Oros Kathleen K, Leblanc Guy, Arcand Suzanna L, Shen Zhen, Perret Chantal, Mes-Masson Anne-Marie, Foulkes William D, Ghadirian Parviz, Provencher Diane, Tonin Patricia N
Department of Human Genetics, McGill University, Montreal, Canada.
BMC Med Genet. 2006 Mar 15;7:23. doi: 10.1186/1471-2350-7-23.
The 3398delAAAAG mutation in BRCA2 was recently found to recur in breast and/or ovarian cancer families from the French Canadian population of Quebec, a population that has genetic attributes consistent with a founder effect. To characterize the contribution of this mutation in this population, this study established the frequency of this mutation in breast and ovarian cancer cases unselected for family history of cancer, and determined if mutation carriers shared a common ancestry.
The frequency was estimated by assaying the mutation in series of French Canadian breast cancer cases diagnosed before age 41 (n = 60) or 80 (n = 127) years of age, and ovarian cancer cases (n = 80) unselected for family history of cancer by mutation analysis. Haplotype analysis was performed to determine if mutation carriers shared a common ancestry. Members from 11 families were analyzed using six polymorphic microsatellite markers (cen-D13S260-D13S1699-D13S1698-D13S1697-D13S1701-D13S171-tel) spanning approximately a 3.6 cM interval at the chromosomal region 13q13.1, which contains BRCA2. Allele frequencies were estimated by genotyping 47 unaffected female individuals derived from the same population. Haplotype reconstruction of unaffected individuals was performed using the program PHASE.
The recurrent BRCA2 mutation occurred in 1 of 60 (1.7%) women diagnosed with breast cancer before 41 years of age and one of 80 (1.3%) women with ovarian cancer. No mutation carriers were identified in the series of breast cancer cases diagnosed before age 80. Mutation carriers harboured one of two haplotypes, 7-3-9-3 - [3/4]-7, that varied with marker D13S1701 and which occurred at a frequency of 0.001. The genetic analysis of D13S1695, a polymorphic marker located approximately 0.3 cM distal to D13S171, did not favour a genetic recombination event to account for the differences in D13S1701 alleles within the haplotype. Although mutation carriers harbour genotypes that are frequent in the French Canadian population, neither mutation-associated haplotype was plausible in reconstructed haplotypes of 47 individuals of French Canadian descent.
These results suggest that mutation carriers share a related ancestry; further supporting the concept that recurrent BRCA1 and BRCA2 mutations in the French Canadian population could be attributed to common founders. This finding provides further support for targeted screening of recurrent mutations in this population before large-scale mutation analyses are performed.
最近发现，BRCA2基因中的3398delAAAAG突变在魁北克法裔加拿大人群的乳腺癌和/或卵巢癌家族中反复出现，该人群具有与奠基者效应一致的遗传特征。为了描述该突变在这一人群中的作用，本研究确定了该突变在未选择癌症家族史的乳腺癌和卵巢癌病例中的频率，并确定突变携带者是否有共同的祖先。
通过对41岁之前（n = 60）或80岁之前（n = 127）诊断的法裔加拿大乳腺癌病例系列以及未选择癌症家族史的卵巢癌病例（n = 80）进行突变分析，来估计该突变的频率。进行单倍型分析以确定突变携带者是否有共同的祖先。使用六个多态性微卫星标记（cen-D13S260-D13S1699-D13S1698-D13S1697-D13S1701-D13S171-tel）对11个家族的成员进行分析，这些标记跨越染色体区域13q13.1中大约3.6 cM的区间，该区域包含BRCA2基因。通过对来自同一人群的47名未受影响的女性个体进行基因分型来估计等位基因频率。使用PHASE程序对未受影响个体进行单倍型重建。
在41岁之前诊断为乳腺癌的60名女性中有1名（1.7%）以及80名卵巢癌女性中有1名（1.3%）出现了反复出现的BRCA2突变。在80岁之前诊断的乳腺癌病例系列中未发现突变携带者。突变携带者具有两种单倍型之一，即7-3-9-3 - [3/4]-7，该单倍型随标记D13S1701而变化，出现频率为0.001。对位于D13S171远端约0.3 cM处的多态性标记D13S1695进行的遗传分析不支持基因重组事件来解释单倍型内D13S1701等位基因的差异。尽管突变携带者的基因型在法裔加拿大人群中很常见，但在47名法裔加拿大血统个体的重建单倍型中，与突变相关的单倍型都不太合理。
这些结果表明突变携带者有相关的祖先；进一步支持了法裔加拿大人群中BRCA1和BRCA2反复出现的突变可能归因于共同奠基者的概念。这一发现为在进行大规模突变分析之前对该人群中的反复出现突变进行靶向筛查提供了进一步的支持。
