Oddoux C, Struewing J P, Clayton C M, Neuhausen S, Brody L C, Kaback M, Haas B, Norton L, Borgen P, Jhanwar S, Goldgar D, Ostrer H, Offit K
Department of Pediatrics, New York University Medical Center, New York 10016, USA.
Nat Genet. 1996 Oct;14(2):188-90. doi: 10.1038/ng1096-188.
Certain germline mutations in either BRCA1 or BRCA2 confer a lifetime risk of developing breast cancer that may approach 90%. The BRCA1 185delAG mutation was found in 20% and the BRCA2 6174delT mutation in 8% of Ashkenazi Jewish women with early-onset breast cancer. The 185delAG mutation was observed in 0.9% of 858 Ashkenazi Jews unselected for a personal or family history of cancer. Assuming comparable age-specific penetrances, a carrier frequency of 0.3% was estimated for the 6174delT BRCA2 mutation. To test this hypothesis, we performed a population survey of 1,255 Jewish individuals. In two independent groups, a prevalence of approximately 1% (C.I. 0.6-1.5) was observed for the 6174delT mutation. The relative risk of developing breast cancer by age 42 was estimated to be 9.3 (C.I. 2.5-22.5) for 6174delT, compared to 31 (C.I. 11-77) for 185delAG. Analysis of 107 Ashkenazi Jewish women with breast cancer and a family history of breast or ovarian cancer confirmed a four-fold greater prevalence for the BRCA1 185delAG mutation compared to the BRCA2 6174delT mutation. Our findings suggest a difference in cumulative life-time penetrance for the two mutations. Genetic counseling for the one in 50 Ashkenazi Jewish individuals harbouring specific germline mutations in BRCA1 or BRCA2 must be tailored to reflect the different risks associated with the two mutations.
BRCA1或BRCA2基因的某些种系突变会使患乳腺癌的终生风险接近90%。在患有早发性乳腺癌的阿什肯纳兹犹太女性中，20%的人发现有BRCA1基因的185delAG突变，8%的人有BRCA2基因的6174delT突变。在858名未因个人或家族癌症病史而被挑选的阿什肯纳兹犹太人中，0.9%的人观察到185delAG突变。假设年龄特异性外显率相当，估计BRCA2基因6174delT突变的携带频率为0.3%。为了验证这一假设，我们对1255名犹太人进行了一项群体调查。在两个独立的组中，观察到6174delT突变的患病率约为1%（置信区间0.6 - 1.5）。与185delAG突变相比，6174delT突变在42岁前患乳腺癌的相对风险估计为9.3（置信区间2.5 - 22.5），而185delAG突变为31（置信区间11 - 77）。对107名患有乳腺癌且有乳腺癌或卵巢癌家族史的阿什肯纳兹犹太女性的分析证实，BRCA1基因185delAG突变的患病率比BRCA2基因6174delT突变高四倍。我们的研究结果表明这两种突变的累积终生外显率存在差异。对于每50名携带BRCA1或BRCA2特定种系突变的阿什肯纳兹犹太个体，必须进行针对性的遗传咨询，以反映与这两种突变相关的不同风险。
