Frequency of HPRT mutant lymphocytes in a human control population as determined by the T-cell cloning procedure

Hüttner, Edith; Holzapfel, B.; Kropf, Siegfried

doi:10.1016/0165-7992(95)00050-x

Cited by 11 publications

(1 citation statement)

References 24 publications

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“…Several subsets of these data have been published. [22][23][24] Normal HPRT M f for comparison are derived from a number of published reports [25][26][27][28][29][30][31] as well as our own contemporaneous data. GPA M f from homozygous and heterozygous FA patients were taken from the report of Sala-Trepat et al 32 and our own ongoing analyses 33,34 of clinical samples and samples provided from the International Fanconi Anemia Registry (IFAR).…”

Section: Controlsmentioning

confidence: 99%

Elevated levels of somatic mutation in a manifesting BRCA1 mutation carrier

Grant

Das²,

Cerceo³

et al. 2007

Pathol. Oncol. Res.

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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.

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