Phenocopies in BRCA1 and BRCA2 families: evidence for modifier genes and implications for screening
Phenocopies in BRCA1 and BRCA2 families: evidence for modifier genes and implications for screening
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DOI：
10.1136/jmg.2006.043091
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发表时间：
2007-01-01
影响因子：
4
通讯作者：
Evans, D. G. R.
中科院分区：
文献类型：
--
作者：
Smith, A.;Moran, A.;Evans, D. G. R.
背景：家族性乳腺癌亲属中 BRCA1 和 BRCA2 突变的鉴定允许对高危亲属进行基因检测。检测呈阴性的人通常会放心，并且停止额外的乳腺癌监测。然而，我们假设在高风险家庭中，例如临床遗传学中心的家庭，患乳腺癌的风险可能不仅受到 BRCA1/BRCA2 突变的影响，还受到修饰基因的影响。其表现之一是 BRCA1/BRCA2 家族中存在表型。方法：对 277 个具有致病性 BRCA1/BRCA2 突变的家族进行了审查，并鉴定了 28 个乳腺癌表型。使用我们的癌症登记处基于当地人群的发病率来评估检测阴性的乳腺癌相对风险。结果：在识别先证者的突变后，表型占乳腺癌女性检测的 24%。 BRCA1/BRCA2 家族突变检测呈阴性的女性的标准化发病率，对于所有亲属为 5.3，对于所有一级亲属 (FDR) 为 5.0，对于其家族中所有其他乳腺癌和卵巢癌病例均可通过所确定的突变来解释的 FDR 为 3.2（95% 置信区间 2.0 至 4.9）。 107 名患有乳腺癌且没有不明原因家族史的 FDR 中，有 13 名 (12.1%) 检测结果呈阴性。结论：在高风险家庭中，家族性 BRCA1/BRCA2 突变检测呈阴性的女性患乳腺癌的风险增加，这与基因修饰一致。有鉴于此，仍应考虑对此类妇女进行持续监测。
Background: The identification of BRCA1 and BRCA2 mutations in familial breast cancer kindreds allows genetic testing of at-risk relatives. Those who test negative are usually reassured and additional breast cancer surveillance is discontinued. However, we postulated that in high-risk families, such as those seen in clinical genetics centres, the risk of breast cancer might be influenced not only by the BRCA1/BRCA2 mutation but also by modifier genes. One manifestation of this would be the presence of phenocopies in BRCA1/BRCA2 kindreds.Methods: 277 families with pathogenic BRCA1/BRCA2 mutations were reviewed and 28 breast cancer phenocopies identified. The relative risk of breast cancer in those testing negative was assessed using incidence rates from our cancer registry based on local population.Results: Phenocopies constituted up to 24% of tests on women with breast cancer after the identification of the mutation in the proband. The standardised incidence ratio for women who tested negative for the BRCA1/ BRCA2 family mutation was 5.3 for all relatives, 5.0 for all first-degree relatives (FDRs) and 3.2 (95% confidence interval 2.0 to 4.9) for FDRs in whose family all other cases of breast and ovarian cancer could be explained by the identified mutation. 13 of 107 (12.1%) FDRs with breast cancer and no unexplained family history tested negative.Conclusion: In high-risk families, women who test negative for the familial BRCA1/BRCA2 mutation have an increased risk of breast cancer consistent with genetic modifiers. In light of this, such women should still be considered for continued surveillance.