携带有 PALB2 基因突变的家族中的乳腺癌风险。
Breast-cancer risk in families with mutations in PALB2.
机构信息
From the Departments of Public Health and Primary Care (A.C.A., D.B., A.L., D.F.E.) and Oncology (D.F.E.), Centre for Cancer Genetic Epidemiology, Department of Oncology (D.F.E.), and Department of Medical Genetics and National Institute for Health Research Cambridge Biomedical Research Centre (M.T.), University of Cambridge, and the Department of Clinical Genetics, East Anglian Regional Genetics Service, Addenbrooke's Hospital (J.R., D.S., M.T.), Cambridge, and the Oncogenetics Team, Institute of Cancer Research and Royal Marsden National Health Service Foundation Trust, London (C.T., S.S., N.R.) - all in the United Kingdom; the Division of Medical Genetics, Department of Medicine, University of Washington, Seattle (S.C., M.-C.K.); the Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital (T.H., S.K., H.N.), and the Department of Clinical Genetics, Helsinki University Central Hospital (K.A.), Helsinki, the Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, and the Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Center NordLab, Oulu University Hospital (K.P., R.W.), and the Department of Clinical Genetics, University of Oulu and Oulu University Hospital (J.S.M.), Oulu, Biocenter Kuopio and Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio (A.M.), and the Institute of Biomedical Technology-Cancer Genomics, University of Tampere, Tampere (A.K.) - all in Finland; the Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium (K.D.L., B.P., K.B.M.C.); the Molecular Diagnostics Laboratory, Institute of Nuclear and Radiologic Sciences and Technology, Energy and Safety, National Center for Scientific Research Demokritos, Athens (F.F., D.Y.); the Department of Genetics, Eastern Ontario Regional Genetics Program, Children's Hospital of Eastern Ontario, Ottawa (E.T.), Samuel Lunenfeld Research
出版信息
N Engl J Med. 2014 Aug 7;371(6):497-506. doi: 10.1056/NEJMoa1400382.
BACKGROUND
Germline loss-of-function mutations in PALB2 are known to confer a predisposition to breast cancer. However, the lifetime risk of breast cancer that is conferred by such mutations remains unknown.
METHODS
We analyzed the risk of breast cancer among 362 members of 154 families who had deleterious truncating, splice, or deletion mutations in PALB2. The age-specific breast-cancer risk for mutation carriers was estimated with the use of a modified segregation-analysis approach that allowed for the effects of PALB2 genotype and residual familial aggregation.
RESULTS
The risk of breast cancer for female PALB2 mutation carriers, as compared with the general population, was eight to nine times as high among those younger than 40 years of age, six to eight times as high among those 40 to 60 years of age, and five times as high among those older than 60 years of age. The estimated cumulative risk of breast cancer among female mutation carriers was 14% (95% confidence interval [CI], 9 to 20) by 50 years of age and 35% (95% CI, 26 to 46) by 70 years of age. Breast-cancer risk was also significantly influenced by birth cohort (P<0.001) and by other familial factors (P=0.04). The absolute breast-cancer risk for PALB2 female mutation carriers by 70 years of age ranged from 33% (95% CI, 25 to 44) for those with no family history of breast cancer to 58% (95% CI, 50 to 66) for those with two or more first-degree relatives with breast cancer at 50 years of age.
CONCLUSIONS
Loss-of-function mutations in PALB2 are an important cause of hereditary breast cancer, with respect both to the frequency of cancer-predisposing mutations and to the risk associated with them. Our data suggest the breast-cancer risk for PALB2 mutation carriers may overlap with that for BRCA2 mutation carriers. (Funded by the European Research Council and others.).
背景
PALB2 种系功能丧失性突变已知可导致乳腺癌易感性。然而，此类突变导致的乳腺癌终生风险尚不清楚。
方法
我们分析了 154 个家族的 362 名成员中携带 PALB2 有害截断、剪接或缺失突变的个体的乳腺癌发病风险。使用改良的分离分析方法估计了突变携带者的乳腺癌年龄特异性发病风险，该方法允许考虑 PALB2 基因型和残留家族聚集的影响。
结果
与一般人群相比，PALB2 突变携带者的乳腺癌发病风险在<40 岁的女性中高 8 至 9 倍，在 40 至 60 岁的女性中高 6 至 8 倍，在>60 岁的女性中高 5 倍。在女性突变携带者中，估计乳腺癌的累积发病风险在 50 岁时为 14%（95%置信区间 [CI]，9 至 20），在 70 岁时为 35%（95% CI，26 至 46）。乳腺癌发病风险还受到出生队列（P<0.001）和其他家族因素（P=0.04）的显著影响。PALB2 女性突变携带者在 70 岁时的绝对乳腺癌发病风险范围从无乳腺癌家族史的个体的 33%（95% CI，25 至 44）到 50 岁时有两个或更多一级亲属患有乳腺癌的个体的 58%（95% CI，50 至 66）。
结论
PALB2 种系功能丧失性突变是遗传性乳腺癌的一个重要原因，无论是从致癌突变的频率还是从相关风险的角度来看都是如此。我们的数据表明，PALB2 突变携带者的乳腺癌发病风险可能与 BRCA2 突变携带者的发病风险重叠。（由欧洲研究理事会等资助）。
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