Ausencia de la mutación BRCA1 del (exones 9-12) en familias con cáncer de seno / ovario fuera de hispanos mexicanos

3 páginasThe frequency and spectrum of germ line mutations in the high-penetrance breast cancer susceptibility genes BRCA1 and BRCA2 shows considerable variation by ethnic group. Most genetic epidemiological studies of the BRCA genes have been performed among Caucasian populations [1], with the exception of a few studies involving other ethnic groups, such as Hispanics [2–4], Asians [5, 6], and African Americans [7–9]. In most of these studies only the frequencies of sequence detectable BRCA mutations were reported and large genomic rearrangements including deletions and insertions of one or more exons, which account for 6–15% of all deleterious mutations in these genes have infrequently been considered [10–12]. Most BRCA mutations are unique; however, few recurrent mutations with founder effects have been found in European, Hispanic, American and Asian populations [13]. In a recent study on Hispanic high-risk breast/ovarian cancer families of mainly Mexican descent from South California, Weitzel and colleagues reported the identification of a novel deletion of BRCA1 exons 9 through 12 using multiplex quantitative differential polymerase chain reaction (PCR) analysis. The deletion was detected in 3.8% of families negative for sequence detectable BRCA mutations [14]. The large genomic rearrangement mutation is considered deleterious as it results in loss of critical functional domains as well as premature truncation of the BRCA1 protein. Given the relatively high prevalence of the deletion in this cohort, the authors suggest to include the screening for this mutation in the genetic testing strategy in Hispanic women without sequence detectable BRCA mutations

Common variants of the <i>BRCA1</i> wild-type allele modify the risk of breast cancer in <i>BRCA1</i> mutation carriers

Mutations in the &lt;i&gt;BRCA1&lt;/i&gt; gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The &lt;i&gt;BRCA1&lt;/i&gt; protein plays a central role in DNA repair, a mechanism that is particularly instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of &lt;i&gt;BRCA1&lt;/i&gt; carried on the wild-type (non-mutated) copy of the &lt;i&gt;BRCA1&lt;/i&gt; gene would modify the risk of breast cancer in carriers of &lt;i&gt;BRCA1&lt;/i&gt; mutations. A total of 9874 &lt;i&gt;BRCA1&lt;/i&gt; mutation carriers were available in the Consortium of Investigators of Modifiers of &lt;i&gt;BRCA1/2&lt;/i&gt; (CIMBA) for haplotype analyses of &lt;i&gt;BRCA1&lt;/i&gt;. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of &lt;i&gt;BRCA1&lt;/i&gt; were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence interval 0.77–0.95, &lt;i&gt;P&lt;/i&gt; = 0.003). Promoter &lt;i&gt;in vitro&lt;/i&gt; assays of the major &lt;i&gt;BRCA1&lt;/i&gt; haplotypes showed that common polymorphisms in the regulatory region alter its activity and that this effect may be attributed to the differential binding affinity of nuclear proteins. In conclusion, variants on the wild-type copy of &lt;i&gt;BRCA1&lt;/i&gt; modify risk of breast cancer among carriers of &lt;i&gt;BRCA1&lt;/i&gt; mutations, possibly by altering the efficiency of &lt;i&gt;BRCA1&lt;/i&gt; transcription