A population-based study of genes previously implicated in breast cancer

Chunling Hu; Steven N. Hart; Rohan Gnanaolivu; Hongyan Huang; Kun Y. Lee; Jie Na; Chi Gao; Jenna Lilyquist; Siddhartha Yadav; Nicholas J. Boddicker; Raed Samara; Josh Klebba; Christine B. Ambrosone; Hoda Anton-Culver; Paul Auer; Elisa V. Bandera; Leslie Bernstein; Kimberly A. Bertrand; Elizabeth S. Burnside; Brian D. Carter; Heather Eliassen; Susan M. Gapstur; Mia Gaudet; Christopher Haiman; James M. Hodge; David J. Hunter; Eric J. Jacobs; Esther M. John; Charles Kooperberg; Allison W. Kurian; Loic Le Marchand; Sara Lindstroem; Tricia Lindstrom; Huiyan Ma; Susan Neuhausen; Polly A. Newcomb; Katie M. O'Brien; Janet E. Olson; Irene M. Ong; Tuya Pal; Julie R. Palmer; Alpa V. Patel; Sonya Reid; Lynn Rosenberg; Dale P. Sandler; Christopher Scott; Rulla Tamimi; Jack A. Taylor; Amy Trentham-Dietz; Celine M. Vachon; Clarice Weinberg; Song Yao; Argyrios Ziogas; Jeffrey N. Weitzel; David E. Goldgar; Susan M. Domchek; Katherine L. Nathanson; Peter Kraft; Eric C. Polley; Fergus J. Couch

doi:10.1056/NEJMoa2005936

A population-based study of genes previously implicated in breast cancer

Chunling Hu, Steven N. Hart, Rohan Gnanaolivu, Hongyan Huang, Kun Y. Lee, Jie Na, Chi Gao, Jenna Lilyquist, Siddhartha Yadav, Nicholas J. Boddicker, Raed Samara, Josh Klebba, Christine B. Ambrosone, Hoda Anton-Culver, Paul Auer, Elisa V. Bandera, Leslie Bernstein, Kimberly A. Bertrand, Elizabeth S. Burnside, Brian D. CarterHeather Eliassen, Susan M. Gapstur, Mia Gaudet, Christopher Haiman, James M. Hodge, David J. Hunter, Eric J. Jacobs, Esther M. John, Charles Kooperberg, Allison W. Kurian, Loic Le Marchand, Sara Lindstroem, Tricia Lindstrom, Huiyan Ma, Susan Neuhausen, Polly A. Newcomb, Katie M. O'Brien, Janet E. Olson, Irene M. Ong, Tuya Pal, Julie R. Palmer, Alpa V. Patel, Sonya Reid, Lynn Rosenberg, Dale P. Sandler, Christopher Scott, Rulla Tamimi, Jack A. Taylor, Amy Trentham-Dietz, Celine M. Vachon, Clarice Weinberg, Song Yao, Argyrios Ziogas, Jeffrey N. Weitzel, David E. Goldgar, Susan M. Domchek, Katherine L. Nathanson, Peter Kraft, Eric C. Polley, Fergus J. Couch

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Abstract

Population-based estimates of the risk of breast cancer associated with germline pathogenic variants in cancer-predisposition genes are critically needed for risk assessment and management in women with inherited pathogenic variants. METHODS In a population-based case-control study, we performed sequencing using a custom multigene amplicon-based panel to identify germline pathogenic variants in 28 cancer-predisposition genes among 32,247 women with breast cancer (case patients) and 32,544 unaffected women (controls) from population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Associations between pathogenic variants in each gene and the risk of breast cancer were assessed. RESULTS Pathogenic variants in 12 established breast cancer-predisposition genes were detected in 5.03% of case patients and in 1.63% of controls. Pathogenic variants in BRCA1 and BRCA2 were associated with a high risk of breast cancer, with odds ratios of 7.62 (95% confidence interval [CI], 5.33 to 11.27) and 5.23 (95% CI, 4.09 to 6.77), respectively. Pathogenic variants in PALB2 were associated with a moderate risk (odds ratio, 3.83; 95% CI, 2.68 to 5.63). Pathogenic variants in BARD1, RAD51C, and RAD51D were associated with increased risks of estrogen receptor-negative breast cancer and triple-negative breast cancer, whereas pathogenic variants in ATM, CDH1, and CHEK2 were associated with an increased risk of estrogen receptor-positive breast cancer. Pathogenic variants in 16 candidate breast cancer-predisposition genes, including the c.657_661del5 founder pathogenic variant in NBN, were not associated with an increased risk of breast cancer. CONCLUSIONS This study provides estimates of the prevalence and risk of breast cancer associated with pathogenic variants in known breast cancer-predisposition genes in the U.S. population. These estimates can inform cancer testing and screening and improve clinical management strategies for women in the general population with inherited pathogenic variants in these genes.

Original language	English (US)
Pages (from-to)	440-451
Number of pages	12
Journal	New England Journal of Medicine
Volume	384
Issue number	5
DOIs	https://doi.org/10.1056/NEJMoa2005936
State	Published - Feb 4 2021

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General Medicine

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10.1056/NEJMoa2005936

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Hu, C., Hart, S. N., Gnanaolivu, R., Huang, H., Lee, K. Y., Na, J., Gao, C., Lilyquist, J., Yadav, S., Boddicker, N. J., Samara, R., Klebba, J., Ambrosone, C. B., Anton-Culver, H., Auer, P., Bandera, E. V., Bernstein, L., Bertrand, K. A., Burnside, E. S., ... Couch, F. J. (2021). A population-based study of genes previously implicated in breast cancer. New England Journal of Medicine, 384(5), 440-451. https://doi.org/10.1056/NEJMoa2005936

Hu, C, Hart, SN, Gnanaolivu, R, Huang, H, Lee, KY, Na, J, Gao, C, Lilyquist, J, Yadav, S, Boddicker, NJ, Samara, R, Klebba, J, Ambrosone, CB, Anton-Culver, H, Auer, P, Bandera, EV, Bernstein, L, Bertrand, KA, Burnside, ES, Carter, BD, Eliassen, H, Gapstur, SM, Gaudet, M, Haiman, C, Hodge, JM, Hunter, DJ, Jacobs, EJ, John, EM, Kooperberg, C, Kurian, AW, Le Marchand, L, Lindstroem, S, Lindstrom, T, Ma, H, Neuhausen, S, Newcomb, PA, O'Brien, KM, Olson, JE, Ong, IM, Pal, T, Palmer, JR, Patel, AV, Reid, S, Rosenberg, L, Sandler, DP, Scott, C, Tamimi, R, Taylor, JA, Trentham-Dietz, A, Vachon, CM, Weinberg, C, Yao, S, Ziogas, A, Weitzel, JN, Goldgar, DE, Domchek, SM, Nathanson, KL, Kraft, P, Polley, EC & Couch, FJ 2021, 'A population-based study of genes previously implicated in breast cancer', New England Journal of Medicine, vol. 384, no. 5, pp. 440-451. https://doi.org/10.1056/NEJMoa2005936

@article{81119b56966c474190b0f581488b1764,

title = "A population-based study of genes previously implicated in breast cancer",

abstract = "Population-based estimates of the risk of breast cancer associated with germline pathogenic variants in cancer-predisposition genes are critically needed for risk assessment and management in women with inherited pathogenic variants. METHODS In a population-based case-control study, we performed sequencing using a custom multigene amplicon-based panel to identify germline pathogenic variants in 28 cancer-predisposition genes among 32,247 women with breast cancer (case patients) and 32,544 unaffected women (controls) from population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Associations between pathogenic variants in each gene and the risk of breast cancer were assessed. RESULTS Pathogenic variants in 12 established breast cancer-predisposition genes were detected in 5.03% of case patients and in 1.63% of controls. Pathogenic variants in BRCA1 and BRCA2 were associated with a high risk of breast cancer, with odds ratios of 7.62 (95% confidence interval [CI], 5.33 to 11.27) and 5.23 (95% CI, 4.09 to 6.77), respectively. Pathogenic variants in PALB2 were associated with a moderate risk (odds ratio, 3.83; 95% CI, 2.68 to 5.63). Pathogenic variants in BARD1, RAD51C, and RAD51D were associated with increased risks of estrogen receptor-negative breast cancer and triple-negative breast cancer, whereas pathogenic variants in ATM, CDH1, and CHEK2 were associated with an increased risk of estrogen receptor-positive breast cancer. Pathogenic variants in 16 candidate breast cancer-predisposition genes, including the c.657_661del5 founder pathogenic variant in NBN, were not associated with an increased risk of breast cancer. CONCLUSIONS This study provides estimates of the prevalence and risk of breast cancer associated with pathogenic variants in known breast cancer-predisposition genes in the U.S. population. These estimates can inform cancer testing and screening and improve clinical management strategies for women in the general population with inherited pathogenic variants in these genes.",

author = "Chunling Hu and Hart, {Steven N.} and Rohan Gnanaolivu and Hongyan Huang and Lee, {Kun Y.} and Jie Na and Chi Gao and Jenna Lilyquist and Siddhartha Yadav and Boddicker, {Nicholas J.} and Raed Samara and Josh Klebba and Ambrosone, {Christine B.} and Hoda Anton-Culver and Paul Auer and Bandera, {Elisa V.} and Leslie Bernstein and Bertrand, {Kimberly A.} and Burnside, {Elizabeth S.} and Carter, {Brian D.} and Heather Eliassen and Gapstur, {Susan M.} and Mia Gaudet and Christopher Haiman and Hodge, {James M.} and Hunter, {David J.} and Jacobs, {Eric J.} and John, {Esther M.} and Charles Kooperberg and Kurian, {Allison W.} and {Le Marchand}, Loic and Sara Lindstroem and Tricia Lindstrom and Huiyan Ma and Susan Neuhausen and Newcomb, {Polly A.} and O'Brien, {Katie M.} and Olson, {Janet E.} and Ong, {Irene M.} and Tuya Pal and Palmer, {Julie R.} and Patel, {Alpa V.} and Sonya Reid and Lynn Rosenberg and Sandler, {Dale P.} and Christopher Scott and Rulla Tamimi and Taylor, {Jack A.} and Amy Trentham-Dietz and Vachon, {Celine M.} and Clarice Weinberg and Song Yao and Argyrios Ziogas and Weitzel, {Jeffrey N.} and Goldgar, {David E.} and Domchek, {Susan M.} and Nathanson, {Katherine L.} and Peter Kraft and Polley, {Eric C.} and Couch, {Fergus J.}",

note = "Publisher Copyright: {\textcopyright} 2021 Massachusetts Medical Society.",

year = "2021",

month = feb,

day = "4",

doi = "10.1056/NEJMoa2005936",

language = "English (US)",

volume = "384",

pages = "440--451",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachussetts Medical Society",

number = "5",

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TY - JOUR

T1 - A population-based study of genes previously implicated in breast cancer

AU - Hu, Chunling

AU - Hart, Steven N.

AU - Gnanaolivu, Rohan

AU - Huang, Hongyan

AU - Lee, Kun Y.

AU - Na, Jie

AU - Gao, Chi

AU - Lilyquist, Jenna

AU - Yadav, Siddhartha

AU - Boddicker, Nicholas J.

AU - Samara, Raed

AU - Klebba, Josh

AU - Ambrosone, Christine B.

AU - Anton-Culver, Hoda

AU - Auer, Paul

AU - Bandera, Elisa V.

AU - Bernstein, Leslie

AU - Bertrand, Kimberly A.

AU - Burnside, Elizabeth S.

AU - Carter, Brian D.

AU - Eliassen, Heather

AU - Gapstur, Susan M.

AU - Gaudet, Mia

AU - Haiman, Christopher

AU - Hodge, James M.

AU - Hunter, David J.

AU - Jacobs, Eric J.

AU - John, Esther M.

AU - Kooperberg, Charles

AU - Kurian, Allison W.

AU - Le Marchand, Loic

AU - Lindstroem, Sara

AU - Lindstrom, Tricia

AU - Ma, Huiyan

AU - Neuhausen, Susan

AU - Newcomb, Polly A.

AU - O'Brien, Katie M.

AU - Olson, Janet E.

AU - Ong, Irene M.

AU - Pal, Tuya

AU - Palmer, Julie R.

AU - Patel, Alpa V.

AU - Reid, Sonya

AU - Rosenberg, Lynn

AU - Sandler, Dale P.

AU - Scott, Christopher

AU - Tamimi, Rulla

AU - Taylor, Jack A.

AU - Trentham-Dietz, Amy

AU - Vachon, Celine M.

AU - Weinberg, Clarice

AU - Yao, Song

AU - Ziogas, Argyrios

AU - Weitzel, Jeffrey N.

AU - Goldgar, David E.

AU - Domchek, Susan M.

AU - Nathanson, Katherine L.

AU - Kraft, Peter

AU - Polley, Eric C.

AU - Couch, Fergus J.

PY - 2021/2/4

Y1 - 2021/2/4

N2 - Population-based estimates of the risk of breast cancer associated with germline pathogenic variants in cancer-predisposition genes are critically needed for risk assessment and management in women with inherited pathogenic variants. METHODS In a population-based case-control study, we performed sequencing using a custom multigene amplicon-based panel to identify germline pathogenic variants in 28 cancer-predisposition genes among 32,247 women with breast cancer (case patients) and 32,544 unaffected women (controls) from population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Associations between pathogenic variants in each gene and the risk of breast cancer were assessed. RESULTS Pathogenic variants in 12 established breast cancer-predisposition genes were detected in 5.03% of case patients and in 1.63% of controls. Pathogenic variants in BRCA1 and BRCA2 were associated with a high risk of breast cancer, with odds ratios of 7.62 (95% confidence interval [CI], 5.33 to 11.27) and 5.23 (95% CI, 4.09 to 6.77), respectively. Pathogenic variants in PALB2 were associated with a moderate risk (odds ratio, 3.83; 95% CI, 2.68 to 5.63). Pathogenic variants in BARD1, RAD51C, and RAD51D were associated with increased risks of estrogen receptor-negative breast cancer and triple-negative breast cancer, whereas pathogenic variants in ATM, CDH1, and CHEK2 were associated with an increased risk of estrogen receptor-positive breast cancer. Pathogenic variants in 16 candidate breast cancer-predisposition genes, including the c.657_661del5 founder pathogenic variant in NBN, were not associated with an increased risk of breast cancer. CONCLUSIONS This study provides estimates of the prevalence and risk of breast cancer associated with pathogenic variants in known breast cancer-predisposition genes in the U.S. population. These estimates can inform cancer testing and screening and improve clinical management strategies for women in the general population with inherited pathogenic variants in these genes.

AB - Population-based estimates of the risk of breast cancer associated with germline pathogenic variants in cancer-predisposition genes are critically needed for risk assessment and management in women with inherited pathogenic variants. METHODS In a population-based case-control study, we performed sequencing using a custom multigene amplicon-based panel to identify germline pathogenic variants in 28 cancer-predisposition genes among 32,247 women with breast cancer (case patients) and 32,544 unaffected women (controls) from population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Associations between pathogenic variants in each gene and the risk of breast cancer were assessed. RESULTS Pathogenic variants in 12 established breast cancer-predisposition genes were detected in 5.03% of case patients and in 1.63% of controls. Pathogenic variants in BRCA1 and BRCA2 were associated with a high risk of breast cancer, with odds ratios of 7.62 (95% confidence interval [CI], 5.33 to 11.27) and 5.23 (95% CI, 4.09 to 6.77), respectively. Pathogenic variants in PALB2 were associated with a moderate risk (odds ratio, 3.83; 95% CI, 2.68 to 5.63). Pathogenic variants in BARD1, RAD51C, and RAD51D were associated with increased risks of estrogen receptor-negative breast cancer and triple-negative breast cancer, whereas pathogenic variants in ATM, CDH1, and CHEK2 were associated with an increased risk of estrogen receptor-positive breast cancer. Pathogenic variants in 16 candidate breast cancer-predisposition genes, including the c.657_661del5 founder pathogenic variant in NBN, were not associated with an increased risk of breast cancer. CONCLUSIONS This study provides estimates of the prevalence and risk of breast cancer associated with pathogenic variants in known breast cancer-predisposition genes in the U.S. population. These estimates can inform cancer testing and screening and improve clinical management strategies for women in the general population with inherited pathogenic variants in these genes.

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A population-based study of genes previously implicated in breast cancer

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