Evidence for increased in vivo mutation and somatic recombination in Bloom's syndrome.

Abstract

The glycophorin A assay was used to estimate the frequency of mutations that accumulate in vivo in somatic cells of persons with Bloom's syndrome (BS). This assay measures the frequency in persons of blood type MN of variant erythrocytes that lack the expression of one allelic form of glycophorin A, presumably due to mutational or recombinational events in erythroid precursor cells. Samples of blood from persons with BS showed dramatic 50-to 100-fold increases in the frequency of variants of three types, those with a hemizygous phenotype, those with a homozygous phenotype, and those with what appears to be partial loss of the expression of one locus. The high frequency of homozygous variants, genetic evidence for altered allelic segregation of a specific biochemical locus, provides evidence for increased somatic crossing-over in vivo in BS. An increased generation of functional hemizygosity and homozygosity in their somatic cells may play an important role in the extreme cancer risk of persons with BS.Bloom's syndrome (BS) (1) is a rare autosomal recessive genetic disorder of growth that greatly increases the affected individual's chance of developing cancer. In the 130 affected individuals in the Bloom's Syndrome Registry, 57 malignant neoplasms have been detected, at a mean age at diagnosis of 24.7 years (2). A wide spectrum of tumor types has been observed in affected individuals, including lymphoid and myeloid leukemias, lymphomas, squamous cell carcinomas, and adenocarcinomas (3).In addition, a distinctive array of cytological abnormalities in a variety of cell types, signifying a remarkable degree of genomic instability, is a constant feature of BS (4, 5). These include high spontaneous frequencies of chromosome breaks and rearrangements (5-8), sister-chromatid exchanges (SCEs) (5, 9-11), micronucleated cells (12, 13), and cells with specific-locus mutations (14-17). A unique cellular abnormality in untreated BS cells in vitro is a dramatic increase over normal in the frequency of a certain type of quadriradial configuration (Qr) in metaphase cells (5,18). The Qrs of BS are the microscopically visible consequence of interchanges that, earlier in the cell cycle, occurred between homologous chromosomes at apparently homologous sites; they are interpreted as cytological evidence for an increased frequency of somatic crossing-over in BS (18)(19)(20)(21). Heterozygous carriers of the BS mutation (bl/+) are clinically and cytologically normal (22). Although the primary genetic defect responsible for BS may not have been defined, DNA ligase I activity has been reported to be decreased (23)(24)(25), and this very possibly is responsible for the genomic instability of BS. The complex cytogenetic abnormalities readily demonstrable in BS cells in vitro raise the possibility that somatic cell mutation (point mutation, chromosome segmental rearrangement, and somatic recombination) is also substantially increased in vivo in BS, and this could explain the extreme cancer risk.In the present study we have used the ...

Benzene induces gene-duplicating but not gene-inactivating mutations at the glycophorin A locus in exposed humans.

“…An excess of both N0 and NN variants was found in patients with Bloom syndrome (with NN variants higher than N0) (37) and Fanconi anemia (39). An increase in only N0 variants was found among Chernobyl clean-up workers exposed to ionizing radiation (33); a greater increase was detected in N0 than in NN variants in germ-cell tumor patients receiving platinum-based chemotherapy (35); and, an increase was found for both variants among childhood Hodgkin disease patients receiving combination chemotherapy (36).…”

“…Elevated frequencies at the GPA locus have been found in subjects exposed to ionizing radiation (31)(32)(33), in patients receiving anti-neoplastic drugs (34)(35)(36), and in people with cancer-prone syndromes (37)(38)(39)). An excess of both N0 and NN variants was found in patients with Bloom syndrome (with NN variants higher than N0) (37) and Fanconi anemia (39).…”

Lessons learned from the study of immigrants to Israel from areas of Russia, Belarus, and Ukraine contaminated by the Chernobyl accident.

“…Increases in the frequency of variants have been found after exposure to mutagenic drugs as well as in cancer-susceptible patients with ataxia telangectasia (32,33) and Bloom's syndrome (34). The GPA somatic mutation assay therefore has been suggested to be useful for assessing cancer risk (30,35).…”

Somatic Mutations at the Glycophorin A (GPA) Locus Measured in Red Cells of Chernobyl Liquidators Who Immigrated to Israel

“…Increases in the frequency of variants have been found after exposure to mutagenic drugs (23) as well as in cancer-susceptible patients with ataxia telangiectasia (24) and Bloom's syndrome (25,26). It has been suggested, therefore, that the GPA somatic mutation assay has value for the assessment of cancer risk (20,27 Kyoizumi et al (20) reported a slightly greater frequency of GPA N0 cells in males than in females (by -10%) in unexposed survivors in Hiroshima and Nagasaki, but no effect of sex on dose response was observed.…”