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.

Keywords: DNA repair genes; Exome sequencing; Familial pancreatic cancer; Pancreatic adenocarcinoma.

Conflict of interest statement

Conflict of Interest Disclosures: The authors declare no conflict of interest.

Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Figures

Figure 1

Schematic of the exome sequencing data analysis. Variants remaining after each filtering step are indicated. SNV, single nucleotide variant; indel, insertion/deletion; PTV, protein-truncating variant; MAF, minor allele frequency.

Figure 2

Pedigrees of the families with FAN1 variants. Carrier status is depicted for all the cases in which germline DNA was available and tested. +/- indicates heterozygous carrier status. +/+ indicates wild-type. Probands are indicated with an arrow. Individuals shaded in black are affected with PC, while individuals shaded in grey are affected with a tumor other than PC. The ages of living family members and the ages of death (d.) for deceased individuals are indicated in years. Tumor types and ages at diagnoses are indicated in years. Other illnesses with ages in years at diagnosis (if known) are shown. NHL, non-Hodgkin's lymphoma; CLL, Chronic lymphocytic leukemia. Maternal and paternal ancestries are indicated.

Figure 3

Pedigrees of the families with NEK1 variants. Carrier status is depicted for all the cases in which germline DNA was available and tested. +/- indicates heterozygous carrier status. +/+ indicates wild-type. Probands are indicated with an arrow. Individuals shaded in black are affected with PC, while individuals shaded in grey are affected with a tumor other than PC. The ages of living family members and the ages of death (d.) for deceased individuals are indicated in years. Tumor types and ages at diagnoses are indicated in years. Other illnesses with ages in years at diagnosis (if known) are shown. BCC, basal cell carcinoma. Maternal and paternal ancestries are indicated.

Figure 4

Pedigrees of the families with RHNO1 variants. Carrier status is depicted for all the cases in which germline DNA was available and tested. +/- indicates heterozygous carrier status. +/+ indicates wild-type. Probands are indicated with an arrow. Individuals shaded in black are affected with PC, while individuals shaded in grey are affected with a tumor other than PC. The ages of living family members and the ages of death (d.) for deceased individuals are indicated in years. Tumor types and ages at diagnoses are indicated in years. NM, non-melanoma. Maternal and paternal ancestries are indicated.

Figure 5

Discovery set Kaplan-Meier survival curves for carriers versus non-carriers of DNA repair gene PTVs for all stages (A), early stage (B) and advanced stage (C) cases. Log-rank p-values are indicated.

Figure 6

Validation set Kaplan-Meier survival curves for carriers versus non-carriers of PTVs in the genes identified in the discovery set (n=41) for all stages (A) and early stage (B), as well as for all 513 putative DNA repair genes (n=513) for all stages (C), early stage (D) and advanced stage (E) cases. Log-rank p-values are indicated.