SUMMARY We performed integrated genomic, transcriptomic and proteomic profiling of 150 pancreatic ductal adenocarcinoma (PDAC) specimens, including samples with characteristic low neoplastic cellularity. Deep whole-exome sequencing revealed recurrent somatic mutations in KRAS, TP53, CDKN2A, SMAD4, RNF43, ARID1A, TGFβR2, GNAS, RREB1 and PBRM1. KRAS wild-type tumors harbored alterations in other oncogenic drivers, including GNAS, BRAF, CTNNB1 and additional RAS pathway genes. A subset of tumors harbored multiple KRAS mutations, with some showing evidence of biallelic mutations. Protein profiling identified a favorable prognosis subset with low epithelial-mesenchymal transition and high MTOR pathway scores. Associations of non-coding RNAs with tumor-specific mRNA subtypes were also identified. Our integrated multi-platform analysis reveals a complex molecular landscape of PDAC and provides a roadmap for precision medicine.
IMPORTANCE Individuals genetically predisposed to pancreatic cancer may benefit from early detection. Genes that predispose to pancreatic cancer and the risks of pancreatic cancer associated with mutations in these genes are not well defined. OBJECTIVE To determine whether inherited germline mutations in cancer predisposition genes are associated with increased risks of pancreatic cancer. DESIGN, SETTING, AND PARTICIPANTS Case-control analysis to identify pancreatic cancer predisposition genes; longitudinal analysis of patients with pancreatic cancer for prognosis. The study included 3030 adults diagnosed as having pancreatic cancer and enrolled in a Mayo Clinic registry between October 12, 2000, and March 31, 2016, with last follow-up on June 22, 2017. Reference controls were 123 136 individuals with exome sequence data in the public Genome Aggregation Database and 53 105 in the Exome Aggregation Consortium database. EXPOSURES Individuals were classified based on carrying a deleterious mutation in cancer predisposition genes and having a personal or family history of cancer. MAIN OUTCOMES AND MEASURES Germline mutations in coding regions of 21 cancer predisposition genes were identified by sequencing of products from a custom multiplex polymerase chain reaction–based panel; associations of genes with pancreatic cancer were assessed by comparing frequency of mutations in genes of pancreatic cancer patients with those of reference controls. RESULTS Comparing 3030 case patients with pancreatic cancer (43.2% female; 95.6% non-Hispanic white; mean age at diagnosis, 65.3 [SD, 10.7] years) with reference controls, significant associations were observed between pancreatic cancer and mutations in CDKN2A (0.3% of cases and 0.02% of controls; odds ratio [OR], 12.33; 95% CI, 5.43–25.61); TP53 (0.2% of cases and 0.02% of controls; OR, 6.70; 95% CI, 2.52–14.95); MLH1 (0.13% of cases and 0.02% of controls; OR, 6.66; 95% CI, 1.94–17.53); BRCA2 (1.9% of cases and 0.3% of controls; OR, 6.20; 95% CI, 4.62–8.17); ATM (2.3% of cases and 0.37% of controls; OR, 5.71; 95% CI, 4.38–7.33); and BRCA1 (0.6% of cases and 0.2% of controls; OR, 2.58; 95% CI, 1.54–4.05). CONCLUSIONS AND RELEVANCE In this case-control study, mutations in 6 genes associated with pancreatic cancer were found in 5.5% of all0 pancreatic cancer patients, including 7.9% of patients with a family history of pancreatic cancer and 5.2% of patients without a family history of pancreatic cancer. Further research is needed for replication in other populations.
Pancreatic cancer is projected to become the second leading cause of cancer-related death in the United States by 2020. A familial aggregation of pancreatic cancer has been established, but the cause of this aggregation in most families is unknown. To determine the genetic basis of susceptibility in these families, we sequenced the germline genome of 638 familial pancreatic cancer patients. We also sequenced the exomes of 39 familial pancreatic adenocarcinomas. Our analyses support the role of previously identified familial pancreatic cancer susceptibility genes such as BRCA2, CDKN2A and ATM, and identify novel candidate genes harboring rare, deleterious germline variants for further characterization. We also show how somatic point mutations that occur during hematopoiesis can affect the interpretation of genome-wide studies of hereditary traits. Our observations have important implications for the etiology of pancreatic cancer and for the identification of susceptibility genes in other common cancer types.
Pancreatic cancer is the fourth leading cause of cancer death in the developed world. Both inherited high-penetrance mutations in BRCA2 (ref. 2), ATM, PALB2 (ref. 4), BRCA1 (ref. 5), STK11 (ref. 6), CDKN2A and mismatch-repair genes and low-penetrance loci are associated with increased risk. To identify new risk loci, we performed a genome-wide association study on 9,925 pancreatic cancer cases and 11,569 controls, including 4,164 newly genotyped cases and 3,792 controls in 9 studies from North America, Central Europe and Australia. We identified three newly associated regions: 17q25.1 (LINC00673, rs11655237, odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.19-1.34, P = 1.42 × 10(-14)), 7p13 (SUGCT, rs17688601, OR = 0.88, 95% CI = 0.84-0.92, P = 1.41 × 10(-8)) and 3q29 (TP63, rs9854771, OR = 0.89, 95% CI = 0.85-0.93, P = 2.35 × 10(-8)). We detected significant association at 2p13.3 (ETAA1, rs1486134, OR = 1.14, 95% CI = 1.09-1.19, P = 3.36 × 10(-9)), a region with previous suggestive evidence in Han Chinese. We replicated previously reported associations at 9q34.2 (ABO), 13q22.1 (KLF5), 5p15.33 (TERT and CLPTM1), 13q12.2 (PDX1), 1q32.1 (NR5A2), 7q32.3 (LINC-PINT), 16q23.1 (BCAR1) and 22q12.1 (ZNRF3). Our study identifies new loci associated with pancreatic cancer risk
Markers are needed to facilitate early detection of pancreatic ductal adenocarcinoma (PDAC), which is often diagnosed too late for effective therapy. Starting with a PDAC cell reprogramming model that recapitulated the progression of human PDAC, we identified secreted proteins and tested and validated a subset of them as potential markers of PDAC. We optimized an ELISA assay using plasma samples from patients with various stages of PDAC, from individuals with benign pancreatic disease, and from healthy controls. Clinical studies including a phase 1 discovery study (N=20 patients), a phase 2a validation study (N=189), and a second phase 2b validation study (N=537) revealed that concentrations of plasma thrombospondin-2 (THBS2) discriminated among all stages of PDAC consistently over the three studies with a Receiver Operating Characteristic (ROC) c-statistic of 0.76 in Phase 1, 0.842 in Phase 2a, and 0.875 in Phase 2b. The concentration of THBS2 in plasma performed as well at discriminating resectable stage I cancer as stage III/IV PDAC. THBS2 concentrations combined with those for CA19-9, a previously identified PDAC marker, yielded a c-statistic of 0.956 in the Phase 2a study and 0.970 in the Phase 2b study. THBS2 data improved the ability of CA19-9 to distinguish PDAC from pancreatitis. With a specificity of 98%, the combination of THBS2 and CA19-9 yielded a sensitivity of 87% for PDAC in the Phase 2b study. Given this, a THBS2 and CA19-9 panel assessed in human blood using a conventional ELISA assay may improve the detection of patients at high risk for PDAC.
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