Elevated levels of somatic mutation in a manifesting BRCA1 mutation carrier

Abstract

Homozygous loss of activity at the breast cancer-predisposing genes BRCA1 and BRCA2 (FANCD1) confers increased susceptibility to DNA double strand breaks, but this genotype occurs only in the tumor itself, following loss of heterozygosity at one of these loci. Thus, if these genes play a role in tumor etiology as opposed to tumor progression, they must manifest a heterozygous phenotype at the cellular level. To investigate the potential consequences of somatic heterozygosity for a BRCA1 mutation demonstrably associated with breast carcinogenesis on background somatic mutational burden, we applied the two standard assays of in vivo human somatic mutation to blood samples from a manifesting carrier of the Q1200X mutation in BRCA1 whose tumor was uniquely ascertained through an MRI screening study. The patient had an alleleloss mutation frequency of 19.4 × 10 −6 at the autosomal GPA locus in erythrocytes and 17.1 × 10 −6 at the X-linked HPRT locus in lymphocytes. Both of these mutation frequencies are significantly higher than expected from age-matched disease-free controls (P < 0.05). Mutation at the HPRT locus was similarly elevated in lymphoblastoid cell lines established from three other BRCA1 mutation carriers with breast cancer. Our patient's GPA mutation frequency is below the level established for diagnosis of homozygous Fanconi anemia patients, but consistent with data from obligate heterozygotes. The increased HPRT mutation frequency is more reminiscent of data from patients with xeroderma pigmentosum, a disease characterized by UV sensitivity and deficiency in the nucleotide excision pathway of DNA repair. Therefore, this BRCA1-associated breast cancer patient manifests a unique phenotype of increased background mutagenesis that likely contributed to the development of her disease independent of loss of heterozygosity at the susceptibility locus.

A selective eradication of human nonhereditary breast cancer cells by phenanthridine-derived polyADP-ribose polymerase inhibitors

“…Because of their genomic instability and fast proliferation, malignant cells might be more susceptible to inhibition of PARP mediated DNA repair than are normal proliferating cells [13,14]. However, eradication of MCF-7 and MDA231 cells was not shared by other non- phenanthridine-derived PARP inhibitors, and the examined cell lines MCF-7 and MDA231 were neither BRCA- deficient cells [21] nor PTEN (phosphatase and tensin homologue)-deficient cells [22], in which DNA-repair mechanisms are impaired [15,23]. …”

“…Several groups of PARP inhibitors (including phenanthridine derivatives) were designed to protect cells under stress conditions from cell death induced by a massive activation of PARP-1 (for example, stroke, inflammation; [10,12]), or to cause cell death in malignant cells by preventing polyADP-ribosylation-dependent DNA repair [9,11]. In accordance with this concept, PARP inhibitors were tested for their therapeutic potential in malignant cells with impaired DNA-repair machinery [13,14] (bearing mutations in the tumor-suppressor genes BRCA1 and BRCA2 that cause an impaired DNA repair [15]) or in combination with DNA-damaging treatments [11]. However, in view of findings indicating that activated PARP-1 highly augments the activity of ERK in the nucleus even in the absence of DNA damage [3,4], a different therapeutic potential of PARP inhibitors is examined in breast cancer cells lacking BRCA mutations.…”

Down-regulation of CD3zeta is a breast cancer biomarker associated with immune suppression

“…Breast cancer pathogenesis involves multiple factors including genetic, environmental, dietetic and immunologic (Hill et al, 2004;Grant et al, 2007;Llanes-Fernandez et al, 2009). Deficient DNA repair contributes to accumulation of DNA damage resulting in breast carcinogenesis and LOH (loss of heterozygosity), combined with allele silencing of tumour suppressor genes, may play a role in the progression of breast cancer (Driouch et al, 1997;Ahomadegbe et al, 2000).…”

Erythropoietin-driven signalling and cell migration mediated by polyADP-ribosylation

“…Clinical trials introducing PARP inhibitors for the treatment of tumours bearing mutations in the tumour-suppressor genes BRCA1 and BRCA2 are currently underway (Bryant et al , 2005; Farmer et al , 2005; Grant et al , 2007; Javle and Curtin, 2011; Rios and Puhalla, 2011). …”