Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer

Matthew B. Yurgelun; Anu B. Chittenden; Vicente Morales-Oyarvide; Douglas A. Rubinson; Richard F. Dunne; Margaret M. Kozak; Zhi Rong Qian; Marisa W. Welch; Lauren K. Brais; Annacarolina Da Silva; Justin L. Bui; Chen Yuan; Tingting Li; Wanwan Li; Atsuhiro Masuda; Mancang Gu; Andrea J. Bullock; Daniel T. Chang; Thomas E. Clancy; David C. Linehan; Jennifer J. Findeis-Hosey; Leona A. Doyle; Aaron R. Thorner; Matthew D. Ducar; Bruce M. Wollison; Natalia Khalaf; Kimberly Perez; Sapna Syngal; Andrew J. Aguirre; William C. Hahn; Matthew L. Meyerson; Charles S. Fuchs; Shuji Ogino; Jason L. Hornick; Aram F. Hezel; Albert C. Koong; Jonathan A. Nowak; Brian M. Wolpin

doi:10.1038/s41436-018-0009-5

Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer

Matthew B. Yurgelun, Anu B. Chittenden, Vicente Morales-Oyarvide, Douglas A. Rubinson, Richard F. Dunne, Margaret M. Kozak, Zhi Rong Qian, Marisa W. Welch, Lauren K. Brais, Annacarolina Da Silva, Justin L. Bui, Chen Yuan, Tingting Li, Wanwan Li, Atsuhiro Masuda, Mancang Gu, Andrea J. Bullock, Daniel T. Chang, Thomas E. Clancy, David C. LinehanJennifer J. Findeis-Hosey, Leona A. Doyle, Aaron R. Thorner, Matthew D. Ducar, Bruce M. Wollison, Natalia Khalaf, Kimberly Perez, Sapna Syngal, Andrew J. Aguirre, William C. Hahn, Matthew L. Meyerson, Charles S. Fuchs, Shuji Ogino, Jason L. Hornick, Aram F. Hezel, Albert C. Koong, Jonathan A. Nowak, Brian M. Wolpin

Radiation Oncology

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

138 Scopus citations

Abstract

Purpose: Germline variants in double-strand DNA damage repair (dsDDR) genes (e.g., BRCA1/2) predispose to pancreatic adenocarcinoma (PDAC) and may predict sensitivity to platinum-based chemotherapy and poly(ADP) ribose polymerase (PARP) inhibitors. We sought to determine the prevalence and significance of germline cancer susceptibility gene variants in PDAC with paired somatic and survival analyses. Methods: Using a customized next-generation sequencing panel, germline/somatic DNA was analyzed from 289 patients with resected PDAC ascertained without preselection for high-risk features (e.g., young age, personal/family history). All identified variants were assessed for pathogenicity. Outcomes were analyzed using multivariable-adjusted Cox proportional hazards regression. Results: We found that 28/289 (9.7%; 95% confidence interval [CI] 6.5–13.7%) patients carried pathogenic/likely pathogenic germline variants, including 21 (7.3%) dsDDR gene variants (3 BRCA1, 4 BRCA2, 14 other dsDDR genes [ATM, BRIP1, CHEK2, NBN, PALB2, RAD50, RAD51C]), 3 Lynch syndrome, and 4 other genes (APC p.I1307K, CDKN2A, TP53). Somatic sequencing and immunohistochemistry identified second hits in the tumor in 12/27 (44.4%) patients with germline variants (1 failed sequencing). Compared with noncarriers, patients with germline dsDDR gene variants had superior overall survival (hazard ratio [HR] 0.54; 95% CI 0.30–0.99; P = 0.05). Conclusion: Nearly 10% of PDAC patients harbor germline variants, although the majority lack somatic second hits, the therapeutic significance of which warrants further study.

Original language	English (US)
Pages (from-to)	213-223
Number of pages	11
Journal	Genetics in Medicine
Volume	21
Issue number	1
DOIs	https://doi.org/10.1038/s41436-018-0009-5
State	Published - Jan 1 2019

Keywords

Familial pancreatic cancer
Hereditary breast and ovarian cancer
Lynch syndrome
PARP inhibitors

ASJC Scopus subject areas

Genetics(clinical)

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10.1038/s41436-018-0009-5

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Yurgelun, M. B., Chittenden, A. B., Morales-Oyarvide, V., Rubinson, D. A., Dunne, R. F., Kozak, M. M., Qian, Z. R., Welch, M. W., Brais, L. K., Da Silva, A., Bui, J. L., Yuan, C., Li, T., Li, W., Masuda, A., Gu, M., Bullock, A. J., Chang, D. T., Clancy, T. E., ... Wolpin, B. M. (2019). Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer. Genetics in Medicine, 21(1), 213-223. https://doi.org/10.1038/s41436-018-0009-5

Yurgelun, MB, Chittenden, AB, Morales-Oyarvide, V, Rubinson, DA, Dunne, RF, Kozak, MM, Qian, ZR, Welch, MW, Brais, LK, Da Silva, A, Bui, JL, Yuan, C, Li, T, Li, W, Masuda, A, Gu, M, Bullock, AJ, Chang, DT, Clancy, TE, Linehan, DC, Findeis-Hosey, JJ, Doyle, LA, Thorner, AR, Ducar, MD, Wollison, BM, Khalaf, N, Perez, K, Syngal, S, Aguirre, AJ, Hahn, WC, Meyerson, ML, Fuchs, CS, Ogino, S, Hornick, JL, Hezel, AF, Koong, AC, Nowak, JA & Wolpin, BM 2019, 'Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer', Genetics in Medicine, vol. 21, no. 1, pp. 213-223. https://doi.org/10.1038/s41436-018-0009-5

@article{cd4d94f517eb44be899368d74f25fd26,

title = "Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer",

abstract = "Purpose: Germline variants in double-strand DNA damage repair (dsDDR) genes (e.g., BRCA1/2) predispose to pancreatic adenocarcinoma (PDAC) and may predict sensitivity to platinum-based chemotherapy and poly(ADP) ribose polymerase (PARP) inhibitors. We sought to determine the prevalence and significance of germline cancer susceptibility gene variants in PDAC with paired somatic and survival analyses. Methods: Using a customized next-generation sequencing panel, germline/somatic DNA was analyzed from 289 patients with resected PDAC ascertained without preselection for high-risk features (e.g., young age, personal/family history). All identified variants were assessed for pathogenicity. Outcomes were analyzed using multivariable-adjusted Cox proportional hazards regression. Results: We found that 28/289 (9.7%; 95% confidence interval [CI] 6.5–13.7%) patients carried pathogenic/likely pathogenic germline variants, including 21 (7.3%) dsDDR gene variants (3 BRCA1, 4 BRCA2, 14 other dsDDR genes [ATM, BRIP1, CHEK2, NBN, PALB2, RAD50, RAD51C]), 3 Lynch syndrome, and 4 other genes (APC p.I1307K, CDKN2A, TP53). Somatic sequencing and immunohistochemistry identified second hits in the tumor in 12/27 (44.4%) patients with germline variants (1 failed sequencing). Compared with noncarriers, patients with germline dsDDR gene variants had superior overall survival (hazard ratio [HR] 0.54; 95% CI 0.30–0.99; P = 0.05). Conclusion: Nearly 10% of PDAC patients harbor germline variants, although the majority lack somatic second hits, the therapeutic significance of which warrants further study.",

keywords = "Familial pancreatic cancer, Hereditary breast and ovarian cancer, Lynch syndrome, PARP inhibitors",

author = "Yurgelun, {Matthew B.} and Chittenden, {Anu B.} and Vicente Morales-Oyarvide and Rubinson, {Douglas A.} and Dunne, {Richard F.} and Kozak, {Margaret M.} and Qian, {Zhi Rong} and Welch, {Marisa W.} and Brais, {Lauren K.} and {Da Silva}, Annacarolina and Bui, {Justin L.} and Chen Yuan and Tingting Li and Wanwan Li and Atsuhiro Masuda and Mancang Gu and Bullock, {Andrea J.} and Chang, {Daniel T.} and Clancy, {Thomas E.} and Linehan, {David C.} and Findeis-Hosey, {Jennifer J.} and Doyle, {Leona A.} and Thorner, {Aaron R.} and Ducar, {Matthew D.} and Wollison, {Bruce M.} and Natalia Khalaf and Kimberly Perez and Sapna Syngal and Aguirre, {Andrew J.} and Hahn, {William C.} and Meyerson, {Matthew L.} and Fuchs, {Charles S.} and Shuji Ogino and Hornick, {Jason L.} and Hezel, {Aram F.} and Koong, {Albert C.} and Nowak, {Jonathan A.} and Wolpin, {Brian M.}",

note = "Publisher Copyright: {\textcopyright} 2018, American College of Medical Genetics and Genomics.",

year = "2019",

month = jan,

day = "1",

doi = "10.1038/s41436-018-0009-5",

language = "English (US)",

volume = "21",

pages = "213--223",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Lippincott Williams and Wilkins",

number = "1",

}

TY - JOUR

T1 - Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer

AU - Yurgelun, Matthew B.

AU - Chittenden, Anu B.

AU - Morales-Oyarvide, Vicente

AU - Rubinson, Douglas A.

AU - Dunne, Richard F.

AU - Kozak, Margaret M.

AU - Qian, Zhi Rong

AU - Welch, Marisa W.

AU - Brais, Lauren K.

AU - Da Silva, Annacarolina

AU - Bui, Justin L.

AU - Yuan, Chen

AU - Li, Tingting

AU - Li, Wanwan

AU - Masuda, Atsuhiro

AU - Gu, Mancang

AU - Bullock, Andrea J.

AU - Chang, Daniel T.

AU - Clancy, Thomas E.

AU - Linehan, David C.

AU - Findeis-Hosey, Jennifer J.

AU - Doyle, Leona A.

AU - Thorner, Aaron R.

AU - Ducar, Matthew D.

AU - Wollison, Bruce M.

AU - Khalaf, Natalia

AU - Perez, Kimberly

AU - Syngal, Sapna

AU - Aguirre, Andrew J.

AU - Hahn, William C.

AU - Meyerson, Matthew L.

AU - Fuchs, Charles S.

AU - Ogino, Shuji

AU - Hornick, Jason L.

AU - Hezel, Aram F.

AU - Koong, Albert C.

AU - Nowak, Jonathan A.

AU - Wolpin, Brian M.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Purpose: Germline variants in double-strand DNA damage repair (dsDDR) genes (e.g., BRCA1/2) predispose to pancreatic adenocarcinoma (PDAC) and may predict sensitivity to platinum-based chemotherapy and poly(ADP) ribose polymerase (PARP) inhibitors. We sought to determine the prevalence and significance of germline cancer susceptibility gene variants in PDAC with paired somatic and survival analyses. Methods: Using a customized next-generation sequencing panel, germline/somatic DNA was analyzed from 289 patients with resected PDAC ascertained without preselection for high-risk features (e.g., young age, personal/family history). All identified variants were assessed for pathogenicity. Outcomes were analyzed using multivariable-adjusted Cox proportional hazards regression. Results: We found that 28/289 (9.7%; 95% confidence interval [CI] 6.5–13.7%) patients carried pathogenic/likely pathogenic germline variants, including 21 (7.3%) dsDDR gene variants (3 BRCA1, 4 BRCA2, 14 other dsDDR genes [ATM, BRIP1, CHEK2, NBN, PALB2, RAD50, RAD51C]), 3 Lynch syndrome, and 4 other genes (APC p.I1307K, CDKN2A, TP53). Somatic sequencing and immunohistochemistry identified second hits in the tumor in 12/27 (44.4%) patients with germline variants (1 failed sequencing). Compared with noncarriers, patients with germline dsDDR gene variants had superior overall survival (hazard ratio [HR] 0.54; 95% CI 0.30–0.99; P = 0.05). Conclusion: Nearly 10% of PDAC patients harbor germline variants, although the majority lack somatic second hits, the therapeutic significance of which warrants further study.

AB - Purpose: Germline variants in double-strand DNA damage repair (dsDDR) genes (e.g., BRCA1/2) predispose to pancreatic adenocarcinoma (PDAC) and may predict sensitivity to platinum-based chemotherapy and poly(ADP) ribose polymerase (PARP) inhibitors. We sought to determine the prevalence and significance of germline cancer susceptibility gene variants in PDAC with paired somatic and survival analyses. Methods: Using a customized next-generation sequencing panel, germline/somatic DNA was analyzed from 289 patients with resected PDAC ascertained without preselection for high-risk features (e.g., young age, personal/family history). All identified variants were assessed for pathogenicity. Outcomes were analyzed using multivariable-adjusted Cox proportional hazards regression. Results: We found that 28/289 (9.7%; 95% confidence interval [CI] 6.5–13.7%) patients carried pathogenic/likely pathogenic germline variants, including 21 (7.3%) dsDDR gene variants (3 BRCA1, 4 BRCA2, 14 other dsDDR genes [ATM, BRIP1, CHEK2, NBN, PALB2, RAD50, RAD51C]), 3 Lynch syndrome, and 4 other genes (APC p.I1307K, CDKN2A, TP53). Somatic sequencing and immunohistochemistry identified second hits in the tumor in 12/27 (44.4%) patients with germline variants (1 failed sequencing). Compared with noncarriers, patients with germline dsDDR gene variants had superior overall survival (hazard ratio [HR] 0.54; 95% CI 0.30–0.99; P = 0.05). Conclusion: Nearly 10% of PDAC patients harbor germline variants, although the majority lack somatic second hits, the therapeutic significance of which warrants further study.

KW - Familial pancreatic cancer

KW - Hereditary breast and ovarian cancer

KW - Lynch syndrome

KW - PARP inhibitors

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U2 - 10.1038/s41436-018-0009-5

DO - 10.1038/s41436-018-0009-5

M3 - Article

C2 - 29961768

AN - SCOPUS:85049198835

SN - 1098-3600

VL - 21

SP - 213

EP - 223

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 1

ER -

Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer

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