Familial and sporadic pancreatic cancer share the same molecular pathogenesis

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is nearly uniformly lethal, with a median overall survival in 2014 of only 6 months. The genetic progression of sporadic PDAC (SPC) is well established, with common somatic alterations in KRAS, p16/CDKN2A, TP53, and SMAD4/DPC4. Up to 10 % of all PDAC cases occur in families with two or more affected first-degree relatives (familial pancreatic cancer, FPC), but these cases do not appear to present at an obviously earlier age of onset. This is unusual because most familial cancer syndrome patients present at a substantially younger age than that of corresponding sporadic cases. Here we collated the reported age of onset for FPC and SPC from the literature. We then used an integrated approach including whole exomic sequencing, whole genome sequencing, RNA sequencing, and high density SNP microarrays to study a cohort of FPC cell lines and corresponding germline samples. We show that the four major SPC driver genes are also consistently altered in FPC and that each of the four detection strategies was able to detect the mutations in these genes, with one exception. We conclude that FPC undergoes a similar somatic molecular pathogenesis as SPC, and that the same gene targets can be used for early detection and minimal residual disease testing in FPC patients.

Fig. 1

Reported age of onset for SPC and FPC, collated from the literature. Literature was separated based on a population-based or b referral cohorts, reported as means (filled symbols) or medians (empty symbols). Symbol sizes are adjusted according to the number of individuals in the study [2*log(n)]. There are no obvious differences in the age of onset for FPC (triangles) compared to SPC (squares)

Fig. 2

Summarized alterations in PDAC molecular progression genes, for SPC and FPC. a PDAC molecular progression model with reported percent alterations of the four driver genes in PanIN lesions, figure modified from Iacobuzio-Donahue, et al. Clin Cancer Res 2012 [56]. b Percent alterations of molecular progression genes in PDAC cancers from SPC and FPC cohorts. As expected, the mutation prevalence in PDACs in panel b are higher than the early PanIN lesions in panel a. *CDKN2A, p = 0.04

Fig. 3

CDKN2A/p16 homozygous deletion initially missed by WGS in one case (PA222C). Visualization of WGS reads for p16 gene region (hg19, chr9:21,951,176–22,102,475) in PA222C sample using IGV (Broad Institute, version 2.3.31) and Karyostudio (Illumina, version 1.4). The 2 protein isoforms of p16 (p14(ARF) and p16(INK4), blue) are shown as well as the adjacent genes, C9orf53 and CDKN2B-AS1 (a). There is clear agreement across the methods for the consensus 97 kb homozygous deletion boundaries (b). The homozygous deletion of p16 was not called by the standard Illumina pipeline for WGS data, despite a clear confirmation of the 5′ deletion by visual inspection, due to reference transcript choice (c). The homozygous deletion was detected by WES, as evidenced by the lack of reads (d). RNA-Seq produced no high quality reads that mapped to this deleted region, but there were reads upstream (MTAP) and downstream (DMRTA1) of the homozygous deletion (e line break indicates upstream or downstream reads shows). High density SNP microarray detected the homozygous deletion (red LogR line drops to −2.00 and scattered B allele frequencies) and the flanking LOH regions (red LogR line at −1.00 and B allele frequencies at 0 or 1) (f). MLPA probes were used to confirm the upstream LOH (black) and homozygous deletion (red) regions (g)