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 journalArticlepeer-review


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 languageEnglish (US)
Pages (from-to)3918-3926
Number of pages9
JournalJournal of Clinical Oncology
Issue number35
StatePublished - Dec 10 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


Dive into the research topics of 'Germline Pathogenic Variants in Cancer Predisposition Genes among Women with Invasive Lobular Carcinoma of the Breast'. Together they form a unique fingerprint.

Cite this