Mechanism for survival of homozygous nonsense mutations in the tumor suppressor gene BRCA1

Abstract

is essential for repair of DNA double-strand breaks by homologous recombination, and hence for survival. Complete loss of its function is lethal during early embryonic development. Patients who are compound heterozygous for truncating mutations and missense alleles that retain some DNA repair capacity may survive, albeit with very high risk of early onset breast or ovarian cancer and features of Fanconi anemia. However, a mechanism enabling survival of patients homozygous for truncating mutations has not been described. We studied two unrelated families in which four children presented with multiple congenital anomalies and severe chromosomal fragility. One child developed T cell acute lymphocytic leukemia (ALL), and a second child developed neuroblastoma. Each of the four children was homozygous for a nonsense mutation in exon 11. Homozygosity for the nonsense mutations was viable thanks to the presence of a naturally occurring alternative splice donor in exon 11 that lies 5' of the mutations. The mutations did not affect the alternative splice site, but transcription from it produced an in-frame message with deletion of 3,309 bp. The translated BRCA1 protein was only 40% of normal length, but with intact N- and C-terminal sequences. These patients extend the range of-related phenotypes and illustrate how naturally occurring alternative splicing can enable survival, albeit with severe consequences, of otherwise lethal genotypes of an essential gene.

Biallelic germline BRCA1 mutations in a patient with early onset breast cancer, mild Fanconi anemia‐like phenotype, and no chromosome fragility

“…In concert with published findings (Domchek et al, ; Freire et al, ; Sawyer et al, ; Seo et al, ), our data suggest that the phenotypic variability of biallelic BRCA1 mutations ranges from embryonic lethality to short body height, microcephaly, early onset BC and toxicity from chemotherapy, whereas residual BRCA1 protein function determines the disease severity. For FA patients homozygously carrying nonsense mutations in exon 11 of the BRCA1 (Freire et al, ; Seo et al, ), it has been demonstrated that a naturally occurring alternative splicing isoform can enable survival, albeit with severe consequences (Seo et al, ). The index patient described by Sawyer et al carried a protein‐truncating BRCA1 mutation, p.Ser198Argfs*35, along with the p.Arg1699Trp high‐risk variant which was shown to elevate the BC risk to 58% by the age of 70 years (Spurdle et al, ).…”

“…Freire et al described a 2.5‐year‐old girl of consanguineous offspring with severe short stature, microcephaly, neurodevelopmental delay, congenital heart disease and dysmorphic features, and the girl was a homozygous carrier of a BRCA1 nonsense mutation in exon 11 (p.Cys903*) (Freire et al, ). In 2018, Seo et al reported multiple congenital anomalies and severe chromosomal fragility in children of consanguineous offspring, all homozygously carrying BRCA1 nonsense mutations affecting exon 11 (p.Trp372*, p.Leu431*)(Seo et al, ). Of note, mitomycin C‐ or diepoxybutane (DEB)‐induced chromosome fragility assays performed by Seo et al are routinely used to confirm clinical FA diagnosis (Castella et al, ).…”

Helicase-inactivating BRIP1 mutation yields Fanconi anemia with microcephaly and other congenital abnormalities

“…However, patients with biallelic mutations in certain other Fanconi anemia genes have cumulative risks of 20% for leukemia and 30% for solid tumors by age 40 (Alter 2014). Biallelic mutations in BRCA2/FANCD1 or BRCA1/FANCS are generally embryonic lethal; surviving patients have very high cancer risks and BRCA2/FANCD1 patients have extremely elevated rates of spontaneous and induced chromosome breakage (Gowen et al 1996;Hakem et al 1996;Ludwig et al 1997;Hirsch et al 2004;Alter et al 2007;Myers et al 2012;Domchek et al 2013;Shaheen et al 2014;Sawyer et al 2015;Loizidou et al 2016;Seo et al 2018, Weinberg-Shukron et al 2018. It is likely that the patients in our study who are homozygous for BRIP1 p.R848H will also be at increased risk for these malignancies and will benefit from ongoing surveillance.…”

Genetic Predisposition to Breast and Ovarian Cancers: How Many and Which Genes to Test?

“…BRCA1 and BRCA2 genes (formerly FANCS and FANCD1, respectively) are also included in this group, even if the involvement of BRCA1 in FA has been debated [103] because its biallelic PV/LPVs have been suggested to be lethal during embryonic development [104,105]. However, there are multiple reports of FA patients with BRCA1 biallelic PV/LPVs, probably due to the retention of a partial activity by the protein [106][107][108][109][110]. Proteins encoded by the FA genes act as tumor suppressors, creating a complex that is activated in case of DNA damage and recruits other proteins involved in DNA repair via HR [111].…”