Dataset Information

Examination of Genetic Susceptibility in Radiation-Associated Meningioma.

ABSTRACT: Previous epidemiological studies have demonstrated elevated susceptibility to ionizing radiation in some families, thus suggesting the presence of genetic components that conferred increased rate of radiation-associated meningioma (RAM). In this study, we exome-sequenced and investigated the segregation pattern of rare deleterious variants in 11 RAM pedigrees. In addition, we performed a rare-variant association analysis in 92 unrelated familial cases of RAM that were ancestry-matched with 88 meningioma-free controls. In the pedigree analysis, we found that each family carried mostly a unique set of rare deleterious variants. A follow-up pathway analysis of the union of the genes that segregated within each of the 11 pedigrees identified a single statistically significant (q value = 7.90E-04) "ECM receptor interaction" set. In the case-control association analysis, we observed no statistically significant variants or genes after multiple testing correction; however, examination of ontological categories of the genes that associated with RAM at nominal P values <0.01 identified biologically relevant pathways such as DNA repair, cell cycle and apoptosis. These results suggest that it is unlikely that a small number of highly penetrant genes are involved in the pathogenesis of RAM. Substantially larger studies are needed to identify genetic risk variants and genes in RAM.

SUBMITTER: Pemov A

PROVIDER: S-EPMC9326809 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Examination of Genetic Susceptibility in Radiation-Associated Meningioma.

Pemov A A Kim J J Jones K K Vogt A A Sadetzki S S Stewart D R DR

Radiation research 20220701 1

Previous epidemiological studies have demonstrated elevated susceptibility to ionizing radiation in some families, thus suggesting the presence of genetic components that conferred increased rate of radiation-associated meningioma (RAM). In this study, we exome-sequenced and investigated the segregation pattern of rare deleterious variants in 11 RAM pedigrees. In addition, we performed a rare-variant association analysis in 92 unrelated familial cases of RAM that were ancestry-matched with 88 me ...[more]

PMID: 35405740

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Project description:PurposeWhile adjuvant radiation therapy (RT) may prolong progression-free survival in resected atypical meningiomas, whether such progression-free survival benefit outweighs potential treatment toxicities remains controversial. Here, we compare the acute and late toxicity outcomes of atypical meningiomas managed with upfront adjuvant RT versus surveillance.Methods and materialsIn our prior single-institution retrospective study of 230 patients with resected atypical meningiomas between 2000 and 2015, adjuvant RT was associated with a significantly lower risk of progression/recurrence compared with surveillance (hazard ratio, 0.21; P < .01), with 36% of surveillance patients eventually requiring salvage RT. In this study, the acute (≤6 months) and late (>6 months) RT toxicities from the same patient cohort for those who received adjuvant (n = 51) versus salvage RT (n = 64) were compared. Additionally, treatment toxicity at the last follow-up was compared between the adjuvant RT (n = 51) and the surveillance (n = 179) groups. Toxicities were graded per the Common Terminology Criteria for Adverse Events v5.0.ResultsRT in the adjuvant compared with the salvage setting was generally associated with greater RT toxicities both in the acute (90% vs 69%, P < .01) and late (57% vs 33%, P = .01) setting. While there was no significant difference in grade 3 to 4 acute toxicities, late grade 3 to 4 toxicities were present in 14% of the adjuvant group versus 3% of the salvage RT group (P = .04). Radionecrosis was present in 18% of adjuvant RT versus 8% of salvage RT group (P = .11). Between the adjuvant RT and surveillance groups, any treatment-related toxicity at the last follow-up was greater in the adjuvant RT group (31% vs 15%, P < .01), with a trend toward greater grade 3 to 4 toxicities (8% vs 3%, P = .10). There was no difference in the rate of cerebrovascular accident (4% vs 4%, P = .99).ConclusionsAdjuvant RT may be associated with greater acute and late treatment toxicities, which can significantly impact the quality of life of patients with atypical meningioma. Potential RT toxicity should be carefully weighed against tumor control benefits in deciding the optimal use and timing of RT.

Project description:High dose ionizing radiation (IR) is a well-known risk factor for breast cancer but the health effects after low-dose (LD, <10 cGy) exposures remain highly uncertain. We explored a systems approach that compared LD-induced chromosome damage and transcriptional responses in strains of mice with genetic differences in their sensitivity to radiation-induced mammary cancer (BALB/c and C57BL/6) for the purpose of identifying mechanisms of mammary cancer susceptibility. Unirradiated mammary and blood tissues of these strains differed significantly in baseline expressions of DNA repair, tumor suppressor, and stress response genes. LD exposures of 7.5 cGy (weekly for 4 weeks) did not induce detectable genomic instability in either strain. However, the mammary glands of the sensitive strain but not the resistant strain showed early transcriptional responses involving: (a) diminished immune response, (b) increased cellular stress, (c) altered TGFβ-signaling, and (d) inappropriate expression of developmental genes. One month after LD exposure, the two strains showed opposing responses in transcriptional signatures linked to proliferation, senescence, and microenvironment functions. We also discovered a pre-exposure expression signature in both blood and mammary tissues that is predictive for poor survival among human cancer patients (p = 0.0001), and a post-LD-exposure signature also predictive for poor patient survival (p<0.0001). There is concordant direction of expression in the LD-exposed sensitive mouse strain, in biomarkers of human DCIS and in biomarkers of human breast tumors. Our findings support the hypothesis that genetic mechanisms that determine susceptibility to LD radiation induced mammary cancer in mice are similar to the tissue mechanisms that determine poor-survival in breast cancer patients. We observed non-linearity of the LD responses providing molecular evidence against the LNT risk model and obtained new evidence that LD responses are strongly influenced by genotype. Our findings suggest that the biological assumptions concerning the mechanisms by which LD radiation is translated into breast cancer risk should be reexamined and suggest a new strategy to identify genetic features that predispose or protect individuals from LD-induced breast cancer.

Dataset Information

Examination of Genetic Susceptibility in Radiation-Associated Meningioma.

Publications

Examination of Genetic Susceptibility in Radiation-Associated Meningioma.

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