Germline coding variants have not been systematically investigated for pancreatic ductal adenocarcinoma (PDAC). Here we report an exome-wide investigation using the Illumina Human Exome Beadchip with 943 PDAC cases and 3908 controls in the Chinese population, followed by two independent replicate samples including 2142 cases and 4697 controls. We identify three low-frequency missense variants associated with the PDAC risk: rs34309238 in PKN1 (OR = 1.77, 95% CI: 1.48-2.12, P = 5.35 × 10-10), rs2242241 in DOK2 (OR = 1.85, 95% CI: 1.50-2.27, P = 4.34 × 10-9), and rs183117027 in APOB (OR = 2.34, 95% CI: 1.72-3.16, P = 4.21 × 10-8). Functional analyses show that the PKN1 rs34309238 variant significantly increases the level of phosphorylated PKN1 and thus enhances PDAC cells' proliferation by phosphorylating and activating the FAK/PI3K/AKT pathway. These findings highlight the significance of coding variants in the development of PDAC and provide more insights into the prevention of this disease.

OBJECTIVES: One of the standard of care regimens for advanced pancreatic cancer is gemcitabine-based chemotherapy. The efficacy of gemcitabine is limited by dose-limiting hematologic toxicities especially neutropenia. Uncovering the variability of these toxicities attributed to germline DNA variation is of great importance. PATIENTS AND METHODS: CALGB 80303 was a randomized study in advanced pancreatic cancer patients treated with gemcitabine with or without bevacizumab. The study protocol included genotyping of genes of gemcitabine disposition (CDA, DCTD, SLC29A1, SLC28A1, and SLC29A2), as well as a genome-wide analysis. The clinical phenotype was time to early high-grade neutropenia event accounting for progression or death or other treatment-terminating adverse events as competing for informative events. The inference was carried out on the basis of the association between genotype and cause-specific hazard of a neutropenic event. RESULTS: The primary analyses were carried out on the basis of 294 genetically estimated European pancreatic cancer patients. For CDA rs2072671 (A>C), AC and CC patients had a lower risk of neutropenia than AA patients (P=0.01, hazard ratio: 0.61, 95% confidence interval: 0.41-0.89). For SLC28A1 rs3825876 (G>A), AA patients have a higher risk of neutropenia than GA and GG patients (P=0.02, hazard ratio: 1.51, 95% confidence interval: 1.06-2.16). CDA rs2072671 was associated with increased mRNA expression in whole blood in three studies (P=2.7e-14, 6.61e-62, and 9.70e-65). In the genome-wide analysis, variants in TGFB2 were among the top hits (lowest P=1.62e-06) but had no effect in luciferase assays. CONCLUSION: This is the first genetic analysis of gemcitabine-induced neutropenia using a competing risk model in a prospective randomized clinical study has proposed a potentially novel mechanism of the protective effect of the CDA rs2072671 variant. Further confirmation is needed.

Previous findings on the association of genetic factors and pancreatic cancer survival are limited and inconsistent. In a two-stage study, we analyzed the existing genome-wide association study dataset of 868 pancreatic cancer patients from MD Anderson Cancer Center in relation to overall survival using Cox regression. Top hits were selected for replication in another 820 patients from the same institution using the Taqman genotyping method. Functional annotation, pathway analysis and gene expression analysis were conducted using existing software and databases. We discovered genome-wide significant associations of patient survival with three imputed SNPs which, in complete LD (r2  = 1), were intronic SNPs of the PAIP2B (rs113988120) and DYSF genes (rs112493246 and rs138529893) located on Chromosome 2. The variant alleles were associated with a 3.06-fold higher risk of death [95% confidence interval (CI) = 2.10-4.47, p=6.4 × 10-9] after adjusting for clinical factors. Eleven SNPs were tested in the replication study and the association of rs113988120 with survival was confirmed (hazard ratio: 1.57, 95% CI: 1.13-2.20,  p=0.008). In silico analysis found rs1139988120 might lead to altered motif. This locus is in LD (D' = 0.77) with three eQTL SNPs near or belong to the NAGK and MCEE genes. According to The Cancer Genome Atlas data and our previous RNA-sequencing data, the mRNA expression level of PAIP2B but not NAGK, MCEE or DYSF was significantly lower in pancreatic tumors than in normal adjacent tissues. Additional validation efforts and functional studies are warranted to demonstrate whether PAIP2B is a novel tumor suppressor gene and a potential therapeutic target for pancreatic cancer.

In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 × 10-8). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium yields new genome-wide significant loci: rs13303010 at 1p36.33 (NOC2L, P = 8.36 × 10-14), rs2941471 at 8q21.11 (HNF4G, P = 6.60 × 10-10), rs4795218 at 17q12 (HNF1B, P = 1.32 × 10-8), and rs1517037 at 18q21.32 (GRP, P = 3.28 × 10-8). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene.

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.

Epidemiological studies have linked body mass index (BMI) with risk of gastrointestinal cancers. However, for gastric cancer, the relationship is more controversial. In particular, it is unclear whether the observed association is due to confounding or bias inherent in conventional observational studies. To investigate whether BMI is causally associated with gastric cancer risk, we applied Mendelian randomization using individual-level data from 2631 gastric cancer cases and 4373 cancer-free controls. We derived a weighted genetic risk score (wGRS) using 37 BMI-associated genetic variants as an instrumental variable. We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations between genetically predicted BMI and gastric cancer risk. We observed that higher genetically determined BMI was associated with increased gastric cancer risk (per standard deviation (SD) increase in the wGRS: OR=1.07, 95% CI: 1.02-1.13, P=4.94 × 10-3). Compared with individuals in the bottom tertile of the BMI wGRS, those in the top tertile had 1.14-fold (95% CI: 1.01-1.29) increased risk of developing gastric cancer. Sensitivity analyses using alternative causal inference measures demonstrated consistent association. Our study indicated that genetically high BMI was associated with increased gastric cancer risk, suggesting that high BMI may have a causal role in the etiology of gastric cancer.

BACKGROUND AND OBJECTIVE: Survival of patients with pancreatic adenocarcinoma is limited and few prognostic factors are known. We conducted a two-stage genome-wide association study (GWAS) to identify germline variants associated with survival in patients with pancreatic adenocarcinoma. METHODS: We analysed overall survival in relation to single nucleotide polymorphisms (SNPs) among 1005 patients from two large GWAS datasets, PanScan I and ChinaPC. Cox proportional hazards regression was used in an additive genetic model with adjustment for age, sex, clinical stage and the top four principal components of population stratification. The first stage included 642 cases of European ancestry (PanScan), from which the top SNPs (p≤10(-5)) were advanced to a joint analysis with 363 additional patients from China (ChinaPC). RESULTS: In the first stage of cases of European descent, the top-ranked loci were at chromosomes 11p15.4, 18p11.21 and 1p36.13, tagged by rs12362504 (p=1.63×10(-7)), rs981621 (p=1.65×10(-7)) and rs16861827 (p=3.75×10(-7)), respectively. 131 SNPs with p≤10(-5) were advanced to a joint analysis with cases from the ChinaPC study. In the joint analysis, the top-ranked SNP was rs10500715 (minor allele frequency, 0.37; p=1.72×10(-7)) on chromosome 11p15.4, which is intronic to the SET binding factor 2 (SBF2) gene. The HR (95% CI) for death was 0.74 (0.66 to 0.84) in PanScan I, 0.79 (0.65 to 0.97) in ChinaPC and 0.76 (0.68 to 0.84) in the joint analysis. CONCLUSIONS: Germline genetic variation in the SBF2 locus was associated with overall survival in patients with pancreatic adenocarcinoma of European and Asian ancestry. This association should be investigated in additional large patient cohorts.

OBJECTIVE: Genetic factors are thought to be one of the causes of individual variability in the adverse reactions observed in cancer patients who received gemcitabine therapy. However, genetic factors determining the risk of adverse reactions of gemcitabine are not fully understood. PATIENTS AND METHODS: To identify a genetic factor(s) determining the risk of gemcitabine-induced leukopenia/neutropenia, we conducted a genome-wide association study, by genotyping over 610 000 single nucleotide polymorphisms (SNPs), and a replication study in a total of 174 patients, including 54 patients with at least grade 3 leukopenia/neutropenia and 120 patients without any toxicities. RESULTS: We identified four loci possibly associated with gemcitabine-induced leukopenia/neutropenia [rs11141915 in DAPK1 on chromosome 9q21, combined P=1.27×10, odds ratio (OR)=4.10; rs1901440 on chromosome 2q12, combined P=3.11×10, OR=34.00; rs12046844 in PDE4B on chromosome 1p31, combined P=4.56×10, OR=4.13; rs11719165 on chromosome 3q29, combined P=5.98×10, OR=2.60]. When we examined the combined effects of these four SNPs, by classifying patients into four groups on the basis of the total number of risk genotypes of these four SNPs, significantly higher risks of gemcitabine-induced leukopenia/neutropenia were observed in the patients having two and three risk genotypes (P=6.25×10, OR=11.97 and P=4.13×10, OR=50.00, respectively) relative to patients with zero or one risk genotype. CONCLUSION: We identified four novel SNPs associated with gemcitabine-induced severe leukopenia/neutropenia. These SNPs might be applicable in predicting the risk of hematological toxicity in patients receiving gemcitabine therapy.

BACKGROUND AND AIMS: Cancer and Leukemia Group B 80303 was a randomized, phase III study in patients with advanced pancreatic cancer treated with gemcitabine plus either bevacizumab or placebo. We prospectively collected germline DNA and conducted a genome-wide association study (GWAS) using overall survival (OS) as the endpoint. EXPERIMENTAL DESIGN: DNA from 351 patients was genotyped for more than 550,000 single-nucleotide polymorphisms (SNP). Associations between OS and SNPs were investigated using the log-linear 2-way multiplicative Cox proportional hazards model. The subset of 294 genetically European patients was used for the primary analysis. RESULTS: A nonsynonymous SNP in interleukin (IL)17F (rs763780, H161R) and an intronic SNP in strong linkage disequilibrium (rs7771466) were associated with OS using genome-wide criteria (P ≤ 10(-7)). Median OS was significantly shorter (P = 2.61 × 10(-8)) for the rs763780 heterozygotes [3.1 months; 95% confidence interval (CI), 2.3-4.3] than for the patients without this variant (6.8 months; 95% CI, 5.8-7.3). After adjustment by stratification factors, the P value for the association was 9.51 × 10(-7). CONCLUSIONS: The variant 161R form of IL-17F is a natural antagonist of the antiangiogenic effects of wild-type 161H IL-17F, and angiogenesis may play an important role in the metastatic spread of pancreatic cancer. In this preliminary study, we hypothesize that the angiogenetic potential of pancreatic cancers in patients with variant IL-17F is higher than that of tumors in patients with wild-type IL-17F, conferring worse prognosis. This exploratory GWAS may provide the foundation for testing the biology and clinical effects of novel genes and their heritable variants through mechanistic and confirmatory studies in pancreatic cancer.

We conducted a genome-wide association study of pancreatic cancer in 3,851 affected individuals (cases) and 3,934 unaffected controls drawn from 12 prospective cohort studies and 8 case-control studies. Based on a logistic regression model for genotype trend effect that was adjusted for study, age, sex, self-described ancestry and five principal components, we identified eight SNPs that map to three loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Two correlated SNPs, rs9543325 (P = 3.27 x 10(-11), per-allele odds ratio (OR) 1.26, 95% CI 1.18-1.35) and rs9564966 (P = 5.86 x 10(-8), per-allele OR 1.21, 95% CI 1.13-1.30), map to a nongenic region on chromosome 13q22.1. Five SNPs on 1q32.1 map to NR5A2, and the strongest signal was at rs3790844 (P = 2.45 x 10(-10), per-allele OR 0.77, 95% CI 0.71-0.84). A single SNP, rs401681 (P = 3.66 x 10(-7), per-allele OR 1.19, 95% CI 1.11-1.27), maps to the CLPTM1L-TERT locus on 5p15.33, which is associated with multiple cancers. Our study has identified common susceptibility loci for pancreatic cancer that warrant follow-up studies.