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Elevated levels of somatic mutation in a manifesting BRCA1 mutation carrier

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Pathology & Oncology Research

Abstract

Homozygous loss of activity at the breast cancer-predisposing genesBRCA1 andBRCA2 (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 aBRCA1 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 inBRCA1 whose tumor was uniquely ascertained through an MRI screening study. The patient had an allele-loss mutation frequency of 19.4 × 10−6 at the autosomalGPA locus in erythrocytes and 17.1×10−6 at the X-linkedHPRT locus in lymphocytes. Both of these mutation frequencies are significantly higher than expected from age-matched disease-free controls (P<0.05). Mutation at theHPRT locus was similarly elevated in lymphoblastoid cell lines established from three otherBRCA1 mutation carriers with breast cancer. Our patient’sGPA mutation frequency is below the level established for diagnosis of homozygous Fanconi anemia patients, but consistent with data from obligate heterozygotes. The increasedHPRT 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, thisBRCA1-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.

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Abbreviations

AT:

ataxia telangiectasia

FA:

Fanconi anemia

GPA:

glycophorin A

HNPCC:

hereditary non-polyposis colorectal cancer

HPRT:

hypoxanthine-guanine phosphoribosyltransferase

M f :

mutation frequency

MRI:

magnetic resonance imaging

NER:

nucleotide excision repair

XP:

xeroderma pigmentosum

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Authors and Affiliations

  1. Department of Environmental and Occupational Health, Graduate School of Public Health, USA

    Stephen G. Grant, Rubina Das & Christina M. Cerceo

  2. Department of Obstetrics, Gynecology and Reproductive Sciences, School of Medicine, University of Pittsburgh, USA

    Stephen G. Grant & Jean J. Latimer

  3. Center for Environmental Oncology, University of Pittsburgh Cancer Institute, 5150 Centre Avenue, 15232, Pittsburgh, PA, USA

    Stephen G. Grant & Jean J. Latimer

  4. Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL

    Wendy S. Rubinstein

  5. Evanston Northwestern Healthcare Center for Medical Genetics, Evanston, IL, USA

    Wendy S. Rubinstein

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  1. Stephen G. Grant
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  2. Rubina Das
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  3. Christina M. Cerceo
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  4. Wendy S. Rubinstein
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  5. Jean J. Latimer
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Correspondence to Stephen G. Grant.

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This work was supported by the following grants and institutions: NIH grant CA 71894, US Army BRCP grants BC991187, BC996714 and BC9963444, Susan G. Komen Foundation grant BCTR0403339, the Ruth Estrin Goldberg Foundation and the Pennsylvania Department of Health.

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Grant, S.G., Das, R., Cerceo, C.M. et al. Elevated levels of somatic mutation in a manifesting BRCA1 mutation carrier. Pathol. Oncol. Res. 13, 276–283 (2007). https://doi.org/10.1007/BF02940305

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  • DOI: https://doi.org/10.1007/BF02940305

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