Susceptibility to breast cancer can be genetically determined by the occurrence of mutations in BRCA1, BRCA2 or other genes. The trait is transmitted by autosomal dominant inheritance. As typical of autosomal dominantly inherited conditions, one single mutation segregates in most families. However, in the past years, several families (although a real minority of all cases) with more than one disease-causing mutation in BRCA genes have been described. In particular, families with one BRCA1 and one BRCA2 mutation or two BRCA1 mutations have been described. Mutations can segregate singularly in different family members, but can also be present in one patient as double heterozygous mutations. Heidemann S et al, 2012 (PMID: 22535016) stated that females carrying one BRCA1 and one BRCA2 mutation can show earlier onset of breast cancer and have more severe disease than single heterozygous BRCA mutation carriers. By contrast, Lavie O et al, 2012 (PMID: 20924075), who found a prevalence of 1,85% of double heterozygotes for one BRCA1 and one BRCA2 disease-causing mutation in a large cohort of Jewish individuals, stated that, besides a slightly younger age at onset, those patients are not actually suffering from a more severe disease than those ones with just one single mutation. Of note, Lavie et al highlighted that, in their cohort, no patients with two mutations in BRCA1 were identified, speculating that such an occurrence might not even be compatible with life. Indeed, Stoppa-Lyonnet et al, 1996 (PMID: 8755940) had previously identified a family with two BRCA1 mutation, but, also in this case, no family members carrying both mutations at once were identified. Very interestingly, Stoppa-Lyonnet et al observed how linkage studies may fail if a second pathogenic allele is not suspected in a family. An additional report of double heterozygous patients is provided by Leegte et al 2012 (PMID: 15744030): also in this case the authors concluded that double heterozygosity does not seem to correlate with a more sever phenotype (they observed that clinical spectrum of BRCA double heterozygosity is ranging from unilateral breast cancer at age 26 to cancer-free survival at age 70). Cortesi L et al 2003 (PMID: 12673274) reported a family with one BRCA1 and one BRCA2 mutation. However, in this family, no patients with double heterozygosity are reported: all affected patients were bearing either the mutation in BRCA1 or the mutation in BRCA2. Also in the family of Ahkenazy Jewish ancestry reported by Liede A et al patients were carrying one single mutation, although three different pathogenic alleles (two in BRCA1 and one in BRCA2) were segregating in the family. Of important note, if it’s true that no homozygous mutations in BRCA1 have been reported to date (and they are hypothesized to be not even compatible with life), homozygous or compound heterozygous mutations in BRCA2 can actually cause Fanconi anemia. Interestingly, a 13 year old boy affected with medulloblastoma was identified to carry a homozygous missense BRCA2 mutation. The father of this patient was heterozygous for the mutation (Bayrakli F et al 2011, PMID: 22044372).
Summarizing, in regard to the possible occurrence of multiple BRCA1/BRCA2 mutations, evidence provided by the current literature seems to indicate the following occurrences as possible:
- segregation of one BRCA1 and one BRCA2 mutations in one family. It is possible that family members are bearing one of the two mutations or both (double heterozygosity). It is still controversial whether double heterozygosity might influence the severity of the phenotype, even if instances of earlier onset have been reported.
- segregation of two BRCA1 mutations in one family. In this case all patients are bearing just one of the two mutations, as compound heterozygosis or homozygosis for two BRCA1 mutations is thought to be not even compatible with life
- homozygosity for BRCA2 mutations: homozygosity or compound heterozygosity for BRCA2 mutation is actually causing Fanconi anemia. An adolescent with medulloblastoma and a homozygous BRCA1 missense mutation was reported.
- segregation of three BRCA genes mutations: one family was reported with two BRCA1 and one BRCA2 mutations. The mutations were segregating separately in different family members.
Summarizing, in regard to the possible occurrence of multiple BRCA1/BRCA2 mutations, evidence provided by the current literature seems to indicate the following occurrences as possible:
- segregation of one BRCA1 and one BRCA2 mutations in one family. It is possible that family members are bearing one of the two mutations or both (double heterozygosity). It is still controversial whether double heterozygosity might influence the severity of the phenotype, even if instances of earlier onset have been reported.
- segregation of two BRCA1 mutations in one family. In this case all patients are bearing just one of the two mutations, as compound heterozygosis or homozygosis for two BRCA1 mutations is thought to be not even compatible with life
- homozygosity for BRCA2 mutations: homozygosity or compound heterozygosity for BRCA2 mutation is actually causing Fanconi anemia. An adolescent with medulloblastoma and a homozygous BRCA1 missense mutation was reported.
- segregation of three BRCA genes mutations: one family was reported with two BRCA1 and one BRCA2 mutations. The mutations were segregating separately in different family members.
References: see text.
