Researchers from Johns Hopkins School of Medicine in Baltimore have recently published a study in Nature Communications that reports the discovery of an increased risk of pancreatic cancer associated with modifications made to five new human genome regions (2018;9(1):556). This study represents possibly the largest pancreatic cancer genome-wide association study to date.
“This study identifies several new common genetic variants that are important in pancreatic cancer risk and also highlights the important genetic factors that are involved in the development of pancreatic cancer,” study leader Alison Klein, PhD, MHS, Professor of Oncology at the Johns Hopkins School of Medicine, told Oncology Times.
For their study, the investigators performed a meta-analysis on data from the Pancreatic Cancer Cohort Consortium (PanScan) I/PanScan II, PanScan III, Pancreatic Cancer Case-Control Consortium (PanC4), and PANcreatic Disease ReseArch (PANDoRA) studies. The PanScan I/II, PanScan III, and PanC4 studies identified a total of 13 genomic loci with 17 independent pancreatic cancer risk signals on various chromosomes. A candidate gene analysis in the PANDoRA study also found an additional independent risk locus. In the PanScan and PanC4 cohorts, a total of 9,040 pancreatic cancer patients and 12,496 controls were included. Overall, more than 11.3 million variants in 21,536 people were analyzed.
In the meta-analysis performed by Klein, et al, on the PanScan I/II, PanScanIII, and PanC4 data, the researchers identified a locus associated with pancreatic cancer at rs78417682 (7p12/TNS3, P=4.35 × 10-8). In PANDoRA, which included pancreatic cancer cases (n=11,537) and controls (n=17,107), researchers identified additional loci that were of genome-wide significance (rs13303010 at 1p36.33 [NOC2L, odds ratio (OR)=1.26; 95% CI 1.19-1.35, P=8.36 × 10-14: Wald test]; rs2941471 at 8q21.11 [HNF4G, OR=0.89, 95% CI 0.85-0.93, P=6.60 × 10-10: Wald test]; rs4795218 at 17q12 [HNF1B, OR=0.88, 95% CI 0.84-0.92, P=1.32 × 10-8: Wald test]; and rs1517037 at 18q21.32 [GRP, P=3.28 × 10-8]).
The new variant in NOC2L is particularly interesting, considering NOC2L is a protein that binds to the p53 tumor protein, which is a pancreatic cancer driver gene. Additionally, the discovery of variants in the HNF4G and HNF1B genes (i.e., hepatocyte growth factors) coincides with published research suggesting variants within these genes may be associated with prostate and ovarian cancer (Oncotarget 2016;7(46):74734-74746, PLoS One 2010;5(5):e10858). Variants in the HNF1B gene, GRP gene, and on TNS3 have been associated with maturity onset diabetes in individuals aged ≤25 years, release of gastrointestinal hormones, and the regulation of cell adhesion and migration as well as metastasis, respectively.
Adding to Genetics Research
Findings from this study come at the heels of genome-wide association studies focused on a variety of malignancies, with currently available research having identified >450 genetic variants that are associated with increased cancer risk (Nat Rev Cancer 2017;17(11):692-704). Studies like these have become even more relevant in an age where greater focus has been placed on personalized, precision medicine.
Despite this surge of recent research, studies have yet to elucidate conclusivity for managing any specific carcinoma. “Metastasis is a key feature of many aggressive cancers, including pancreatic cancer, and is caused by a variety of factors such as changes in gene expression of the tumor cell, the microenvironment, and angiogenesis,” according to Alvin Makohon-Moore of the Memorial Sloan Kettering Cancer Center. “However, although the genetic events associated with carcinogenesis are well-delineated, the relevance of genetic events to these steps of tumor progression is unknown.” In his paper published in Genome Medicine, Makohon-Moore and colleagues suggest more work is needed at the population level for using genomic information in guiding the diagnosis and treatment of pancreatic cancer (2013;5(3):26).
Future Directions in Research
As for Klein and her investigative team at Johns Hopkins, the work in genomics pancreatic research has just begun. “We are continuing collaborative work with ongoing large-scale studies and researchers at leading pancreatic cancer clinical centers to conduct even larger studies,” noted Klein. “In addition, we hope to conduct studies in other racial and ethnic groups. We have recently developed a collaboration to study the genetics of pancreatic cancer in African-Americans.”
The future research in African-Americans is certainly welcomed, since pancreatic cancer incidence is approximately 50-90 percent higher in this demographic compared with other racial groups, and African-Americans also suffer from worse overall prognosis (Pancreas 2015;44(4):522-527). Compared with Caucasians, African-Americans also have higher rates of KRAS mutations, which have been associated with pancreatic cancer in previous research (J Clin Oncol 2017; doi: 10.1200/jco.2013.31.15_suppl.e15018). Likewise, the KRAS gene has shown promise for targeted therapy in this patient population (Eur J Cancer 2016;54:75-83, Front Physiol 2014;4:407).
Researchers at Johns Hopkins are also exploring other research avenues in a quest to understand pancreatic cancer. “We are about to open a clinical study funded by Stand Up to Cancer which will examine germline genetic testing for all newly diagnosed pancreatic cancer patients, as well as cascade testing in the relatives of mutation carriers,” explained Klein. “Relatives with high-risk mutations would be eligible to enroll in early-detection screening trials, with these trials including novel imaging, preventative vaccines, and biomarkers.”
In addition, Klein and her colleagues are continually working “to study blood-based early-detection screening tests for pancreatic cancer, as included in the CancerSEEK Panel,” which tests for eight common cancers (i.e., breast, colorectal, esophagus, liver, lung, ovary, pancreas, and stomach).
“Understanding rare, high-risk variants that are important in pancreatic cancer risk has enabled better targeted treatment,” noted Klein. “For example, pancreatic cancer patients with germline BRCA2 and PALB2 mutations have been shown to respond better to platinum-based therapy.”
This comment by Klein mirrors that of previous research, which has revealed that, due to advancements in genomics research, pancreatic cancer patients with genetic germline mutations in BRCA2 now have better targeted chemotherapy options (e.g., mitomycin C or poly(ADP ribose)polymerase inhibitors) that utilize cancer defects in DNA damage repair (Mol Cancer Ther 2011;10(1):3-8, Lancet 2010;376(9737):235-244).
“For common variants,” Klein concluded, “we think the impact our research has on clinical care may be in better risk stratification, thereby enabling targeted prevention and early-detection screening for these high-risk individuals.”
Brandon May is a contributing writer.
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