somatic repositories of sequencing data from which future investigations of genetic variation can be performed. |
