Inherited predisposition to breast cancer in the Carolina Breast Cancer Study

Tom Walsh,Charles M Perou,Ming K Lee,H Shelton Earp,Andrew F Olshan,Mary-Claire King,Suleyman Gulsuner,Melissa A Troester

doi:10.1038/s41523-020-00214-4

Abstract

The Carolina Breast Cancer Study (CBCS) phases I–II was a case-control study of biological and social risk factors for invasive breast cancer that enrolled cases and controls between 1993 and 1999. Case selection was population-based and stratified by ancestry and age at diagnosis. Controls were matched to cases by age, self-identified race, and neighborhood of residence. Sequencing genomic DNA from 1370 cases and 1635 controls yielded odds ratios (with 95% confidence limits) for breast cancer of all subtypes of 26.7 (3.59, 189.1) for BRCA1, 8.8 (3.44, 22.48) for BRCA2, and 9.0 (2.06, 39.60) for PALB2; and for triple-negative breast cancer (TNBC) of 55.0 (7.01, 431.4) for BRCA1, 12.1 (4.18, 35.12) for BRCA2, and 10.8 (1.97, 59.11) for PALB2. Overall, 5.6% of patients carried a pathogenic variant in BRCA1, BRCA2, PALB2, or TP53, the four most highly penetrant breast cancer genes. Analysis of cases by tumor subtype revealed the expected association of TNBC versus other tumor subtypes with BRCA1, and suggested a significant association between TNBC versus other tumor subtypes with BRCA2 or PALB2 among African-American (AA) patients [2.95 (1.18, 7.37)], but not among European-American (EA) patients [0.62 (0.18, 2.09)]. AA patients with pathogenic variants in BRCA2 or PALB2 were 11 times more likely to be diagnosed with TNBC versus another tumor subtype than were EA patients with pathogenic variants in either of these genes (P = 0.001). If this pattern is confirmed in other comparisons of similarly ascertained AA and EA breast cancer patients, it could in part explain the higher prevalence of TNBC among AA breast cancer patients.

Highlights

The Carolina Breast Cancer Study (CBCS) was designed in the early1990s to evaluate genetic and social risk factors for invasive breast cancer[1]
Enrollment for CBCS phases I–II occurred before genetic screening was available to this population, so women with mutations were not protected from becoming cases by prior genetic testing and risk-reducing surgery
As reported previously from the CBCS2, triple-negative breast cancer (TNBC) was more frequent among AA cases (178 of 509, 35%) than among EA cases (127 of 684, 19%); Odds ratios (OR) = 2.35, 95% confidence intervals (CI) (1.80, 3.06)

Summary

Introduction

1990s to evaluate genetic and social risk factors for invasive breast cancer[1]. Until now, the CBCS cohort was never comprehensively sequenced for mutations in genes predisposing to breast cancer. The CBCS cohort is uniquely valuable in several ways for evaluation of genetic influences on breast cancer risk. Enrollment for CBCS phases I–II occurred before genetic screening was available to this population, so women with mutations were not protected from becoming cases by prior genetic testing and risk-reducing surgery ( even only a small fraction of BRCA1 or BRCA2 mutation carriers are identified prior to diagnosis). DNA samples were collected at enrollment, within 6 months of diagnosis, so participation was minimally subject to survival bias, and DNA was still available from the vast majority of participants

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Conclusion