Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer

AOCS study group, Ovarian Cancer Association Consortium

Research output: Contribution to journalArticle

135 Citations (Scopus)

Abstract

BACKGROUND: Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, responsible for 13 000 deaths per year in the United States. Risk prediction based on identifying germline mutations in ovarian cancer susceptibility genes could have a clinically significant impact on reducing disease mortality.

METHODS: Next generation sequencing was used to identify germline mutations in the coding regions of four candidate susceptibility genes-BRIP1, BARD1, PALB2 and NBN-in 3236 invasive EOC case patients and 3431 control patients of European origin, and in 2000 unaffected high-risk women from a clinical screening trial of ovarian cancer (UKFOCSS). For each gene, we estimated the prevalence and EOC risks and evaluated associations between germline variant status and clinical and epidemiological risk factor information. All statistical tests were two-sided.

RESULTS: We found an increased frequency of deleterious mutations in BRIP1 in case patients (0.9%) and in the UKFOCSS participants (0.6%) compared with control patients (0.09%) (P = 1 x 10(-4) and 8 x 10(-4), respectively), but no differences for BARD1 (P = .39), NBN1 ( P = .61), or PALB2 (P = .08). There was also a difference in the frequency of rare missense variants in BRIP1 between case patients and control patients (P = 5.5 x 10(-4)). The relative risks associated with BRIP1 mutations were 11.22 for invasive EOC (95% confidence interval [CI] = 3.22 to 34.10, P = 1 x 10(-4)) and 14.09 for high-grade serous disease (95% CI = 4.04 to 45.02, P = 2 x 10(-5)). Segregation analysis in families estimated the average relative risks in BRIP1 mutation carriers compared with the general population to be 3.41 (95% CI = 2.12 to 5.54, P = 7×10(-7)).

CONCLUSIONS: Deleterious germline mutations in BRIP1 are associated with a moderate increase in EOC risk. These data have clinical implications for risk prediction and prevention approaches for ovarian cancer and emphasize the critical need for risk estimates based on very large sample sizes before genes of moderate penetrance have clinical utility in cancer prevention.

Original languageEnglish (US)
JournalJournal of the National Cancer Institute
Volume107
Issue number11
DOIs
StatePublished - Nov 1 2015
Externally publishedYes

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Germ-Line Mutation
Ovarian Neoplasms
Genes
Confidence Intervals
Mutation
Penetrance
Neoplasm Genes
Mutation Rate
Sample Size
Neoplasms
Ovarian epithelial cancer
Clinical Trials
Mortality

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer. / AOCS study group; Ovarian Cancer Association Consortium.

In: Journal of the National Cancer Institute, Vol. 107, No. 11, 01.11.2015.

Research output: Contribution to journalArticle

AOCS study group ; Ovarian Cancer Association Consortium. / Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer. In: Journal of the National Cancer Institute. 2015 ; Vol. 107, No. 11.
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title = "Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer",
abstract = "BACKGROUND: Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, responsible for 13 000 deaths per year in the United States. Risk prediction based on identifying germline mutations in ovarian cancer susceptibility genes could have a clinically significant impact on reducing disease mortality.METHODS: Next generation sequencing was used to identify germline mutations in the coding regions of four candidate susceptibility genes-BRIP1, BARD1, PALB2 and NBN-in 3236 invasive EOC case patients and 3431 control patients of European origin, and in 2000 unaffected high-risk women from a clinical screening trial of ovarian cancer (UKFOCSS). For each gene, we estimated the prevalence and EOC risks and evaluated associations between germline variant status and clinical and epidemiological risk factor information. All statistical tests were two-sided.RESULTS: We found an increased frequency of deleterious mutations in BRIP1 in case patients (0.9{\%}) and in the UKFOCSS participants (0.6{\%}) compared with control patients (0.09{\%}) (P = 1 x 10(-4) and 8 x 10(-4), respectively), but no differences for BARD1 (P = .39), NBN1 ( P = .61), or PALB2 (P = .08). There was also a difference in the frequency of rare missense variants in BRIP1 between case patients and control patients (P = 5.5 x 10(-4)). The relative risks associated with BRIP1 mutations were 11.22 for invasive EOC (95{\%} confidence interval [CI] = 3.22 to 34.10, P = 1 x 10(-4)) and 14.09 for high-grade serous disease (95{\%} CI = 4.04 to 45.02, P = 2 x 10(-5)). Segregation analysis in families estimated the average relative risks in BRIP1 mutation carriers compared with the general population to be 3.41 (95{\%} CI = 2.12 to 5.54, P = 7×10(-7)).CONCLUSIONS: Deleterious germline mutations in BRIP1 are associated with a moderate increase in EOC risk. These data have clinical implications for risk prediction and prevention approaches for ovarian cancer and emphasize the critical need for risk estimates based on very large sample sizes before genes of moderate penetrance have clinical utility in cancer prevention.",
author = "{AOCS study group} and {Ovarian Cancer Association Consortium} and Ramus, {Susan J.} and Honglin Song and Ed Dicks and Tyrer, {Jonathan P.} and Rosenthal, {Adam N.} and Intermaggio, {Maria P.} and Lindsay Fraser and Aleksandra Gentry-Maharaj and Jane Hayward and Susan Philpott and Christopher Anderson and Edlund, {Christopher K.} and David Conti and Patricia Harrington and Daniel Barrowdale and Bowtell, {David D.} and Kathryn Alsop and Gillian Mitchell and Mine Cicek and Cunningham, {Julie M} and Fridley, {Brooke L.} and Jennifer Alsop and Mercedes Jimenez-Linan and Samantha Poblete and Shashi Lele and Lara Sucheston-Campbell and Moysich, {Kirsten B.} and Weiva Sieh and Valerie McGuire and Jenny Lester and Natalia Bogdanova and Matthias D{\"u}rst and Peter Hillemanns and Kunle Odunsi and Whittemore, {Alice S.} and Karlan, {Beth Y.} and Thilo D{\"o}rk and Goode, {Ellen L} and Usha Menon and Jacobs, {Ian J.} and Antoniou, {Antonis C.} and Pharoah, {Paul D P} and Gayther, {Simon A.}",
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TY - JOUR

T1 - Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer

AU - AOCS study group

AU - Ovarian Cancer Association Consortium

AU - Ramus, Susan J.

AU - Song, Honglin

AU - Dicks, Ed

AU - Tyrer, Jonathan P.

AU - Rosenthal, Adam N.

AU - Intermaggio, Maria P.

AU - Fraser, Lindsay

AU - Gentry-Maharaj, Aleksandra

AU - Hayward, Jane

AU - Philpott, Susan

AU - Anderson, Christopher

AU - Edlund, Christopher K.

AU - Conti, David

AU - Harrington, Patricia

AU - Barrowdale, Daniel

AU - Bowtell, David D.

AU - Alsop, Kathryn

AU - Mitchell, Gillian

AU - Cicek, Mine

AU - Cunningham, Julie M

AU - Fridley, Brooke L.

AU - Alsop, Jennifer

AU - Jimenez-Linan, Mercedes

AU - Poblete, Samantha

AU - Lele, Shashi

AU - Sucheston-Campbell, Lara

AU - Moysich, Kirsten B.

AU - Sieh, Weiva

AU - McGuire, Valerie

AU - Lester, Jenny

AU - Bogdanova, Natalia

AU - Dürst, Matthias

AU - Hillemanns, Peter

AU - Odunsi, Kunle

AU - Whittemore, Alice S.

AU - Karlan, Beth Y.

AU - Dörk, Thilo

AU - Goode, Ellen L

AU - Menon, Usha

AU - Jacobs, Ian J.

AU - Antoniou, Antonis C.

AU - Pharoah, Paul D P

AU - Gayther, Simon A.

PY - 2015/11/1

Y1 - 2015/11/1

N2 - BACKGROUND: Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, responsible for 13 000 deaths per year in the United States. Risk prediction based on identifying germline mutations in ovarian cancer susceptibility genes could have a clinically significant impact on reducing disease mortality.METHODS: Next generation sequencing was used to identify germline mutations in the coding regions of four candidate susceptibility genes-BRIP1, BARD1, PALB2 and NBN-in 3236 invasive EOC case patients and 3431 control patients of European origin, and in 2000 unaffected high-risk women from a clinical screening trial of ovarian cancer (UKFOCSS). For each gene, we estimated the prevalence and EOC risks and evaluated associations between germline variant status and clinical and epidemiological risk factor information. All statistical tests were two-sided.RESULTS: We found an increased frequency of deleterious mutations in BRIP1 in case patients (0.9%) and in the UKFOCSS participants (0.6%) compared with control patients (0.09%) (P = 1 x 10(-4) and 8 x 10(-4), respectively), but no differences for BARD1 (P = .39), NBN1 ( P = .61), or PALB2 (P = .08). There was also a difference in the frequency of rare missense variants in BRIP1 between case patients and control patients (P = 5.5 x 10(-4)). The relative risks associated with BRIP1 mutations were 11.22 for invasive EOC (95% confidence interval [CI] = 3.22 to 34.10, P = 1 x 10(-4)) and 14.09 for high-grade serous disease (95% CI = 4.04 to 45.02, P = 2 x 10(-5)). Segregation analysis in families estimated the average relative risks in BRIP1 mutation carriers compared with the general population to be 3.41 (95% CI = 2.12 to 5.54, P = 7×10(-7)).CONCLUSIONS: Deleterious germline mutations in BRIP1 are associated with a moderate increase in EOC risk. These data have clinical implications for risk prediction and prevention approaches for ovarian cancer and emphasize the critical need for risk estimates based on very large sample sizes before genes of moderate penetrance have clinical utility in cancer prevention.

AB - BACKGROUND: Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, responsible for 13 000 deaths per year in the United States. Risk prediction based on identifying germline mutations in ovarian cancer susceptibility genes could have a clinically significant impact on reducing disease mortality.METHODS: Next generation sequencing was used to identify germline mutations in the coding regions of four candidate susceptibility genes-BRIP1, BARD1, PALB2 and NBN-in 3236 invasive EOC case patients and 3431 control patients of European origin, and in 2000 unaffected high-risk women from a clinical screening trial of ovarian cancer (UKFOCSS). For each gene, we estimated the prevalence and EOC risks and evaluated associations between germline variant status and clinical and epidemiological risk factor information. All statistical tests were two-sided.RESULTS: We found an increased frequency of deleterious mutations in BRIP1 in case patients (0.9%) and in the UKFOCSS participants (0.6%) compared with control patients (0.09%) (P = 1 x 10(-4) and 8 x 10(-4), respectively), but no differences for BARD1 (P = .39), NBN1 ( P = .61), or PALB2 (P = .08). There was also a difference in the frequency of rare missense variants in BRIP1 between case patients and control patients (P = 5.5 x 10(-4)). The relative risks associated with BRIP1 mutations were 11.22 for invasive EOC (95% confidence interval [CI] = 3.22 to 34.10, P = 1 x 10(-4)) and 14.09 for high-grade serous disease (95% CI = 4.04 to 45.02, P = 2 x 10(-5)). Segregation analysis in families estimated the average relative risks in BRIP1 mutation carriers compared with the general population to be 3.41 (95% CI = 2.12 to 5.54, P = 7×10(-7)).CONCLUSIONS: Deleterious germline mutations in BRIP1 are associated with a moderate increase in EOC risk. These data have clinical implications for risk prediction and prevention approaches for ovarian cancer and emphasize the critical need for risk estimates based on very large sample sizes before genes of moderate penetrance have clinical utility in cancer prevention.

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U2 - 10.1093/jnci/djv214

DO - 10.1093/jnci/djv214

M3 - Article

VL - 107

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

SN - 0027-8874

IS - 11

ER -