乳腺癌既可遗传，又不可遗传。体细胞基因致病突变引起的乳腺癌通常不可遗传，而生殖细胞（种系）基因致病突变引起的乳腺癌才有可能遗传。上世纪90年代中期，乳腺癌易感基因BRCA1和BRCA2被相继发现以后，至今尚无其他同样重要的生殖细胞基因致病突变被发现。2006年，哈佛大学医学院、达纳法伯癌症研究院、纽约纪念医院斯隆凯特林癌症中心、梅奥医学中心首先发现BRCA2结合蛋白编码基因PALB2致病突变也与乳腺癌密切相关，被英国剑桥大学学者认为是潜在的第三种乳腺癌易感基因。
2020年4月27日，美国癌症学会《癌症》在线发表浙江大学医学院附属第二医院、上海爱她基因科技、福建医科大学附属协和医院、宁波市妇女儿童医院、义乌市妇幼保健院、宁波市医疗中心李惠利医院东院、复旦大学上海医学院、复旦大学生物医学研究院的研究报告，对将近2万例中国女性的PALB2基因种系突变发生比例和分布以及乳腺癌风险和临床病理特征进行了大规模调查分析。
该研究于2015～2018年从中国10个省市入组乳腺癌患者21216例（福建5398例、浙江4908例、北京4890例、河南2258例、上海2116例、安徽725例、山东354例、辽宁353例、江苏191例、湖南23例）与健康对照者5890例，通过大规模并行测序对PALB2基因种系突变进行筛查。
结果，16501例BRCA阴性乳腺癌患者与5890例健康对照者相比，PALB2基因致病突变携带比例显著较高（0.97%比0.19%，比值比：5.23，95%置信区间：2.84～9.65，P<0.0001），尤其年龄≤30岁女性（1.85%，比值比：10.09，95%置信区间：3.95～25.79，P<0.0001）。
新发现PALB2基因突变41种，其中c.751胞嘧啶→胸腺嘧啶占10.63%。
与PALB2突变密切相关的临床特征包括：
乳腺癌或卵巢癌家族史（P<0.0001）
肿瘤≥2厘米（P=0.04）
三阴性乳腺癌（P=0.004）
淋巴结阳性（P=0.018）
双侧乳腺癌（P=0.003）
因此，该研究结果全面揭示了中国女性PALB2基因种系突变及其相关乳腺癌的特征。PALB2基因种系突变可以引起乳腺癌风险增加，尤其对于年龄≤30岁的中国女性人群。该研究结果将为乳腺癌患者和健康女性PALB2基因种系突变的遗传咨询提供有力证据，尤其对于中国人群和全球华裔。
相关链接
Cancer. 2020 Apr 27. [Epub ahead of print]
Spectrum of PALB2 germline mutations and characteristics of PALB2-related breast cancer: Screening of 16,501 unselected patients with breast cancer and 5890 controls by next-generation sequencing.
Zhou J, Wang H, Fu F, Li Z, Feng Q, Wu W, Liu Y, Wang C, Chen Y.
Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; AITA Biomedical Research Institute, Shanghai, China; Affiliated Union Hospital, Fujian Medical University, Fuzhou, China; Women and Children's Hospital of Ningbo, Ningbo, China; Yiwu Maternity and Child Care Hospital, Yiwu, China; Ningbo Medical Center, Li Huili Eastern Hospital, Ningbo, China; Shanghai Medical College, Fudan University, Shanghai, China; Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
This study reveals a comprehensive spectrum of partner and localizer BRCA2 (PALB2) germline mutations and characteristics of PALB2-related breast cancer, including the PALB2-related breast cancer risk and distinctive clinical characteristics. Clinically, this study will provide solid evidence for the genetic counseling of patients with breast cancer and healthy women with PALB2 germline mutations, especially in the Chinese population and among those with Chinese ethnicities worldwide.
BACKGROUND: Partner and localizer BRCA2 (PALB2) is a breast cancer predisposition gene, but the clinical relevance of PALB2 germline mutations in Chinese patients with breast cancer remains unknown. This study attempted to investigate the full prevalence and spectrum of PALB2 germline mutations in China and the associations between PALB2 germline mutations and breast cancer risk.
METHODS: A total of 21,216 unselected patients with breast cancer were enrolled from 10 provinces in China, and 5890 Chinese women without cancer were enrolled as healthy controls. PALB2 screening was based on next-generation sequencing.
RESULTS: A total of 16,501 BRCA1/2-negative patients with breast cancer were analyzed. Deleterious PALB2 mutation carriers accounted for 0.97% (n = 160) in the breast cancer cohort and for 0.19% (n = 11) in the healthy control cohort. Forty-one novel PALB2 germline mutations were identified. A high frequency of PALB2 c.751C>T was detected, and it accounted for 10.63% of the PALB2 germline mutations detected (17 of 160). PALB2 mutations were significantly associated with increased breast cancer risk (odds ratio [OR], 5.23; 95% confidence interval [CI], 2.84-9.65; P < .0001), especially among women 30 years old or younger (OR, 10.09; 95% CI, 3.95-25.79; P < .0001). Clinical characteristics, including a family history, bigger tumor size, triple-negative breast cancer, positive lymph nodes, and bilateral breast cancer, were closely related to PALB2 mutations.
CONCLUSIONS: This study revealed a comprehensive spectrum of PALB2 germline mutations and characteristics of PALB2-related breast cancer in China. PALB2 germline mutations confer a moderately increased risk for breast cancer but profoundly increase breast cancer risk for those 30 years old or younger in the Chinese population.
KEYWORDS: breast cancer risk, clinical characteristics, germline mutation, next-generation sequencing, partner and localizer BRCA2 (PALB2)
DOI: 10.1002/cncr.32905
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