Germline mutations in DNA repair genes predispose asbestos-exposed patients to malignant pleural mesothelioma

Betti, Marta; Casalone, Elisabetta; Ferrante, Daniela; Aspesi, Anna; Morleo, Giulia; Biasi, Alessandra; Sculco, Marika; Mancuso, Giuseppe; Guarrera, Simonetta; Righi, Luisella; Grosso, Federica; Libener, Roberta; Pavesi, M; Mariani, Narciso; Casadio, Caterina; Boldorini, Renzo; Mirabelli, Dario; Pasini, Barbara; Magnani, Corrado; Matullo, Giuseppe; Dianzani, Irma

doi:10.1016/j.canlet.2017.06.028

Cited by 83 publications

(89 citation statements)

References 40 publications

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“…Among them, 43 of 79 patients had deleterious germline BAP1 mutations: their median age at diagnosis was 54 years, and the median survival was 5 years . Among the remaining 36 patients with no BAP1 mutation, the median age at diagnosis was 45 years, the median survival was 9 years, and 12 of 36 patients (33%) had deleterious mutations of other tumor suppressors, such as MLH1 (Lynch syndrome), TP53 (Li‐Fraumeni syndrome), and/or mutations in genes that regulate DNA repair or that were previously found mutated in mesothelioma . Thus, on one hand, germline mutations favor the development of mesothelioma and of other cancers, but, conversely, for reasons that currently are unclear, these same mutations appear to mitigate aggressive tumor growth as these patients live much longer.…”

Section: Staging and Prognosismentioning

confidence: 99%

“…Moreover, a proportion of these germline mutations may be actionable, and patients can be enrolled in targeted clinical trials. Therefore, patients who present with clinical indicators denoting heritability (familial history of mesothelioma or other cancers at a young age [≤50 years]) should undergo genetic testing by targeted NGS using a gene panel covering all DNA repair and tumor suppressor genes to test for cancer inheritability . Ideally, all patients with mesothelioma should undergo genetic testing together with genetic counseling.…”

Section: Staging and Prognosismentioning

confidence: 99%

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Mesothelioma: Scientific clues for prevention, diagnosis, and therapy

Carbone

Adusumilli

Alexander

et al. 2019

CA A Cancer J Clinicians

341

488

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Mesothelioma affects mostly older individuals who have been occupationally exposed to asbestos. The global mesothelioma incidence and mortality rates are unknown, because data are not available from developing countries that continue to use large amounts of asbestos. The incidence rate of mesothelioma has decreased in Australia, the United States, and Western Europe, where the use of asbestos was banned or strictly regulated in the 1970s and 1980s, demonstrating the value of these preventive measures. However, in these same countries, the overall number of deaths from mesothelioma has not decreased as the size of the population and the percentage of old people have increased. Moreover, hotspots of mesothelioma may occur when carcinogenic fibers that are present in the environment are disturbed as rural areas are being developed. Novel immunohistochemical and molecular markers have improved the accuracy of diagnosis; however, about 14% (high-resource countries) to 50% (developing countries) of mesothelioma diagnoses are incorrect, resulting in inadequate treatment and complicating epidemiological studies. The discovery that germline BRCA1-asssociated protein 1 (BAP1) mutations cause mesothelioma and other cancers (BAP1 cancer syndrome) elucidated some of the key pathogenic mechanisms, and treatments targeting these molecular mechanisms and/or modulating the immune response are being tested. The role of surgery in pleural mesothelioma is controversial as it is difficult to predict who will benefit from aggressive management, even when local therapies are added to existing or novel systemic treatments. Treatment outcomes are improving, however, for peritoneal mesothelioma. Multidisciplinary international collaboration will be necessary to improve prevention, early detection, and treatment. CA Cancer J Clin 2019;69:402-429.

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Section: Staging and Prognosismentioning

confidence: 99%

Section: Staging and Prognosismentioning

confidence: 99%

Mesothelioma: Scientific clues for prevention, diagnosis, and therapy

Carbone

Adusumilli

Alexander

et al. 2019

CA A Cancer J Clinicians

341

488

View full text Add to dashboard Cite

show abstract

“…Inherited mutations in all genes except POT1 and MLH1 have been reported in patients with mesothelioma (15,31). Patient MNH153, diagnosed with peritoneal mesothelioma at age 54, carried a nonsense mutation in POT1 (SI Appendix, Table S1).…”

Section: Resultsmentioning

confidence: 99%

“…In this analysis, survival of patients with germline mutations in tumor suppressor genes was compared with survival of patients with no detectable damaging germline mutation. However, loss of function of BAP1 due to purely somatic events is well established for mesothelioma (31). Loss of function of BAP1, or of other tumor suppressor genes, due to purely somatic events is likely to have the same effect on response to therapy and on survival as loss of function due to germline plus somatic mutation.…”

Section: Discussionmentioning

confidence: 99%

Inherited predisposition to malignant mesothelioma and overall survival following platinum chemotherapy

Hassan

Morrow

Thomas

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

113

126

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Survival from malignant mesothelioma, particularly pleural mesothelioma, is very poor. For patients with breast, ovarian, or prostate cancers, overall survival is associated with increased sensitivity to platinum chemotherapy due to loss-of-function mutations in DNA repair genes. The goal of this project was to evaluate, in patients with malignant mesothelioma, the relationship between inherited loss-of-function mutations in DNA repair and other tumor suppressor genes and overall survival following platinum chemotherapy. Patients with histologically confirmed malignant mesothelioma were evaluated for inherited mutations in tumor suppressor genes. Survival was evaluated with respect to genotype and site of mesothelioma. Among 385 patients treated with platinum chemotherapy, median overall survival was significantly longer for patients with loss-of-function mutations in any of the targeted genes compared with patients with no such mutation (P = 0.0006). The effect of genotype was highly significant for patients with pleural mesothelioma (median survival 7.9 y versus 2.4 y, P = 0.0012), but not for patients with peritoneal mesothelioma (median survival 8.2 y versus 5.4 y, P = 0.47). Effect of patient genotype on overall survival, measured at 3 y, remained independently significant after adjusting for gender and age at diagnosis, two other known prognostic factors. Patients with pleural mesothelioma with inherited mutations in DNA repair and other tumor suppressor genes appear to particularly benefit from platinum chemotherapy compared with patients without inherited mutations. These patients may also benefit from other DNA repair targeted therapies such as poly-ADP ribose polymerase (PARP) inhibitors.

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“…Many studies have identified molecular pathways and mutations important in MPM, including BAP1; yet, there remains a paucity of biomarkers that are currently in the clinical setting . Susceptibility and prognostic markers may allow personalized screening, detection, and treatment approaches, which have been a challenge for MPM that is typically diagnosed in its later stage.…”

Section: Discussionmentioning

confidence: 99%

Association of two BRM promoter polymorphisms and smoking status with malignant pleural mesothelioma risk and prognosis

Lee

Kuehne

Hueniken

et al. 2019

Molecular Carcinogenesis

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Brahma (BRM), of the SWI/SNF complex, has two 6 to 7 bp insertion promoter polymorphisms (BRM‐741/BRM‐1321) that cause epigenetic BRM suppression, and are associated with risk of multiple cancers. BRM polymorphisms were genotyped in malignant pleural mesothelioma (MPM) cases and asbestos‐exposed controls. Multivariable logistic regression (risk) and Cox regression (prognosis) were performed, including stratified analyses by smoking status to investigate the effect of polymorphisms on MPM risk and prognosis. Although there was no significant association overall between BRM‐741/BRM‐1321 and risk in patients with MPM, a differential effect by smoking status was observed (P‐interaction < .001), where homozygous variants were protective (aOR of 0.18‐0.28) in ever smokers, while never smokers had increased risk when carrying homozygous variants (aOR of 2.7‐4.4). While there was no association between BRM polymorphisms and OS in ever‐smokers, the aHR of carrying homozygous‐variants of BRM‐741, BRM‐1321 or both were 4.0 to 8.6 in never‐smokers when compared to wild‐type carriers. Mechanistically, lower mRNA expression of BRM was associated with poorer general cancer prognosis. Electrophoretic mobility shift assays and chromatin immunoprecipitation experiments (ChIP) revealed high BRM insertion variant homology to MEF2 regulatory binding sites. ChIP experimentation confirmed MEF2 binding only occurs in the presence of insertion variants. DNA‐affinity purification assays revealed YWHA scaffold proteins as vital to BRM mRNA expression. Never‐smokers who carry BRM homozygous variants have an increased chance of developing MPM, which results in worse prognosis. In contrast, in ever‐smokers, there may be a protective effect, with no difference in overall survival. Mechanisms for the interaction between BRM and smoking require further study.

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Germline mutations in DNA repair genes predispose asbestos-exposed patients to malignant pleural mesothelioma

Cited by 83 publications

References 40 publications

Mesothelioma: Scientific clues for prevention, diagnosis, and therapy

Mesothelioma: Scientific clues for prevention, diagnosis, and therapy

Inherited predisposition to malignant mesothelioma and overall survival following platinum chemotherapy

Association of two BRM promoter polymorphisms and smoking status with malignant pleural mesothelioma risk and prognosis

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