Germline Pathogenic Variants in Cancer Predisposition Genes among Women with Invasive Lobular Carcinoma of the Breast

Siddhartha Yadav; Chunling Hu; Katherine L. Nathanson; Jeffrey N. Weitzel; David E. Goldgar; Peter Kraft; Rohan D. Gnanaolivu; Jie Na; Hongyan Huang; Nicholas J. Boddicker; Nicole Larson; Chi Gaoc; Song Yao; Clarice Weinberg; Celine M. Vachon; Amy Trentham-Dietz; Jack A. Taylor; Dale R. Sandler; Alpa Patel; Julie R. Palmer; Janet E. Olson; Susan Neuhausen; Elena Martinez; Sara Lindstrom; James V. Lacey; Allison W. Kurian; Esther M. John; Christopher Haiman; Leslie Bernstein; Paul W. Auer; Hoda Anton-Culver; Christine B. Ambrosone; Rachid Karam; Elizabeth Chao; Amal Yussuf; Tina Pesaran; Jill S. Dolinsky; Steven N. Hart; Holly LaDuca; Eric C. Polley; Susan M. Domchek; Fergus J. Couch

doi:10.1200/JCO.21.00640

Germline Pathogenic Variants in Cancer Predisposition Genes among Women with Invasive Lobular Carcinoma of the Breast

Siddhartha Yadav, Chunling Hu, Katherine L. Nathanson, Jeffrey N. Weitzel, David E. Goldgar, Peter Kraft, Rohan D. Gnanaolivu, Jie Na, Hongyan Huang, Nicholas J. Boddicker, Nicole Larson, Chi Gaoc, Song Yao, Clarice Weinberg, Celine M. Vachon, Amy Trentham-Dietz, Jack A. Taylor, Dale R. Sandler, Alpa Patel, Julie R. PalmerJanet E. Olson, Susan Neuhausen, Elena Martinez, Sara Lindstrom, James V. Lacey, Allison W. Kurian, Esther M. John, Christopher Haiman, Leslie Bernstein, Paul W. Auer, Hoda Anton-Culver, Christine B. Ambrosone, Rachid Karam, Elizabeth Chao, Amal Yussuf, Tina Pesaran, Jill S. Dolinsky, Steven N. Hart, Holly LaDuca, Eric C. Polley, Susan M. Domchek, Fergus J. Couch

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

Abstract

PURPOSE To determine the contribution of germline pathogenic variants (PVs) in hereditary cancer testing panel genes to invasive lobular carcinoma (ILC) of the breast. MATERIALS AND METHODS The study included 2,999 women with ILC from a population-based cohort and 3,796 women with ILC undergoing clinical multigene panel testing (clinical cohort). Frequencies of germline PVs in breast cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53) were compared between women with ILC and unaffected female controls and between women with ILC and infiltrating ductal carcinoma (IDC). RESULTS The frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analysis, CDH1 and BRCA2 PVs were associated with high risks of ILC (odds ratio [OR] . 4) and CHEK2, ATM, and PALB2 PVs were associated with moderate (OR = 2-4) risks. BRCA1 PVs and CHEK2 p.Ile157Thr were not associated with clinically relevant risks (OR , 2) of ILC. Compared with IDC, CDH1 PVs were . 10-fold enriched, whereas PVs in BRCA1 were substantially reduced in ILC. CONCLUSION The study establishes that PVs in ATM, BRCA2, CDH1, CHEK2, and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. Similar to IDC, multigene panel testing may be appropriate for women with ILC, but CDH1 should be specifically discussed because of low prevalence and gastric cancer risk.

Original language	English (US)
Pages (from-to)	3918-3926
Number of pages	9
Journal	Journal of Clinical Oncology
Volume	39
Issue number	35
DOIs	https://doi.org/10.1200/JCO.21.00640
State	Published - Dec 10 2021

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1200/JCO.21.00640

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Yadav, S., Hu, C., Nathanson, K. L., Weitzel, J. N., Goldgar, D. E., Kraft, P., Gnanaolivu, R. D., Na, J., Huang, H., Boddicker, N. J., Larson, N., Gaoc, C., Yao, S., Weinberg, C., Vachon, C. M., Trentham-Dietz, A., Taylor, J. A., Sandler, D. R., Patel, A., ... Couch, F. J. (2021). Germline Pathogenic Variants in Cancer Predisposition Genes among Women with Invasive Lobular Carcinoma of the Breast. Journal of Clinical Oncology, 39(35), 3918-3926. https://doi.org/10.1200/JCO.21.00640

Yadav, S, Hu, C, Nathanson, KL, Weitzel, JN, Goldgar, DE, Kraft, P, Gnanaolivu, RD, Na, J, Huang, H, Boddicker, NJ, Larson, N, Gaoc, C, Yao, S, Weinberg, C, Vachon, CM, Trentham-Dietz, A, Taylor, JA, Sandler, DR, Patel, A, Palmer, JR, Olson, JE, Neuhausen, S, Martinez, E, Lindstrom, S, Lacey, JV, Kurian, AW, John, EM, Haiman, C, Bernstein, L, Auer, PW, Anton-Culver, H, Ambrosone, CB, Karam, R, Chao, E, Yussuf, A, Pesaran, T, Dolinsky, JS, Hart, SN, LaDuca, H, Polley, EC, Domchek, SM & Couch, FJ 2021, 'Germline Pathogenic Variants in Cancer Predisposition Genes among Women with Invasive Lobular Carcinoma of the Breast', Journal of Clinical Oncology, vol. 39, no. 35, pp. 3918-3926. https://doi.org/10.1200/JCO.21.00640

@article{3dd013d873c141ffb34926fb42949778,

title = "Germline Pathogenic Variants in Cancer Predisposition Genes among Women with Invasive Lobular Carcinoma of the Breast",

abstract = "PURPOSE To determine the contribution of germline pathogenic variants (PVs) in hereditary cancer testing panel genes to invasive lobular carcinoma (ILC) of the breast. MATERIALS AND METHODS The study included 2,999 women with ILC from a population-based cohort and 3,796 women with ILC undergoing clinical multigene panel testing (clinical cohort). Frequencies of germline PVs in breast cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53) were compared between women with ILC and unaffected female controls and between women with ILC and infiltrating ductal carcinoma (IDC). RESULTS The frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analysis, CDH1 and BRCA2 PVs were associated with high risks of ILC (odds ratio [OR] . 4) and CHEK2, ATM, and PALB2 PVs were associated with moderate (OR = 2-4) risks. BRCA1 PVs and CHEK2 p.Ile157Thr were not associated with clinically relevant risks (OR , 2) of ILC. Compared with IDC, CDH1 PVs were . 10-fold enriched, whereas PVs in BRCA1 were substantially reduced in ILC. CONCLUSION The study establishes that PVs in ATM, BRCA2, CDH1, CHEK2, and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. Similar to IDC, multigene panel testing may be appropriate for women with ILC, but CDH1 should be specifically discussed because of low prevalence and gastric cancer risk.",

author = "Siddhartha Yadav and Chunling Hu and Nathanson, {Katherine L.} and Weitzel, {Jeffrey N.} and Goldgar, {David E.} and Peter Kraft and Gnanaolivu, {Rohan D.} and Jie Na and Hongyan Huang and Boddicker, {Nicholas J.} and Nicole Larson and Chi Gaoc and Song Yao and Clarice Weinberg and Vachon, {Celine M.} and Amy Trentham-Dietz and Taylor, {Jack A.} and Sandler, {Dale R.} and Alpa Patel and Palmer, {Julie R.} and Olson, {Janet E.} and Susan Neuhausen and Elena Martinez and Sara Lindstrom and Lacey, {James V.} and Kurian, {Allison W.} and John, {Esther M.} and Christopher Haiman and Leslie Bernstein and Auer, {Paul W.} and Hoda Anton-Culver and Ambrosone, {Christine B.} and Rachid Karam and Elizabeth Chao and Amal Yussuf and Tina Pesaran and Dolinsky, {Jill S.} and Hart, {Steven N.} and Holly LaDuca and Polley, {Eric C.} and Domchek, {Susan M.} and Couch, {Fergus J.}",

note = "Publisher Copyright: {\textcopyright} 2021 by American Society of Clinical Oncology.",

year = "2021",

month = dec,

day = "10",

doi = "10.1200/JCO.21.00640",

language = "English (US)",

volume = "39",

pages = "3918--3926",

journal = "Journal of Clinical Oncology",

issn = "0732-183X",

publisher = "American Society of Clinical Oncology",

number = "35",

}

TY - JOUR

T1 - Germline Pathogenic Variants in Cancer Predisposition Genes among Women with Invasive Lobular Carcinoma of the Breast

AU - Yadav, Siddhartha

AU - Hu, Chunling

AU - Nathanson, Katherine L.

AU - Weitzel, Jeffrey N.

AU - Goldgar, David E.

AU - Kraft, Peter

AU - Gnanaolivu, Rohan D.

AU - Na, Jie

AU - Huang, Hongyan

AU - Boddicker, Nicholas J.

AU - Larson, Nicole

AU - Gaoc, Chi

AU - Yao, Song

AU - Weinberg, Clarice

AU - Vachon, Celine M.

AU - Trentham-Dietz, Amy

AU - Taylor, Jack A.

AU - Sandler, Dale R.

AU - Patel, Alpa

AU - Palmer, Julie R.

AU - Olson, Janet E.

AU - Neuhausen, Susan

AU - Martinez, Elena

AU - Lindstrom, Sara

AU - Lacey, James V.

AU - Kurian, Allison W.

AU - John, Esther M.

AU - Haiman, Christopher

AU - Bernstein, Leslie

AU - Auer, Paul W.

AU - Anton-Culver, Hoda

AU - Ambrosone, Christine B.

AU - Karam, Rachid

AU - Chao, Elizabeth

AU - Yussuf, Amal

AU - Pesaran, Tina

AU - Dolinsky, Jill S.

AU - Hart, Steven N.

AU - LaDuca, Holly

AU - Polley, Eric C.

AU - Domchek, Susan M.

AU - Couch, Fergus J.

PY - 2021/12/10

Y1 - 2021/12/10

N2 - PURPOSE To determine the contribution of germline pathogenic variants (PVs) in hereditary cancer testing panel genes to invasive lobular carcinoma (ILC) of the breast. MATERIALS AND METHODS The study included 2,999 women with ILC from a population-based cohort and 3,796 women with ILC undergoing clinical multigene panel testing (clinical cohort). Frequencies of germline PVs in breast cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53) were compared between women with ILC and unaffected female controls and between women with ILC and infiltrating ductal carcinoma (IDC). RESULTS The frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analysis, CDH1 and BRCA2 PVs were associated with high risks of ILC (odds ratio [OR] . 4) and CHEK2, ATM, and PALB2 PVs were associated with moderate (OR = 2-4) risks. BRCA1 PVs and CHEK2 p.Ile157Thr were not associated with clinically relevant risks (OR , 2) of ILC. Compared with IDC, CDH1 PVs were . 10-fold enriched, whereas PVs in BRCA1 were substantially reduced in ILC. CONCLUSION The study establishes that PVs in ATM, BRCA2, CDH1, CHEK2, and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. Similar to IDC, multigene panel testing may be appropriate for women with ILC, but CDH1 should be specifically discussed because of low prevalence and gastric cancer risk.

AB - PURPOSE To determine the contribution of germline pathogenic variants (PVs) in hereditary cancer testing panel genes to invasive lobular carcinoma (ILC) of the breast. MATERIALS AND METHODS The study included 2,999 women with ILC from a population-based cohort and 3,796 women with ILC undergoing clinical multigene panel testing (clinical cohort). Frequencies of germline PVs in breast cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53) were compared between women with ILC and unaffected female controls and between women with ILC and infiltrating ductal carcinoma (IDC). RESULTS The frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analysis, CDH1 and BRCA2 PVs were associated with high risks of ILC (odds ratio [OR] . 4) and CHEK2, ATM, and PALB2 PVs were associated with moderate (OR = 2-4) risks. BRCA1 PVs and CHEK2 p.Ile157Thr were not associated with clinically relevant risks (OR , 2) of ILC. Compared with IDC, CDH1 PVs were . 10-fold enriched, whereas PVs in BRCA1 were substantially reduced in ILC. CONCLUSION The study establishes that PVs in ATM, BRCA2, CDH1, CHEK2, and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. Similar to IDC, multigene panel testing may be appropriate for women with ILC, but CDH1 should be specifically discussed because of low prevalence and gastric cancer risk.

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SN - 0732-183X

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JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

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ER -

Germline Pathogenic Variants in Cancer Predisposition Genes among Women with Invasive Lobular Carcinoma of the Breast

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