This paper discussed a study done in Israel on women of Ashkenazi-Jewish decent. It has been previously proven that women of Ashkenazi-Jewish decent are more likely to have a certain mutation in the BRCA 1 and/or the BRCA 2 genes. It has also been previously proven that somatic mutations inactivating the p53 gene often accompany tumors associated with BRCA 1/2 mutations. The researchers therefore decided to study whether particular SNP’s (Single Nucleotide Polymorphisms) in the p53 are associated with a higher risk of breast cancer in the Ashkenazi-Jewish women who are carriers of the BRCA1/2 gene. Based on the incomplete penetrance of the BRCA1 and BRCA 2 genes the age range in disease onset the researchers believe there is a possibility that other non-BRCA1/2 genes are affecting the level and age of penetrance.

As we have already learned in class the BRCA1/2 genes are tumor suppressors and when mutated are associated with a increased risk of developing breast and ovarian cancers. The BRCA1/2 genes are also associated with a younger development of breast and ovarian cancer. p53 is also a known tumor suppressor and mutations of the p53 gene are often found in BRCA1/2 tumors. The p53/BRCA pathways are involved in genomic stability maintenance and the two pathways converge at DNA damage response or replicative stress response points. The researchers involved in this study decided to look at four genes in the p53/BRCA pathway to see whether SNP’s in those genes caused elevated risk of developing cancer. The four genes chosen were: AKT1, CHEK2, PERP, and ZNF350/ZBKR1. AKT1 and CHEK 2 act upstream of p53 and BRCA1/2 while PERP and ZNF350/ZBKR1 act downstream. These genes were chosen based on their importance to the p53/BRCA1/2 pathway.

All participants in the study were of Ashkenazi-Jewish decent. 269 BRCA1/2 carriers were studied, of the 269 148 women developed breast/ovarian cancer and 121 women were unaffected. There were 210 women who participated in the study who had sporadic cases of cancer and were proven not to carry the BRCA1/2 genes. Lastly there was a control group consisting of 138 women who were not carriers of BRCA1/2 and who did not have cancer.

To obtain the DNA for the screen the researchers used mass spectrometry and PCR to extract the genomic DNA of interest. After the lab work was completed they found no significant difference in genotype distribution of the four SNP’s between symptomatic BRCA1/2 carriers and asymptomatic BRCA1/2 carriers. There was a significant correlation found between the AKT1 TT genotype and early onset of cancer in BRCA1/2 carriers, and no correlation was found between different genotypes and disease onset in the sporadic cancer cases. An allele in the CHEK2 SNP was significantly more present in BRCA 1 carriers’ diagnosed with cancer before the age of 51 whereas in the BRCA 2 carriers and the women with sporadic cancer there was no correlation. The ZBRK1/ZNF gene also showed significant evidence for early onset of cancer. However no association was found between the PERP SNP and cancer risk for either BRCA1 or BRCA 2 carriers. None of the genes conferred higher risks in the sporadic cancer cases indicating a possibility that they interact with the p53/BRCA1/2 pathway to cause an elevated risk of cancer development only in BRCA1/2 carriers.

This paper found inconclusive evidence as to how other genes/SNP’s can act upon the known BRCA1/2 and p53 mutations to possibly increase the chances of Ashkenazi-Jewish BRCA1/2 carriers developing breast and/or ovarian cancer. I think that this research is a step in the right direction to find out what other genes affect the BRCA1/2 mutations, however I believe many more studies like this need to be done in order to fully understand the incomplete penetrance and age range of disease development in Ashkenazi-Jewish carries of the BRCA1/2 gene.