Mutation frequency in human blood cells increases with age

Akiyama, Mitoshi; Kyoizumi, Seishi; Hirai, Yuko; Kusunoki, Yoichiro; Iwamoto, Keisuke S.; Nakamura, Nori

doi:10.1016/0921-8734(95)00019-3

Cited by 77 publications

(43 citation statements)

References 27 publications

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“…We have argued that the distribution of mutations in stem cells is complex, being skewed and those from early life being overrepresented; 12,38 so it seems unlikely that the simple relationship we have demonstrated here arises from stem cells. In contrast, mutations from more differentiated cells appear to be approximately constant throughout life, 12,38 implying the event causing APL is restricted to cells committed to differentiation, a conclusion for which there is other experimental evidence. [34][35][36][37] Presumably, the mutation rate for the PML/RAR␣ translocation is so low that its occurrence is negligible in cells as infrequent and slowly dividing as stem cells.…”

Section: Discussionmentioning

confidence: 95%

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The incidence of acute promyelocytic leukemia appears constant over most of a human lifespan, implying only one rate limiting mutation

Vickers¹,

Jackson

Taylor

2000

Leukemia

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It is believed that most malignancies become more common with increasing age due to the requirement for several mutations to accumulate and subsequently interact. The age specific incidence of acute promyelocytic leukemia (APL) was investigated using population-based data from 77 million subject years of observation, yielding 149 consecutive cases. The incidence appears approximately constant with respect to age, an observation not previously reported with any other malignancy. These findings are most easily explained by there being only one rate limiting genetic event required to initiate the disease, although other, non-rate limiting mutations may also be necessary for disease development. It is also argued that this mutation is probably restricted to cells committed to differentiation, which may explain why APL is curable by chemotherapy. Leukemia (2000) 14, 722-726.

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Section: Discussionmentioning

confidence: 95%

“…11 Finally, the accumulation of bone marrow mutations in humans can be accounted for by the underlying kinetics of cell division, with a linear increase with age and little evidence for any variation in the underlying mutation rate. 12 We therefore consider the assumption of a constant mutation rate to be reasonable, although not proven.…”

Section: Introductionmentioning

confidence: 99%

The incidence of acute promyelocytic leukemia appears constant over most of a human lifespan, implying only one rate limiting mutation

Vickers¹,

Jackson

Taylor

2000

Leukemia

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“…On the hypothesis that RAG expression might be more likely in cells with absent or decreased expression of TCR from the cell surface, as we observed in B cells, we decided to isolate the TCR variant cells with a CD4 ϩ CD3 low phenotype that arise spontaneously in the periphery. These variant cells exist in detectable numbers (average, 2.4 ϫ 10 Ϫ4 ) among in vivo mature T cell populations and were reported to increase significantly with age (22,23).…”

Section: Cd3 Low Mature T Cellsmentioning

confidence: 99%

Cutting Edge: Recombinase-Activating Gene Expression and V(D)J Recombination in CD4+CD3low Mature T Lymphocytes

Lantelme

Palermo

Granziero

et al. 2000

The Journal of Immunology

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The recombinase-activating genes, RAG-1 and RAG-2, can be expressed by a subset of B cells within germinal centers, where they mediate secondary V(D)J rearrangements. This receptor revision mechanism could serve either receptor diversification or tolerance-induced functions. Alternatively, it might rescue those cells the receptors of which have been damaged by somatic mutation. Less is known about the occurrence of similar mechanisms in T cells. Here we show that mature T cells with defective TCR surface expression can express RAG genes and are capable of initiating secondary V(D)J rearrangements. The possibility that a cell rescue mechanism based on the generation of a novel Ag receptor might be active in peripheral T cells is envisaged.

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“…Background GPA Mf (estimate for 0 Gy exposure) was lower in Nagasaki than in Hiroshima and lower in females than in males. An increase in GPA Mf with age of the subject at examination was only marginally significant, probably because age-dependent increase in GPA Mf reaches a plateau after about 50 years of age (21). There was an initial increase in the GPA response with bone marrow dose, followed by an attenuation in the slope (negative quadratic term).…”

Section: Resultsmentioning

confidence: 83%

Individual Variation of Somatic Gene Mutability in Relation to Cancer Susceptibility: Prospective Study on Erythrocyte Glycophorin A Gene Mutations of Atomic Bomb Survivors

Kyoizumi¹,

Kusunoki²,

Hayashi³

et al. 2005

Cancer Research

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It has previously been reported that hemizygous mutant fraction (Mf) at the glycophorin A (GPA) locus in erythrocytes increased with radiation dose in heterozygotes among Hiroshima and Nagasaki atomic bomb survivors. In the present study, we analyzed the relationship between GPA Mf and cancer risk using newly developed cancers among previously cancer-free subjects whose GPA Mf had been measured between 1988 and 1996. Among 1,723 survivors (1,117 in Hiroshima and 606 in Nagasaki), we identified 186 subjects who developed a first cancer by the end of 2000. We compared the radiation dose responses of GPA Mf between cancer and cancer-free groups using a linear-quadratic model fit by multiple regression analysis in combination with age, sex, and city. The slope of the GPA Mf dose-response curve was significantly higher in the cancer group than in the cancerfree group among Hiroshima subjects. Moreover, no significant difference of GPA Mf between cancer and cancer-free groups was found in unexposed controls in the two cities. The same conclusions were obtained using a linear dose-response model and by further analysis using Cox regression of cancer incidence. These findings suggest that there might be interindividual variation in mutability of somatic genes and that Hiroshima survivors who have higher mutability in response to radiation exposure would be expected to have a higher probability of suffering radiation-related cancer. (Cancer Res 2005; 65(12): 5462-9)

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Mutation frequency in human blood cells increases with age

Cited by 77 publications

References 27 publications

The incidence of acute promyelocytic leukemia appears constant over most of a human lifespan, implying only one rate limiting mutation

The incidence of acute promyelocytic leukemia appears constant over most of a human lifespan, implying only one rate limiting mutation

Cutting Edge: Recombinase-Activating Gene Expression and V(D)J Recombination in CD4+CD3low Mature T Lymphocytes

Individual Variation of Somatic Gene Mutability in Relation to Cancer Susceptibility: Prospective Study on Erythrocyte Glycophorin A Gene Mutations of Atomic Bomb Survivors

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