Association between inherited germline mutations in cancer predisposition genes and risk of pancreatic cancer

Chunling Hu, Steven Hart, Eric Polley, Rohan Gnanaolivu, Hermela Shimelis, Kun Y. Lee, Jenna Lilyquist, Jie Na, Raymond Moore, Samuel Antwi, William R. Bamlet, Kari G. Chaffee, John DiCarlo, Zhong Wu, Raed Samara, Pashtoon M. Kasi, Robert R Mc Williams, Gloria M Petersen, Fergus J Couch

Research output: Contribution to journalArticle

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Abstract

IMPORTANCE Individuals genetically predisposed to pancreatic cancer may benefit from early detection. Genes that predispose to pancreatic cancer and the risks of pancreatic cancer associated with mutations in these genes are not well defined. OBJECTIVE To determine whether inherited germline mutations in cancer predisposition genes are associated with increased risks of pancreatic cancer. DESIGN, SETTING, AND PARTICIPANTS Case-control analysis to identify pancreatic cancer predisposition genes; longitudinal analysis of patients with pancreatic cancer for prognosis. The study included 3030 adults diagnosed as having pancreatic cancer and enrolled in aMayo Clinic registry between October 12, 2000, and March 31, 2016, with last follow-up on June 22, 2017. Reference controls were 123 136 individuals with exome sequence data in the public Genome Aggregation Database and 53 105 in the Exome Aggregation Consortium database. EXPOSURES Individuals were classified based on carrying a deleterious mutation in cancer predisposition genes and having a personal or family history of cancer. MAIN OUTCOMES AND MEASURES Germline mutations in coding regions of 21 cancer predisposition genes were identified by sequencing of products from a custom multiplex polymerase chain reaction-based panel; associations of genes with pancreatic cancer were assessed by comparing frequency of mutations in genes of pancreatic cancer patients with those of reference controls. RESULTS Comparing 3030 case patients with pancreatic cancer (43.2%female; 95.6% non-Hispanic white; mean age at diagnosis, 65.3 [SD, 10.7] years) with reference controls, significant associations were observed between pancreatic cancer and mutations in CDKN2A (0.3%of cases and 0.02%of controls; odds ratio [OR], 12.33; 95%CI, 5.43-25.61); TP53 (0.2%of cases and 0.02%of controls; OR, 6.70; 95%CI, 2.52-14.95); MLH1 (0.13%of cases and 0.02%of controls; OR, 6.66; 95%CI, 1.94-17.53); BRCA2 (1.9%of cases and 0.3%of controls; OR, 6.20; 95%CI, 4.62-8.17); ATM (2.3%of cases and 0.37%of controls; OR, 5.71; 95%CI, 4.38-7.33); and BRCA1 (0.6%of cases and 0.2%of controls; OR, 2.58; 95%CI, 1.54-4.05). CONCLUSIONS AND RELEVANCE In this case-control study, mutations in 6 genes associated with pancreatic cancer were found in 5.5%of all pancreatic cancer patients, including 7.9%of patients with a family history of pancreatic cancer and 5.2%of patients without a family history of pancreatic cancer. Further research is needed for replication in other populations.

Original languageEnglish (US)
Pages (from-to)2401-2409
Number of pages9
JournalJAMA - Journal of the American Medical Association
Volume319
Issue number23
DOIs
StatePublished - Jun 19 2018

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Germ-Line Mutation
Neoplasm Genes
Pancreatic Neoplasms
Odds Ratio
Exome
Mutation
Genes
Databases
Multiplex Polymerase Chain Reaction
Mutation Rate
Registries

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Association between inherited germline mutations in cancer predisposition genes and risk of pancreatic cancer. / Hu, Chunling; Hart, Steven; Polley, Eric; Gnanaolivu, Rohan; Shimelis, Hermela; Lee, Kun Y.; Lilyquist, Jenna; Na, Jie; Moore, Raymond; Antwi, Samuel; Bamlet, William R.; Chaffee, Kari G.; DiCarlo, John; Wu, Zhong; Samara, Raed; Kasi, Pashtoon M.; Mc Williams, Robert R; Petersen, Gloria M; Couch, Fergus J.

In: JAMA - Journal of the American Medical Association, Vol. 319, No. 23, 19.06.2018, p. 2401-2409.

Research output: Contribution to journalArticle

Hu, C, Hart, S, Polley, E, Gnanaolivu, R, Shimelis, H, Lee, KY, Lilyquist, J, Na, J, Moore, R, Antwi, S, Bamlet, WR, Chaffee, KG, DiCarlo, J, Wu, Z, Samara, R, Kasi, PM, Mc Williams, RR, Petersen, GM & Couch, FJ 2018, 'Association between inherited germline mutations in cancer predisposition genes and risk of pancreatic cancer', JAMA - Journal of the American Medical Association, vol. 319, no. 23, pp. 2401-2409. https://doi.org/10.1001/jama.2018.6228
Hu, Chunling ; Hart, Steven ; Polley, Eric ; Gnanaolivu, Rohan ; Shimelis, Hermela ; Lee, Kun Y. ; Lilyquist, Jenna ; Na, Jie ; Moore, Raymond ; Antwi, Samuel ; Bamlet, William R. ; Chaffee, Kari G. ; DiCarlo, John ; Wu, Zhong ; Samara, Raed ; Kasi, Pashtoon M. ; Mc Williams, Robert R ; Petersen, Gloria M ; Couch, Fergus J. / Association between inherited germline mutations in cancer predisposition genes and risk of pancreatic cancer. In: JAMA - Journal of the American Medical Association. 2018 ; Vol. 319, No. 23. pp. 2401-2409.
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abstract = "IMPORTANCE Individuals genetically predisposed to pancreatic cancer may benefit from early detection. Genes that predispose to pancreatic cancer and the risks of pancreatic cancer associated with mutations in these genes are not well defined. OBJECTIVE To determine whether inherited germline mutations in cancer predisposition genes are associated with increased risks of pancreatic cancer. DESIGN, SETTING, AND PARTICIPANTS Case-control analysis to identify pancreatic cancer predisposition genes; longitudinal analysis of patients with pancreatic cancer for prognosis. The study included 3030 adults diagnosed as having pancreatic cancer and enrolled in aMayo Clinic registry between October 12, 2000, and March 31, 2016, with last follow-up on June 22, 2017. Reference controls were 123 136 individuals with exome sequence data in the public Genome Aggregation Database and 53 105 in the Exome Aggregation Consortium database. EXPOSURES Individuals were classified based on carrying a deleterious mutation in cancer predisposition genes and having a personal or family history of cancer. MAIN OUTCOMES AND MEASURES Germline mutations in coding regions of 21 cancer predisposition genes were identified by sequencing of products from a custom multiplex polymerase chain reaction-based panel; associations of genes with pancreatic cancer were assessed by comparing frequency of mutations in genes of pancreatic cancer patients with those of reference controls. RESULTS Comparing 3030 case patients with pancreatic cancer (43.2{\%}female; 95.6{\%} non-Hispanic white; mean age at diagnosis, 65.3 [SD, 10.7] years) with reference controls, significant associations were observed between pancreatic cancer and mutations in CDKN2A (0.3{\%}of cases and 0.02{\%}of controls; odds ratio [OR], 12.33; 95{\%}CI, 5.43-25.61); TP53 (0.2{\%}of cases and 0.02{\%}of controls; OR, 6.70; 95{\%}CI, 2.52-14.95); MLH1 (0.13{\%}of cases and 0.02{\%}of controls; OR, 6.66; 95{\%}CI, 1.94-17.53); BRCA2 (1.9{\%}of cases and 0.3{\%}of controls; OR, 6.20; 95{\%}CI, 4.62-8.17); ATM (2.3{\%}of cases and 0.37{\%}of controls; OR, 5.71; 95{\%}CI, 4.38-7.33); and BRCA1 (0.6{\%}of cases and 0.2{\%}of controls; OR, 2.58; 95{\%}CI, 1.54-4.05). CONCLUSIONS AND RELEVANCE In this case-control study, mutations in 6 genes associated with pancreatic cancer were found in 5.5{\%}of all pancreatic cancer patients, including 7.9{\%}of patients with a family history of pancreatic cancer and 5.2{\%}of patients without a family history of pancreatic cancer. Further research is needed for replication in other populations.",
author = "Chunling Hu and Steven Hart and Eric Polley and Rohan Gnanaolivu and Hermela Shimelis and Lee, {Kun Y.} and Jenna Lilyquist and Jie Na and Raymond Moore and Samuel Antwi and Bamlet, {William R.} and Chaffee, {Kari G.} and John DiCarlo and Zhong Wu and Raed Samara and Kasi, {Pashtoon M.} and {Mc Williams}, {Robert R} and Petersen, {Gloria M} and Couch, {Fergus J}",
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TY - JOUR

T1 - Association between inherited germline mutations in cancer predisposition genes and risk of pancreatic cancer

AU - Hu, Chunling

AU - Hart, Steven

AU - Polley, Eric

AU - Gnanaolivu, Rohan

AU - Shimelis, Hermela

AU - Lee, Kun Y.

AU - Lilyquist, Jenna

AU - Na, Jie

AU - Moore, Raymond

AU - Antwi, Samuel

AU - Bamlet, William R.

AU - Chaffee, Kari G.

AU - DiCarlo, John

AU - Wu, Zhong

AU - Samara, Raed

AU - Kasi, Pashtoon M.

AU - Mc Williams, Robert R

AU - Petersen, Gloria M

AU - Couch, Fergus J

PY - 2018/6/19

Y1 - 2018/6/19

N2 - IMPORTANCE Individuals genetically predisposed to pancreatic cancer may benefit from early detection. Genes that predispose to pancreatic cancer and the risks of pancreatic cancer associated with mutations in these genes are not well defined. OBJECTIVE To determine whether inherited germline mutations in cancer predisposition genes are associated with increased risks of pancreatic cancer. DESIGN, SETTING, AND PARTICIPANTS Case-control analysis to identify pancreatic cancer predisposition genes; longitudinal analysis of patients with pancreatic cancer for prognosis. The study included 3030 adults diagnosed as having pancreatic cancer and enrolled in aMayo Clinic registry between October 12, 2000, and March 31, 2016, with last follow-up on June 22, 2017. Reference controls were 123 136 individuals with exome sequence data in the public Genome Aggregation Database and 53 105 in the Exome Aggregation Consortium database. EXPOSURES Individuals were classified based on carrying a deleterious mutation in cancer predisposition genes and having a personal or family history of cancer. MAIN OUTCOMES AND MEASURES Germline mutations in coding regions of 21 cancer predisposition genes were identified by sequencing of products from a custom multiplex polymerase chain reaction-based panel; associations of genes with pancreatic cancer were assessed by comparing frequency of mutations in genes of pancreatic cancer patients with those of reference controls. RESULTS Comparing 3030 case patients with pancreatic cancer (43.2%female; 95.6% non-Hispanic white; mean age at diagnosis, 65.3 [SD, 10.7] years) with reference controls, significant associations were observed between pancreatic cancer and mutations in CDKN2A (0.3%of cases and 0.02%of controls; odds ratio [OR], 12.33; 95%CI, 5.43-25.61); TP53 (0.2%of cases and 0.02%of controls; OR, 6.70; 95%CI, 2.52-14.95); MLH1 (0.13%of cases and 0.02%of controls; OR, 6.66; 95%CI, 1.94-17.53); BRCA2 (1.9%of cases and 0.3%of controls; OR, 6.20; 95%CI, 4.62-8.17); ATM (2.3%of cases and 0.37%of controls; OR, 5.71; 95%CI, 4.38-7.33); and BRCA1 (0.6%of cases and 0.2%of controls; OR, 2.58; 95%CI, 1.54-4.05). CONCLUSIONS AND RELEVANCE In this case-control study, mutations in 6 genes associated with pancreatic cancer were found in 5.5%of all pancreatic cancer patients, including 7.9%of patients with a family history of pancreatic cancer and 5.2%of patients without a family history of pancreatic cancer. Further research is needed for replication in other populations.

AB - IMPORTANCE Individuals genetically predisposed to pancreatic cancer may benefit from early detection. Genes that predispose to pancreatic cancer and the risks of pancreatic cancer associated with mutations in these genes are not well defined. OBJECTIVE To determine whether inherited germline mutations in cancer predisposition genes are associated with increased risks of pancreatic cancer. DESIGN, SETTING, AND PARTICIPANTS Case-control analysis to identify pancreatic cancer predisposition genes; longitudinal analysis of patients with pancreatic cancer for prognosis. The study included 3030 adults diagnosed as having pancreatic cancer and enrolled in aMayo Clinic registry between October 12, 2000, and March 31, 2016, with last follow-up on June 22, 2017. Reference controls were 123 136 individuals with exome sequence data in the public Genome Aggregation Database and 53 105 in the Exome Aggregation Consortium database. EXPOSURES Individuals were classified based on carrying a deleterious mutation in cancer predisposition genes and having a personal or family history of cancer. MAIN OUTCOMES AND MEASURES Germline mutations in coding regions of 21 cancer predisposition genes were identified by sequencing of products from a custom multiplex polymerase chain reaction-based panel; associations of genes with pancreatic cancer were assessed by comparing frequency of mutations in genes of pancreatic cancer patients with those of reference controls. RESULTS Comparing 3030 case patients with pancreatic cancer (43.2%female; 95.6% non-Hispanic white; mean age at diagnosis, 65.3 [SD, 10.7] years) with reference controls, significant associations were observed between pancreatic cancer and mutations in CDKN2A (0.3%of cases and 0.02%of controls; odds ratio [OR], 12.33; 95%CI, 5.43-25.61); TP53 (0.2%of cases and 0.02%of controls; OR, 6.70; 95%CI, 2.52-14.95); MLH1 (0.13%of cases and 0.02%of controls; OR, 6.66; 95%CI, 1.94-17.53); BRCA2 (1.9%of cases and 0.3%of controls; OR, 6.20; 95%CI, 4.62-8.17); ATM (2.3%of cases and 0.37%of controls; OR, 5.71; 95%CI, 4.38-7.33); and BRCA1 (0.6%of cases and 0.2%of controls; OR, 2.58; 95%CI, 1.54-4.05). CONCLUSIONS AND RELEVANCE In this case-control study, mutations in 6 genes associated with pancreatic cancer were found in 5.5%of all pancreatic cancer patients, including 7.9%of patients with a family history of pancreatic cancer and 5.2%of patients without a family history of pancreatic cancer. Further research is needed for replication in other populations.

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