Deleterious germline mutations in patients with apparently sporadic pancreatic adenocarcinoma

Koji Shindo, Jun Yu, Masaya Suenaga, Shahriar Fesharakizadeh, Christy Cho, Anne Macgregor-Das, Abdulrehman Siddiqui, P. Dane Witmer, Koji Tamura, Tae Jun Song, Jose Alejandro Navarro Almario, Aaron Brant, Michael Borges, Madeline Ford, Thomas Barkley, Jin He, Matthew J Weiss, Christopher Wolfgang, Nicholas Roberts, Ralph H HrubanAlison Klein, Michael S Goggins

Research output: Contribution to journalArticle

Abstract

Purpose Deleterious germline mutations contribute to pancreatic cancer susceptibility and are well documented in families in which multiple members have had pancreatic cancer. Methods To define the prevalence of these germline mutations in patients with apparently sporadic pancreatic cancer, we sequenced 32 genes, including known pancreatic cancer susceptibility genes, in DNA prepared from normal tissue obtained from 854 patients with pancreatic ductal adenocarcinoma, 288 patients with other pancreatic and periampullary neoplasms, and 51 patients with non-neoplastic diseases who underwent pancreatic resection at Johns Hopkins Hospital between 2000 and 2015. Results Thirty-three (3.9%; 95% CI, 3.0% to 5.8%) of 854 patients with pancreatic cancer had a deleterious germline mutation, 31 (3.5%) of which affected known familial pancreatic cancer susceptibility genes: BRCA2 (12 patients), ATM (10 patients), BRCA1 (3 patients), PALB2 (2 patients), MLH1 (2 patients), CDKN2A (1 patient), and TP53 (1 patient). Patients with these germline mutations were younger than those without (mean 6 SD, 60.8 6 10.6 v 65.1 6 10.5 years; P = .03). Deleterious germline mutations were also found in BUB1B (1) and BUB3 (1). Only three of these 33 patients had reported a family history of pancreatic cancer, and most did not have a cancer family history to suggest an inherited cancer syndrome. Five (1.7%) of 288 patients with other periampullary neoplasms also had a deleterious germline mutation. Conclusion Germline mutations in pancreatic cancer susceptibility genes are commonly identified in patients with pancreatic cancer without a significant family history of cancer. These deleterious pancreatic cancer susceptibility gene mutations, some of which are therapeutically targetable, will be missed if current family history guidelines are the main criteria used to determine the appropriateness of gene testing.

Original languageEnglish (US)
Pages (from-to)3382-3390
Number of pages9
JournalJournal of Clinical Oncology
Volume35
Issue number30
DOIs
StatePublished - Oct 20 2017

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Germ-Line Mutation
Adenocarcinoma
Pancreatic Neoplasms
Neoplasm Genes
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Deleterious germline mutations in patients with apparently sporadic pancreatic adenocarcinoma. / Shindo, Koji; Yu, Jun; Suenaga, Masaya; Fesharakizadeh, Shahriar; Cho, Christy; Macgregor-Das, Anne; Siddiqui, Abdulrehman; Witmer, P. Dane; Tamura, Koji; Song, Tae Jun; Almario, Jose Alejandro Navarro; Brant, Aaron; Borges, Michael; Ford, Madeline; Barkley, Thomas; He, Jin; Weiss, Matthew J; Wolfgang, Christopher; Roberts, Nicholas; Hruban, Ralph H; Klein, Alison; Goggins, Michael S.

In: Journal of Clinical Oncology, Vol. 35, No. 30, 20.10.2017, p. 3382-3390.

Research output: Contribution to journalArticle

Shindo, K, Yu, J, Suenaga, M, Fesharakizadeh, S, Cho, C, Macgregor-Das, A, Siddiqui, A, Witmer, PD, Tamura, K, Song, TJ, Almario, JAN, Brant, A, Borges, M, Ford, M, Barkley, T, He, J, Weiss, MJ, Wolfgang, C, Roberts, N, Hruban, RH, Klein, A & Goggins, MS 2017, 'Deleterious germline mutations in patients with apparently sporadic pancreatic adenocarcinoma', Journal of Clinical Oncology, vol. 35, no. 30, pp. 3382-3390. https://doi.org/10.1200/JCO.2017.72.3502
Shindo, Koji ; Yu, Jun ; Suenaga, Masaya ; Fesharakizadeh, Shahriar ; Cho, Christy ; Macgregor-Das, Anne ; Siddiqui, Abdulrehman ; Witmer, P. Dane ; Tamura, Koji ; Song, Tae Jun ; Almario, Jose Alejandro Navarro ; Brant, Aaron ; Borges, Michael ; Ford, Madeline ; Barkley, Thomas ; He, Jin ; Weiss, Matthew J ; Wolfgang, Christopher ; Roberts, Nicholas ; Hruban, Ralph H ; Klein, Alison ; Goggins, Michael S. / Deleterious germline mutations in patients with apparently sporadic pancreatic adenocarcinoma. In: Journal of Clinical Oncology. 2017 ; Vol. 35, No. 30. pp. 3382-3390.
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abstract = "Purpose Deleterious germline mutations contribute to pancreatic cancer susceptibility and are well documented in families in which multiple members have had pancreatic cancer. Methods To define the prevalence of these germline mutations in patients with apparently sporadic pancreatic cancer, we sequenced 32 genes, including known pancreatic cancer susceptibility genes, in DNA prepared from normal tissue obtained from 854 patients with pancreatic ductal adenocarcinoma, 288 patients with other pancreatic and periampullary neoplasms, and 51 patients with non-neoplastic diseases who underwent pancreatic resection at Johns Hopkins Hospital between 2000 and 2015. Results Thirty-three (3.9{\%}; 95{\%} CI, 3.0{\%} to 5.8{\%}) of 854 patients with pancreatic cancer had a deleterious germline mutation, 31 (3.5{\%}) of which affected known familial pancreatic cancer susceptibility genes: BRCA2 (12 patients), ATM (10 patients), BRCA1 (3 patients), PALB2 (2 patients), MLH1 (2 patients), CDKN2A (1 patient), and TP53 (1 patient). Patients with these germline mutations were younger than those without (mean 6 SD, 60.8 6 10.6 v 65.1 6 10.5 years; P = .03). Deleterious germline mutations were also found in BUB1B (1) and BUB3 (1). Only three of these 33 patients had reported a family history of pancreatic cancer, and most did not have a cancer family history to suggest an inherited cancer syndrome. Five (1.7{\%}) of 288 patients with other periampullary neoplasms also had a deleterious germline mutation. Conclusion Germline mutations in pancreatic cancer susceptibility genes are commonly identified in patients with pancreatic cancer without a significant family history of cancer. These deleterious pancreatic cancer susceptibility gene mutations, some of which are therapeutically targetable, will be missed if current family history guidelines are the main criteria used to determine the appropriateness of gene testing.",
author = "Koji Shindo and Jun Yu and Masaya Suenaga and Shahriar Fesharakizadeh and Christy Cho and Anne Macgregor-Das and Abdulrehman Siddiqui and Witmer, {P. Dane} and Koji Tamura and Song, {Tae Jun} and Almario, {Jose Alejandro Navarro} and Aaron Brant and Michael Borges and Madeline Ford and Thomas Barkley and Jin He and Weiss, {Matthew J} and Christopher Wolfgang and Nicholas Roberts and Hruban, {Ralph H} and Alison Klein and Goggins, {Michael S}",
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T1 - Deleterious germline mutations in patients with apparently sporadic pancreatic adenocarcinoma

AU - Shindo, Koji

AU - Yu, Jun

AU - Suenaga, Masaya

AU - Fesharakizadeh, Shahriar

AU - Cho, Christy

AU - Macgregor-Das, Anne

AU - Siddiqui, Abdulrehman

AU - Witmer, P. Dane

AU - Tamura, Koji

AU - Song, Tae Jun

AU - Almario, Jose Alejandro Navarro

AU - Brant, Aaron

AU - Borges, Michael

AU - Ford, Madeline

AU - Barkley, Thomas

AU - He, Jin

AU - Weiss, Matthew J

AU - Wolfgang, Christopher

AU - Roberts, Nicholas

AU - Hruban, Ralph H

AU - Klein, Alison

AU - Goggins, Michael S

PY - 2017/10/20

Y1 - 2017/10/20

N2 - Purpose Deleterious germline mutations contribute to pancreatic cancer susceptibility and are well documented in families in which multiple members have had pancreatic cancer. Methods To define the prevalence of these germline mutations in patients with apparently sporadic pancreatic cancer, we sequenced 32 genes, including known pancreatic cancer susceptibility genes, in DNA prepared from normal tissue obtained from 854 patients with pancreatic ductal adenocarcinoma, 288 patients with other pancreatic and periampullary neoplasms, and 51 patients with non-neoplastic diseases who underwent pancreatic resection at Johns Hopkins Hospital between 2000 and 2015. Results Thirty-three (3.9%; 95% CI, 3.0% to 5.8%) of 854 patients with pancreatic cancer had a deleterious germline mutation, 31 (3.5%) of which affected known familial pancreatic cancer susceptibility genes: BRCA2 (12 patients), ATM (10 patients), BRCA1 (3 patients), PALB2 (2 patients), MLH1 (2 patients), CDKN2A (1 patient), and TP53 (1 patient). Patients with these germline mutations were younger than those without (mean 6 SD, 60.8 6 10.6 v 65.1 6 10.5 years; P = .03). Deleterious germline mutations were also found in BUB1B (1) and BUB3 (1). Only three of these 33 patients had reported a family history of pancreatic cancer, and most did not have a cancer family history to suggest an inherited cancer syndrome. Five (1.7%) of 288 patients with other periampullary neoplasms also had a deleterious germline mutation. Conclusion Germline mutations in pancreatic cancer susceptibility genes are commonly identified in patients with pancreatic cancer without a significant family history of cancer. These deleterious pancreatic cancer susceptibility gene mutations, some of which are therapeutically targetable, will be missed if current family history guidelines are the main criteria used to determine the appropriateness of gene testing.

AB - Purpose Deleterious germline mutations contribute to pancreatic cancer susceptibility and are well documented in families in which multiple members have had pancreatic cancer. Methods To define the prevalence of these germline mutations in patients with apparently sporadic pancreatic cancer, we sequenced 32 genes, including known pancreatic cancer susceptibility genes, in DNA prepared from normal tissue obtained from 854 patients with pancreatic ductal adenocarcinoma, 288 patients with other pancreatic and periampullary neoplasms, and 51 patients with non-neoplastic diseases who underwent pancreatic resection at Johns Hopkins Hospital between 2000 and 2015. Results Thirty-three (3.9%; 95% CI, 3.0% to 5.8%) of 854 patients with pancreatic cancer had a deleterious germline mutation, 31 (3.5%) of which affected known familial pancreatic cancer susceptibility genes: BRCA2 (12 patients), ATM (10 patients), BRCA1 (3 patients), PALB2 (2 patients), MLH1 (2 patients), CDKN2A (1 patient), and TP53 (1 patient). Patients with these germline mutations were younger than those without (mean 6 SD, 60.8 6 10.6 v 65.1 6 10.5 years; P = .03). Deleterious germline mutations were also found in BUB1B (1) and BUB3 (1). Only three of these 33 patients had reported a family history of pancreatic cancer, and most did not have a cancer family history to suggest an inherited cancer syndrome. Five (1.7%) of 288 patients with other periampullary neoplasms also had a deleterious germline mutation. Conclusion Germline mutations in pancreatic cancer susceptibility genes are commonly identified in patients with pancreatic cancer without a significant family history of cancer. These deleterious pancreatic cancer susceptibility gene mutations, some of which are therapeutically targetable, will be missed if current family history guidelines are the main criteria used to determine the appropriateness of gene testing.

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