Candidate DNA repair susceptibility genes identified by exome sequencing in high-risk pancreatic cancer

Alyssa L. Smith; Najmeh Alirezaie; Ashton Connor; Michelle Chan-Seng-Yue; Robert Grant; Iris Selander; Claire Bascuñana; Ayelet Borgida; Anita Hall; Thomas Whelan; Spring Holter; Treasa McPherson; Sean Cleary; Gloria M. Petersen; Atilla Omeroglu; Emmanouil Saloustros; John McPherson; Lincoln D. Stein; William D. Foulkes; Jacek Majewski; Steven Gallinger; George Zogopoulos

doi:10.1016/j.canlet.2015.10.030

Candidate DNA repair susceptibility genes identified by exome sequencing in high-risk pancreatic cancer

Alyssa L. Smith, Najmeh Alirezaie, Ashton Connor, Michelle Chan-Seng-Yue, Robert Grant, Iris Selander, Claire Bascuñana, Ayelet Borgida, Anita Hall, Thomas Whelan, Spring Holter, Treasa McPherson, Sean Cleary, Gloria M. Petersen, Atilla Omeroglu, Emmanouil Saloustros, John McPherson, Lincoln D. Stein, William D. Foulkes, Jacek MajewskiSteven Gallinger, George Zogopoulos

Quantitative Health Sciences

Research output: Contribution to journal › Article › peer-review

32 Scopus citations

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.

Original language	English (US)
Pages (from-to)	302-312
Number of pages	11
Journal	Cancer Letters
Volume	370
Issue number	2
DOIs	https://doi.org/10.1016/j.canlet.2015.10.030
State	Published - Jan 28 2016

Keywords

DNA repair genes
Exome sequencing
Familial pancreatic cancer
Pancreatic adenocarcinoma

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.canlet.2015.10.030

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Smith, A. L., Alirezaie, N., Connor, A., Chan-Seng-Yue, M., Grant, R., Selander, I., Bascuñana, C., Borgida, A., Hall, A., Whelan, T., Holter, S., McPherson, T., Cleary, S., Petersen, G. M., Omeroglu, A., Saloustros, E., McPherson, J., Stein, L. D., Foulkes, W. D., ... Zogopoulos, G. (2016). Candidate DNA repair susceptibility genes identified by exome sequencing in high-risk pancreatic cancer. Cancer Letters, 370(2), 302-312. https://doi.org/10.1016/j.canlet.2015.10.030

Smith, AL, Alirezaie, N, Connor, A, Chan-Seng-Yue, M, Grant, R, Selander, I, Bascuñana, C, Borgida, A, Hall, A, Whelan, T, Holter, S, McPherson, T, Cleary, S, Petersen, GM, Omeroglu, A, Saloustros, E, McPherson, J, Stein, LD, Foulkes, WD, Majewski, J, Gallinger, S & Zogopoulos, G 2016, 'Candidate DNA repair susceptibility genes identified by exome sequencing in high-risk pancreatic cancer', Cancer Letters, vol. 370, no. 2, pp. 302-312. https://doi.org/10.1016/j.canlet.2015.10.030

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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",

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T1 - Candidate DNA repair susceptibility genes identified by exome sequencing in high-risk pancreatic cancer

AU - Smith, Alyssa L.

AU - Alirezaie, Najmeh

AU - Connor, Ashton

AU - Chan-Seng-Yue, Michelle

AU - Grant, Robert

AU - Selander, Iris

AU - Bascuñana, Claire

AU - Borgida, Ayelet

AU - Hall, Anita

AU - Whelan, Thomas

AU - Holter, Spring

AU - McPherson, Treasa

AU - Cleary, Sean

AU - Petersen, Gloria M.

AU - Omeroglu, Atilla

AU - Saloustros, Emmanouil

AU - McPherson, John

AU - Stein, Lincoln D.

AU - Foulkes, William D.

AU - Majewski, Jacek

AU - Gallinger, Steven

AU - Zogopoulos, George

PY - 2016/1/28

Y1 - 2016/1/28

N2 - 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.

AB - 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.

KW - DNA repair genes

KW - Exome sequencing

KW - Familial pancreatic cancer

KW - Pancreatic adenocarcinoma

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Candidate DNA repair susceptibility genes identified by exome sequencing in high-risk pancreatic cancer

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