Whole genomes redefine the mutational landscape of pancreatic cancer

Abstract

Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.

Construction of thousands of single cell genome sequencing libraries using combinatorial indexing

“…The cluster 2 population further split into two additional populations that were clearly identified in the HMM calls; however, the distinction was less clear in the intersection calls. Taken together, we were able to estimate an epithelial tumor cell purity of 53.2%, which is in line with the expected range for PDAC 28 , with the predominantly euploid population most likely comprised of a mix normal epithelial cells as well as infiltrating immune cells and vessels. Interestingly, the two subpopulations have significantly different CNV profiles, with the majority cells in cluster 2 having a deletion of chromosomes 9 and 14, and amplifications of chromosomes 15, 19q, and 22, all of which are not observed in cells assigned to cluster 3.…”

Long Noncoding RNAs CUPID1 and CUPID2 Mediate Breast Cancer Risk at 11q13 by Modulating the Response to DNA Damage

“…The same signature has previously been shown to be associated with mutations in two other HRR genes, BRCA1 (MIM: 113705) and BRCA2 (MIM: 600185). 29 Consistent with impaired HRR, low CUPID1, CUPID2, or CCND1 expression was associated with a large number of structural variants distributed through the genome 19 ( Figures 3B, S13B, S14, and S15).…”

“…Somatic structural variants (SVs) were identified with the qsv tool, and for genomes with >200 SV events, distinct patterns or clusters of breakpoint distributions were determined as described previously. [19][20][21] For the characterization of genomic breakpoint distributions, chromosomes bearing a significantly clustered distribution of breakpoints (as described in Korbel and Campbell 22 ; goodness-of-fit threshold p < 0.00001) and those containing outlying high numbers of rearrangement events were identified (outliers had a breakpoint-per-megabase rate exceeding 5 times the length of the inter-quartile range from the 75 th percentile for each sample with a minimum threshold of 30 breakpoints per chromosome). Genomes with fewer than 8 chromosomes with significantly clustered breakpoints and at least 1 containing an extreme outlying density of breakpoints were classified as containing focal rearrangement events.…”

Truncating PREX2 mutations activate its GEF activity and alter gene expression regulation in NRAS-mutant melanoma

“…PREX2 has recently been shown to regulate insulin signaling and glucose homeostasis through modulation of the PI3K (phosphatidyl inositol 3 kinase) pathway, and also to regulate Rac1 mediated cellular invasion in a manner that cross-talks with PTEN signaling (8). Further expanding the significance of genetic perturbations of PREX2 in cancer, a recent report by the International Cancer Genome Consortium (ICGC) described the identification PREX2 as a significantly mutated gene in pancreatic ductal adenocarcinoma (PDAC) (9). Interestingly, PREX2 harbors a wide spectrum of mutations including missense and truncating mutations in PDAC, similar to observations in melanoma (3,9).…”