美国梅奥诊所Fergus J. Couch团队进行了一项基于美国人群的乳腺癌相关基因研究。2021年1月20日，该研究发表在《新英格兰医学杂志》上。

以人群为基础评估与癌症易感基因种系致病性变体相关的乳腺癌风险，对于遗传致病性变体女性的风险评估和管理是非常必要的。

在一项以人群为基础的病例对照研究中，研究组招募了32247名乳腺癌女性（病例患者）和32544名未受影响的女性（对照组），使用一个自定义的基于多基因扩增子的面板进行测序，以确定该人群中28个癌症易感基因的种系致病性变体，并评估了每个基因的致病性变体与乳腺癌风险之间的关系。

在12个已确定的乳腺癌易感基因中，5.03%的病例患者和1.63%的对照组检测到致病性变体。BRCA1和BRCA2的致病性变异与乳腺癌的高风险相关，优势比分别为7.62和5.23。PALB2的致病性变异与乳腺癌中度风险相关，优势比为3.83。

BARD1、RAD51C和RAD51D中的致病性变体与雌激素受体阴性乳腺癌和三阴性乳腺癌的风险增加相关，而ATM、CDH1和CHEK2中的致病性变体与雌激素受体阳性乳腺癌的风险增加相关。16个候选乳腺癌易感基因中的致病性变体，包括NBN中的c.657_661del5致病性变体，均与乳腺癌风险增加无关。

这项研究估计了美国人群中已知乳腺癌易感基因的致病性变体与乳腺癌的患病率和风险。这些估计可以为癌症检测和筛查提供信息，并改善在这些基因中存在遗传致病性变体的普通女性人群的临床管理策略。

附：英文原文

Title: A Population-Based Study of Genes Previously Implicated in Breast Cancer

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

Issue&Volume: 2021-01-20

Abstract:

Background

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.

DOI: 10.1056/NEJMoa2005936

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2005936