Elevated Levels of Somatic Mutation in a Manifesting BRCA1 Mutation Carrier

Stephen G GRANT3, Rubina DAS1, Christina M CERCEO1, Wendy S RUBINSTEIN4, Jean J LATIMER2

1Department of Environmental and Occupational Health, Graduate School of Public Health, Pittsburgh, USA
2Department of Obstetrics, Gynecology and Reproductive Sciences, School of Medicine, University of Pittsburgh, Pittsburgh, USA
3Center for Environmental Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, USA
4Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, USA
5Evanston Northwestern Healthcare Center for Medical Genetics, Evanston, USA


Homozygous loss of activity at the breast cancerpredisposing 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 allele-loss mutation frequency of 19.4 x 10-6 at the autosomal GPA locus in erythrocytes and 17.1 x 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. Pathology & Oncology Research, Vol 13, Nr 4, 276-283, 2007

Key words: somatic mutation; hypoxanthine-guanine phosphoribosyl transferase; glycophorin A; BRCA1 gene; inherited breast cancer syndrome; Fanconi anemia; xeroderma pigmentosum

Received: Feb 23, 2007; accepted: Sep 21, 2007
Correspondence: Stephen G GRANT, Center for Environmental Oncology, University of Pittsburgh Cancer Institute, 5150 Centre Avenue Pittsburgh 15232, USA; Tel: (412) 623-1180, Fax: (412) 623-3201; E-mail:

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