Whole genomes redefine the mutational landscape of pancreatic cancer

By N. Waddell, M. Pajic, A. Patch, D. Chang, K. Kassahn, Peter Bailey, A. Johns, David K. Miller, K. Nones, Kelly Quek and 79 more. Nature, 2015

2,461 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/e31a7963487277de0301ff28f619880b38d7dc4c

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Citations in the corpus

Organoid profiling identifies common responders to chemotherapy in pancreatic cancer (2018, background): “To date, PDAC driver mutations have been hard to target in the clinical 109 setting, with the exception of microsatellite instability (8), BRCA2 mutations (9) and potentially targetable, 110 uncommon KRAS mutations (10).”
PARP Inhibitors: The First Synthetic Lethal Targeted Therapy (2017, background): “Large-scale cancer genome sequencing projects also revealed that somatic mutations in genes involved in HRR occur in a wide spectrum of tumors (34), in particular in significant fractions of high-grade serous ovarian cancer (HGS-OVCa) (38), advanced prostate cancer (39) and pancreatic cancer (40, 41”
Inflammatory responses and inflammation-associated diseases in organs (2015, background): “Pancreatic cancer (PC) remains one of the most lethal of malignancies and a major health burden [121], and is the fourth most common cause of death from cancer in the US [118].”
Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer. (2018, positive): “Our data emphasize that structural variations may inactivate tumor suppressors by disrupting the coding region of these genes (Patch et al., 2015; Waddell et al., 2015), whereas both fusions and alterations affecting intergenic regulatory elements appear to activate driver genes.”
Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma (2017, neutral): “These mutation counts are comparable to those previously observed in genomes from pancreatic cancer (9) (74 sSNVs and 5 indels per tumor), liver cancer with biliary phenotype (10) (79 sSNVs and 24 indels per tumor) and hepatocellular carcinoma (11) (70 sSNVs and 6 indels per tumor).”
Genomic analyses identify molecular subtypes of pancreatic cancer (2016, background): “0011 Fisher’s exact test); (2) pancreatic progenitor and (3) immunogenic with mucinous non-cystic (colloid) adenocarcinomas and carcinomas arising from IPMN, which are mucinous (P = 0.”
GRIDSS: sensitive and specific genomic rearrangement detection using positional de Bruijn graph assembly (2017, background): “It was only with the advent of high-throughput sequencing that the extent of genomic rearrangement in cancer, the role of catastrophic chromosome-scale events such as chromothripsis [5], the broader clinical relevance of SVs [6] and their predictive value [7] were identified.”