Coinheritance ofBRCA1 andBRCA2 mutations with Fanconi anemia and Bloom syndrome mutations in Ashkenazi Jewish population: Possible role in risk modification for cancer development

Abstract

Fanconi anemia (FA) and Bloom syndrome (BS) are rare autosomal recessive genetic disorders manifesting in childhood, with a predisposition to cancer development in adolescence and adulthood. Both syndromes are relatively prevalent among the Ashkenazi Jewish population, and, in both syndromes, mutations specific to this population have been identified. Similarly, unique Ashkenazi mutations were found in the genes BRCA1 and BRCA2. These two genes, when mutated, play important roles in familial breast and ovarian carcinogenesis. The genes involved in the pathogenesis of the FA and BS belong to the general class of instability genes. Heterozygosity for the FA gene has no known promalignant potential, while the BS mutation carrier state was associated with an increased frequency of colorectal cancer. The especially frequent carrier state among the Ashkenazi Jewish population coupled with the high prevalence of BRCA1 and BRCA2 in the same population has led us to search for coinheritance affecting the potential for cancer development. One hundred Ashkenazi women with known BRCA1 and BRCA2 mutations were screened for the FA mutation IVS4+4 AfiT and the BS mutation blm Ash . Our results indicate that there is an increased prevalence of both FA and BS mutation carriers among the population studied compared with the general Ashkenazi population (prevalence of FA mutation 4/100 women [4%] as compared to 35/3104 previously published controls [1.1%], P = 0.031, and for BS mutation 3/100 [3.2%] as compared to 36/4001 [0.9%], P = 0.058). There was no statistically significant effect of the coinheritance on cancer prevalence, type of cancer, or age of cancer onset. Coinheritance of FA and/or BS mutations seems to be more prevalent among BRCA mutation carriers, but a larger study encompassing more women may help in clarifying this issue. Am.

High prevalence and breast cancer predisposing role of the BLM c.1642 C>T (Q548X) mutation in Russia

“…As LOH test was performed on microdissected tumor sample, failure to detect allelic loss cannot be explained by the presence of the normal cells in the analyzed material. Combined heterozygosity involving BRCA1 germline inactivation has been repeatedly described for BRCA2, CHEK2, NBS1 and BLM mutation carriers 9, 38–40. Surprisingly, subjects with combined cancer‐predisposing alleles do not have evident multiplication of cancer risk and often remain healthy in their mid‐life 9, 39, 40…”

“…Combined heterozygosity involving BRCA1 germline inactivation has been repeatedly described for BRCA2, CHEK2, NBS1 and BLM mutation carriers 9, 38–40. Surprisingly, subjects with combined cancer‐predisposing alleles do not have evident multiplication of cancer risk and often remain healthy in their mid‐life 9, 39, 40…”

Prevalence of the BLM nonsense mutation, p.Q548X, in ovarian cancer patients from Central and Eastern Europe

“…This is a common BRCA1 mutation in ovarian cancer patients from Belarus [3], so the co-inheritance may be a chance finding. But the observation is in line with results from breast cancer studies that BLM truncations can coincide with BRCA1 mutations [7,9,15,17]. The BLM mutation was further investigated for LOH in one serous ovarian (Table 3).…”

“…Former studies included the analyses of BRCA1 and BRCA2 founder mutations as well as specific mutations in other breast cancer susceptibility genes such as CHEK2, ATM, NBN and PALB2. Identified carriers were not excluded in the present BLM mutational screening since evidence indicated that digenic heterozygosity may play a role in some breast cancer patients [9,15]. All persons gave their informed consent prior to their inclusion in the study, and the study has been approved by the appropriate ethics committees at the participating institutions.…”

Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease

“…An inherited predisposition to cancer can be monogenic, but is also very likely to have an oligogenic aetiology in many instances (Fearnhead et al 2004; Koren-Michowitz et al 2005; Okkels et al 2006; Küry et al 2008; Wasielewski et al 2010; Martinez and Kolodner 2010; Plon et al 2011; Morak et al 2011; Gracia-Aznarez et al 2013). In amyotrophic lateral sclerosis, van Blitterswijk et al (2012a) detected FUS and TARDBP mutations in combination with ANG mutations, and C9orf72 repeat expansions with TARDBP , SOD1 and FUS mutations.…”