title: Multiple rare variants in high-risk pancreatic cancer-related genes may increase risk for pancreatic cancer in a subset of patients with and without germline CDKN2A mutations.
abstract: The risk of pancreatic cancer (PC) is increased in melanoma-prone families but the causal relationship between germline CDKN2A mutations and PC risk is uncertain, suggesting the existence of non-CDKN2A factors. One genetic possibility involves patients having mutations in multiple high-risk PC-related genes; however, no systematic examination has yet been conducted. We used next-generation sequencing data to examine 24 putative PC-related genes in 43 PC patients with and 23 PC patients without germline CDKN2A mutations and 1001 controls. For each gene and the four pathways in which they occurred, we tested whether PC patients (overall or CDKN2A+ and CDKN2A- cases separately) had an increased number of rare nonsynonymous variants. Overall, we identified 35 missense variants in PC patients, 14 in CDKN2A+ and 21 in CDKN2A- PC cases. We found nominally significant associations for mismatch repair genes (MLH1, MSH2, MSH6, PMS2) in all PC patients and for ATM, CPA1, and PMS2 in CDKN2A- PC patients. Further, nine CDKN2A+ and four CDKN2A- PC patients had rare potentially deleterious variants in multiple PC-related genes. Loss-of-function variants were only observed in CDKN2A- PC patients, with ATM having the most pathogenic variants. Also, ATM variants (n = 5) were only observed in CDKN2A- PC patients with a family history that included digestive system tumors. Our results suggest that a subset of PC patients may have increased risk because of germline mutations in multiple PC-related genes.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Xiaohong R
authors.initials: XR
authors.lastname: Yang
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.|Division of Cancer Control and Population Studies, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Rotunno
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Yanzi
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Department of Surgery, Lund University Hospital, Lund, Sweden.
authors.forename: Christian
authors.initials: C
authors.lastname: Ingvar
authors.affiliation: Department of Oncology Pathology, Karolinska Institutet and Karolinska University Hospital, Solna, Stockholm, Sweden.
authors.forename: Hildur
authors.initials: H
authors.lastname: Helgadottir
authors.affiliation: Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy.|Genetics of Rare Cancers, IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Lorenza
authors.initials: L
authors.lastname: Pastorino
authors.affiliation: Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Remco
authors.initials: R
authors.lastname: van Doorn
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Hunter
authors.initials: H
authors.lastname: Bennett
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Cole
authors.initials: C
authors.lastname: Graham
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Joshua N
authors.initials: JN
authors.lastname: Sampson
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.|Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Malasky
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.|Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD, USA.
authors.forename: Aurelie
authors.initials: A
authors.lastname: Vogt
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.|Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhu
authors.affiliation: Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy.|Genetics of Rare Cancers, IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Bianchi-Scarra
authors.affiliation: Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy.|Genetics of Rare Cancers, IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: William
authors.initials: W
authors.lastname: Bruno
authors.affiliation: Medical Oncology Unit, IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Queirolo
authors.affiliation: Medical Oncology Unit, IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Fornarini
authors.affiliation: Department of Oncology Pathology, Karolinska Institutet and Karolinska University Hospital, Solna, Stockholm, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Hansson
authors.affiliation: Department of Oncology Pathology, Karolinska Institutet and Karolinska University Hospital, Solna, Stockholm, Sweden.
authors.forename: Rainer
authors.initials: R
authors.lastname: Tuominen
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.|Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD, USA.
authors.forename: Laurie
authors.initials: L
authors.lastname: Burdett
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.|Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD, USA.
authors.forename: Belynda
authors.initials: B
authors.lastname: Hicks
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.|Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Hutchinson
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.|Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD, USA.
authors.forename: Kristine
authors.initials: K
authors.lastname: Jones
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.|Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD, USA.
authors.forename: Meredith
authors.initials: M
authors.lastname: Yeager
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Landi
authors.affiliation: Department of Oncology Pathology, Karolinska Institutet and Karolinska University Hospital, Solna, Stockholm, Sweden.
authors.forename: Veronica
authors.initials: V
authors.lastname: Höiom
authors.affiliation: Department of Oncology, Lund University Hospital, Lund, Sweden.
authors.forename: Håkan
authors.initials: H
authors.lastname: Olsson
authors.affiliation: Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Nelleke
authors.initials: N
authors.lastname: Gruis
authors.affiliation: Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy.|Genetics of Rare Cancers, IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Ghiorzo
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Tucker
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. goldstea@mail.nih.gov.|, 9609 Medical Center Dr, Bethesda, MD, 20892-9769, USA. goldstea@mail.nih.gov.
authors.forename: Alisa M
authors.initials: AM
authors.lastname: Goldstein
mesh_terms: D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics; D012878:Skin Neoplasms; D000096142:Cutaneous Malignant Melanoma
chemical_list: C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; D009363:Neoplasm Proteins