Despite dramatic increases in the survival of cancer in general over the last 5 decades, the 5-year survival of pancreatic ductal adenocarcinoma (PDAC) remains relatively unchanged at 6%. Approximately 10% of PDAC cases are familial pancreatic cancer (FPC), involving two or more affected first-degree relatives. Despite large sequencing efforts over the past decade, less than 20% of FPC cases have an identified causal germline mutation, despite recent large-scale sequencing efforts by our group and others.
Unlike the majority of familial cancer syndromes, our analysis shows that FPC is not associated with an earlier age of onset compared to its sporadic counterpart. We theorized that the similar age of onset may be the result of shared between sporadic and familial PDAC driver genes, KRAS, TP53, CDKN2A/p16, and DPC4/SMAD4. Our analysis of PDAC driver genes in our cohort of FPC cancer cell lines, using high density SNP microarray, whole exome sequencing (WES), whole genome sequencing (WGS), and RNA-Seq, confirmed that FPC has alterations in the PDAC driver genes and at the same prevalence as sporadic.
Given that the genes p16 and SMAD4 are commonly inactivated by deletions, we hypothesized that the underlying structural rearrangements could provide insight into the mechanism of driver gene deletions in cancer. Our breakpoint analysis of the p16 and SMAD4 deletions using WGS data revealed a novel structural variant that we have termed “TransFlip mutations.” A TransFlip mutation is an inter-chromosomal translocation on one side and an inversion on the other side, flanking a deletion.
My thesis work highlights the similarity of FPC with sporadic PDAC, both in the driver genes and in the age of onset. Here I report the discovery of TransFlip mutations, a new structural variant in cancer, highlighting the complexity of cancer genomes and the challenges of reliably calling structural variants.
Advisor:
Dr. James R. Eshleman (Reader)
Thesis Committee:
Dr. Sarah J. Wheelan (Reader)
Dr. Kenneth Kinzler (Chair)
Dr. Ralph H. Hruban
Dr. Alison P. Klei
