title: Candidate DNA repair susceptibility genes identified by exome sequencing in high-risk pancreatic cancer.
abstract: The genetic basis underlying the majority of hereditary pancreatic adenocarcinoma (PC) is unknown. Since DNA repair genes are widely implicated in gastrointestinal malignancies, including PC, we hypothesized that there are novel DNA repair PC susceptibility genes. As germline DNA repair gene mutations may lead to PC subtypes with selective therapeutic responses, we also hypothesized that there is an overall survival (OS) difference in mutation carriers versus non-carriers. We therefore interrogated the germline exomes of 109 high-risk PC cases for rare protein-truncating variants (PTVs) in 513 putative DNA repair genes. We identified PTVs in 41 novel genes among 36 kindred. Additional genetic evidence for causality was obtained for 17 genes, with FAN1, NEK1 and RHNO1 emerging as the strongest candidates. An OS difference was observed for carriers versus non-carriers of PTVs with early stage (≤IIB) disease. This adverse survival trend in carriers with early stage disease was also observed in an independent series of 130 PC cases. We identified candidate DNA repair PC susceptibility genes and suggest that carriers of a germline PTV in a DNA repair gene with early stage disease have worse survival.
authors.affiliation: Research Institute of the McGill University Health Centre, 1001 Décarie Boulevard, Montreal, QC, Canada H4A 3J1; Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue West, Montreal, QC, Canada H3A 1A3.
authors.forename: Alyssa L
authors.initials: AL
authors.lastname: Smith
authors.affiliation: McGill University and Genome Quebec Innovation Centre, 740 Dr. Penfield Avenue, Montreal, QC, Canada H3A 0G1.
authors.forename: Najmeh
authors.initials: N
authors.lastname: Alirezaie
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON, Canada M5G 1X5; MaRS Centre, Ontario Institute for Cancer Research, 661 University Avenue, Toronto, ON, Canada M5G 0A3.
authors.forename: Ashton
authors.initials: A
authors.lastname: Connor
authors.affiliation: MaRS Centre, Ontario Institute for Cancer Research, 661 University Avenue, Toronto, ON, Canada M5G 0A3.
authors.forename: Michelle
authors.initials: M
authors.lastname: Chan-Seng-Yue
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON, Canada M5G 1X5.
authors.forename: Robert
authors.initials: R
authors.lastname: Grant
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON, Canada M5G 1X5.
authors.forename: Iris
authors.initials: I
authors.lastname: Selander
authors.affiliation: Research Institute of the McGill University Health Centre, 1001 Décarie Boulevard, Montreal, QC, Canada H4A 3J1; Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue West, Montreal, QC, Canada H3A 1A3.
authors.forename: Claire
authors.initials: C
authors.lastname: Bascuñana
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON, Canada M5G 1X5; Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, 60 Murray Street, Toronto, ON, Canada M5T 3H7.
authors.forename: Ayelet
authors.initials: A
authors.lastname: Borgida
authors.affiliation: Research Institute of the McGill University Health Centre, 1001 Décarie Boulevard, Montreal, QC, Canada H4A 3J1; Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue West, Montreal, QC, Canada H3A 1A3.
authors.forename: Anita
authors.initials: A
authors.lastname: Hall
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON, Canada M5G 1X5.
authors.forename: Thomas
authors.initials: T
authors.lastname: Whelan
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON, Canada M5G 1X5; Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, 60 Murray Street, Toronto, ON, Canada M5T 3H7.
authors.forename: Spring
authors.initials: S
authors.lastname: Holter
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON, Canada M5G 1X5.
authors.forename: Treasa
authors.initials: T
authors.lastname: McPherson
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON, Canada M5G 1X5; Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, 60 Murray Street, Toronto, ON, Canada M5T 3H7.
authors.forename: Sean
authors.initials: S
authors.lastname: Cleary
authors.affiliation: Department of Health Sciences Research, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Gloria M
authors.initials: GM
authors.lastname: Petersen
authors.affiliation: Department of Pathology, McGill University Health Centre, 1001 Décarie Boulevard, Montreal, QC, Canada H4A 3J1.
authors.forename: Atilla
authors.initials: A
authors.lastname: Omeroglu
authors.affiliation: Department of Medical Oncology, Hereditary Cancer Clinic, University Hospital of Heraklion, Voutes, Heraklion 71110, Greece.
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Saloustros
authors.affiliation: MaRS Centre, Ontario Institute for Cancer Research, 661 University Avenue, Toronto, ON, Canada M5G 0A3.
authors.forename: John
authors.initials: J
authors.lastname: McPherson
authors.affiliation: MaRS Centre, Ontario Institute for Cancer Research, 661 University Avenue, Toronto, ON, Canada M5G 0A3.
authors.forename: Lincoln D
authors.initials: LD
authors.lastname: Stein
authors.affiliation: Program in Cancer Genetics, Departments of Oncology and Human Genetics, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, 3755 Côte-Ste-Catherine Road, Montreal, QC, Canada H3T 1E2.
authors.forename: William D
authors.initials: WD
authors.lastname: Foulkes
authors.affiliation: McGill University and Genome Quebec Innovation Centre, 740 Dr. Penfield Avenue, Montreal, QC, Canada H3A 0G1.
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON, Canada M5G 1X5; MaRS Centre, Ontario Institute for Cancer Research, 661 University Avenue, Toronto, ON, Canada M5G 0A3; Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, 60 Murray Street, Toronto, ON, Canada M5T 3H7. Electronic address: steven.gallinger@uhn.ca.
authors.forename: Steven
authors.initials: S
authors.lastname: Gallinger
authors.affiliation: Research Institute of the McGill University Health Centre, 1001 Décarie Boulevard, Montreal, QC, Canada H4A 3J1; Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue West, Montreal, QC, Canada H3A 1A3; Program in Cancer Genetics, Departments of Oncology and Human Genetics, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, 3755 Côte-Ste-Catherine Road, Montreal, QC, Canada H3T 1E2. Electronic address: george.zogopoulos@mcgill.ca.
authors.forename: George
authors.initials: G
authors.lastname: Zogopoulos
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology; D004260:DNA Repair / Q000235:genetics*; D059472:Exome; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006801:Humans; D000072380:NIMA-Related Kinase 1; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000401:mortality; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology; D012307:Risk Factors; D017422:Sequence Analysis, DNA
chemical_list: D018797:Cell Cycle Proteins; C000606914:NEK1 protein, human; D000072380:NIMA-Related Kinase 1; D017346:Protein Serine-Threonine Kinases
keywords: DNA repair genes; Exome sequencing; Familial pancreatic cancer; Pancreatic adenocarcinoma