Deleterious Germline Mutations Are a Risk Factor for Neoplastic Progression Among High-Risk Individuals Undergoing Pancreatic Surveillance

Toshiya Abe, Amanda L. Blackford, Koji Tamura, Madeline Ford, Patrick McCormick, Miguel Chuidian, Jose Alejandro Almario, Michael Borges, Anne Marie O'Broin-Lennon, Eun Shin, Alison Klein, Ralph H Hruban, Marcia Canto, Michael S Goggins

Research output: Contribution to journalArticle

Abstract

PURPOSE: To compare the risk of neoplastic progression by germline mutation status versus family history without a known germline mutation (familial risk) among individuals with an increased risk for pancreatic cancer who are undergoing surveillance. METHODS: Of 464 high-risk individuals in the Cancer of the Pancreas Screening program at Johns Hopkins Hospital who were undergoing pancreatic surveillance, 119 had a known deleterious germline mutation in a pancreatic cancer susceptibility gene; 345 met family history criteria for pancreatic surveillance but were not known to harbor a germline mutation. We used next-generation sequencing to identify previously unrecognized germline mutations among these 345 individuals. We compared the development of pancreatic cancer, high-grade dysplasia, or clinically worrisome features, adjusting for competing mortality, among all germline mutation carriers with the risk of progression in a cohort without a known germline mutation. RESULTS: Fifteen (4.3%) of 345 individuals classified as having familial risk had a previously unrecognized pancreatic cancer susceptibility gene mutation (nine that involved ATM, two BRCA2, one BRCA1, one PALB2, one TP53, and one CPA1). The cumulative incidence of pancreatic cancer, high-grade dysplasia, or worrisome features on pancreatic imaging was significantly higher in the germline mutation risk group (n = 134) than in the familial risk group (n = 330 [for pancreatic cancer, hazard ratio, 2.85; 95% CI, 1.0 to 8.18; P = .05]). CONCLUSION: The cumulative incidence of pancreatic cancer is significantly higher among individuals with an identifiable deleterious germline mutation in a pancreatic cancer susceptibility gene than it is among individuals with a strong family history but no identified mutation. Gene testing of individuals who meet criteria for pancreatic surveillance on the basis of their family history may better define those most at risk for neoplastic progression.

Original languageEnglish (US)
Pages (from-to)1070-1080
Number of pages11
JournalJournal of clinical oncology : official journal of the American Society of Clinical Oncology
Volume37
Issue number13
DOIs
StatePublished - May 1 2019

Fingerprint

Germ-Line Mutation
Pancreatic Neoplasms
Neoplasm Genes
Mutation
Incidence
Early Detection of Cancer
Mortality

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Deleterious Germline Mutations Are a Risk Factor for Neoplastic Progression Among High-Risk Individuals Undergoing Pancreatic Surveillance. / Abe, Toshiya; Blackford, Amanda L.; Tamura, Koji; Ford, Madeline; McCormick, Patrick; Chuidian, Miguel; Almario, Jose Alejandro; Borges, Michael; O'Broin-Lennon, Anne Marie; Shin, Eun; Klein, Alison; Hruban, Ralph H; Canto, Marcia; Goggins, Michael S.

In: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Vol. 37, No. 13, 01.05.2019, p. 1070-1080.

Research output: Contribution to journalArticle

@article{ce93744a8ba5472a9bd73b40aa2cdcc4,
title = "Deleterious Germline Mutations Are a Risk Factor for Neoplastic Progression Among High-Risk Individuals Undergoing Pancreatic Surveillance",
abstract = "PURPOSE: To compare the risk of neoplastic progression by germline mutation status versus family history without a known germline mutation (familial risk) among individuals with an increased risk for pancreatic cancer who are undergoing surveillance. METHODS: Of 464 high-risk individuals in the Cancer of the Pancreas Screening program at Johns Hopkins Hospital who were undergoing pancreatic surveillance, 119 had a known deleterious germline mutation in a pancreatic cancer susceptibility gene; 345 met family history criteria for pancreatic surveillance but were not known to harbor a germline mutation. We used next-generation sequencing to identify previously unrecognized germline mutations among these 345 individuals. We compared the development of pancreatic cancer, high-grade dysplasia, or clinically worrisome features, adjusting for competing mortality, among all germline mutation carriers with the risk of progression in a cohort without a known germline mutation. RESULTS: Fifteen (4.3{\%}) of 345 individuals classified as having familial risk had a previously unrecognized pancreatic cancer susceptibility gene mutation (nine that involved ATM, two BRCA2, one BRCA1, one PALB2, one TP53, and one CPA1). The cumulative incidence of pancreatic cancer, high-grade dysplasia, or worrisome features on pancreatic imaging was significantly higher in the germline mutation risk group (n = 134) than in the familial risk group (n = 330 [for pancreatic cancer, hazard ratio, 2.85; 95{\%} CI, 1.0 to 8.18; P = .05]). CONCLUSION: The cumulative incidence of pancreatic cancer is significantly higher among individuals with an identifiable deleterious germline mutation in a pancreatic cancer susceptibility gene than it is among individuals with a strong family history but no identified mutation. Gene testing of individuals who meet criteria for pancreatic surveillance on the basis of their family history may better define those most at risk for neoplastic progression.",
author = "Toshiya Abe and Blackford, {Amanda L.} and Koji Tamura and Madeline Ford and Patrick McCormick and Miguel Chuidian and Almario, {Jose Alejandro} and Michael Borges and O'Broin-Lennon, {Anne Marie} and Eun Shin and Alison Klein and Hruban, {Ralph H} and Marcia Canto and Goggins, {Michael S}",
year = "2019",
month = "5",
day = "1",
doi = "10.1200/JCO.18.01512",
language = "English (US)",
volume = "37",
pages = "1070--1080",
journal = "Journal of Clinical Oncology",
issn = "0732-183X",
publisher = "American Society of Clinical Oncology",
number = "13",

}

TY - JOUR

T1 - Deleterious Germline Mutations Are a Risk Factor for Neoplastic Progression Among High-Risk Individuals Undergoing Pancreatic Surveillance

AU - Abe, Toshiya

AU - Blackford, Amanda L.

AU - Tamura, Koji

AU - Ford, Madeline

AU - McCormick, Patrick

AU - Chuidian, Miguel

AU - Almario, Jose Alejandro

AU - Borges, Michael

AU - O'Broin-Lennon, Anne Marie

AU - Shin, Eun

AU - Klein, Alison

AU - Hruban, Ralph H

AU - Canto, Marcia

AU - Goggins, Michael S

PY - 2019/5/1

Y1 - 2019/5/1

N2 - PURPOSE: To compare the risk of neoplastic progression by germline mutation status versus family history without a known germline mutation (familial risk) among individuals with an increased risk for pancreatic cancer who are undergoing surveillance. METHODS: Of 464 high-risk individuals in the Cancer of the Pancreas Screening program at Johns Hopkins Hospital who were undergoing pancreatic surveillance, 119 had a known deleterious germline mutation in a pancreatic cancer susceptibility gene; 345 met family history criteria for pancreatic surveillance but were not known to harbor a germline mutation. We used next-generation sequencing to identify previously unrecognized germline mutations among these 345 individuals. We compared the development of pancreatic cancer, high-grade dysplasia, or clinically worrisome features, adjusting for competing mortality, among all germline mutation carriers with the risk of progression in a cohort without a known germline mutation. RESULTS: Fifteen (4.3%) of 345 individuals classified as having familial risk had a previously unrecognized pancreatic cancer susceptibility gene mutation (nine that involved ATM, two BRCA2, one BRCA1, one PALB2, one TP53, and one CPA1). The cumulative incidence of pancreatic cancer, high-grade dysplasia, or worrisome features on pancreatic imaging was significantly higher in the germline mutation risk group (n = 134) than in the familial risk group (n = 330 [for pancreatic cancer, hazard ratio, 2.85; 95% CI, 1.0 to 8.18; P = .05]). CONCLUSION: The cumulative incidence of pancreatic cancer is significantly higher among individuals with an identifiable deleterious germline mutation in a pancreatic cancer susceptibility gene than it is among individuals with a strong family history but no identified mutation. Gene testing of individuals who meet criteria for pancreatic surveillance on the basis of their family history may better define those most at risk for neoplastic progression.

AB - PURPOSE: To compare the risk of neoplastic progression by germline mutation status versus family history without a known germline mutation (familial risk) among individuals with an increased risk for pancreatic cancer who are undergoing surveillance. METHODS: Of 464 high-risk individuals in the Cancer of the Pancreas Screening program at Johns Hopkins Hospital who were undergoing pancreatic surveillance, 119 had a known deleterious germline mutation in a pancreatic cancer susceptibility gene; 345 met family history criteria for pancreatic surveillance but were not known to harbor a germline mutation. We used next-generation sequencing to identify previously unrecognized germline mutations among these 345 individuals. We compared the development of pancreatic cancer, high-grade dysplasia, or clinically worrisome features, adjusting for competing mortality, among all germline mutation carriers with the risk of progression in a cohort without a known germline mutation. RESULTS: Fifteen (4.3%) of 345 individuals classified as having familial risk had a previously unrecognized pancreatic cancer susceptibility gene mutation (nine that involved ATM, two BRCA2, one BRCA1, one PALB2, one TP53, and one CPA1). The cumulative incidence of pancreatic cancer, high-grade dysplasia, or worrisome features on pancreatic imaging was significantly higher in the germline mutation risk group (n = 134) than in the familial risk group (n = 330 [for pancreatic cancer, hazard ratio, 2.85; 95% CI, 1.0 to 8.18; P = .05]). CONCLUSION: The cumulative incidence of pancreatic cancer is significantly higher among individuals with an identifiable deleterious germline mutation in a pancreatic cancer susceptibility gene than it is among individuals with a strong family history but no identified mutation. Gene testing of individuals who meet criteria for pancreatic surveillance on the basis of their family history may better define those most at risk for neoplastic progression.

UR - http://www.scopus.com/inward/record.url?scp=85065348016&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85065348016&partnerID=8YFLogxK

U2 - 10.1200/JCO.18.01512

DO - 10.1200/JCO.18.01512

M3 - Article

C2 - 30883245

AN - SCOPUS:85065348016

VL - 37

SP - 1070

EP - 1080

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 13

ER -