Consensus report of the 8 and 9th Weinman Symposia on Gene x Environment Interaction in carcinogenesis: novel opportunities for precision medicine

Carbone, Michele; Amelio, Ivano; Affar, El Bachir; Brugarolas, James; Cannon-Albright, Lisa; Cantley, Lewis C.; Cavenee, Webster K.; Chen, Zhijian; Croce, Carlo M.; andrea, A. D.; Gandara, David R.; Giorgi, Carlotta; Jia, Weiping; Lan, Qing; Mak, Tak W.; Manley, James L.; Mikoshiba, Katsuhiko; Onuchic, José N.; Pass, Harvey I.; Pinton, Paolo; Prives, Carol; Rothman, Nathaniel; Sebti, Saı̈d M.; Turkson, James; Wu, Xifeng; Yang, Haining; Yu, Herbert; Melino, Gerry

doi:10.1038/s41418-018-0213-5

Cited by 31 publications

(19 citation statements)

References 213 publications

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“…Various studies identified genetic factors that confer susceptibility to MM, highlighting the need for genetic testing in some patients and their relatives, which could result in earlier diagnosis or provide the opportunity for possible selective treatments. It is estimated that at least 12% of MMs develop in carriers of genetic mutations: beyond BAP1 , which is found inactivated by both germline and somatic mutations in MM, other tumor suppressor genes, such as TP53 and BRCA2 , or genes that regulate DNA repair, bear germline mutations in MMs 5 , 6 .…”

Section: Introductionmentioning

confidence: 99%

P53-regulated miR-320a targets PDL1 and is downregulated in malignant mesothelioma

et al. 2020

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Malignant pleural mesothelioma (MPM) is an aggressive cancer, related to asbestos exposure, which has a dismal prognosis. MPM diagnosis is late and often challenging, suggesting the need to identify more reliable molecular biomarkers. Here, we set out to identify differentially expressed miRNAs in epithelioid, biphasic, and sarcomatoid MPMs versus normal mesothelium and explored specific miRNA contribution to mesothelial tumorigenesis. We screened an LNA™-based miRNA-microrray with 14 formalin-fixed paraffin-embedded (FFPE) MPMs and 6 normal controls. Through real-time qRT-PCR we extended the analysis of a miRNA subset and further investigated miR-320a role through state-of-the-art techniques. We identified 16 upregulated and 32 downregulated miRNAs in MPMs versus normal tissue, including the previously identified potential biomarkers miR-21, miR-126, miR-143, miR-145. We showed in an extended series that miR-145, miR-10b, and miR-320a levels can discriminate tumor versus controls with high specificity and sensitivity. We focused on miR-320a because other family members were found downregulated in MPMs. However, stable miR-320a ectopic expression induced higher proliferation and migration ability, whereas miR-320a silencing reduced these processes, not supporting a classic tumor-suppressor role in MPM cell lines. Among putative targets, we found that miR-320a binds the 3′-UTR of the immune inhibitory receptor ligand PDL1 and, consistently, miR-320a modulation affects PDL1 levels in MPM cells. Finally, we showed that p53 over-expression induces the upregulation of miR-320a, along with miR-200a and miR-34a, both known to target PDL1, and reduces PDL1 levels in MPM cells. Our data suggest that PDL1 expression might be due to a defective p53-regulated miRNA response, which could contribute to MPM immune evasion or tumorigenesis through tumor-intrinsic roles.

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Section: Introductionmentioning

confidence: 99%

P53-regulated miR-320a targets PDL1 and is downregulated in malignant mesothelioma

et al. 2020

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Section: Carcinogenic Mechanismsmentioning

confidence: 99%

“…In addition to “spontaneous” and “induced” somatic mutations, a growing percentage of cancers are attributed to inherited mutations of DNA repair genes and of other genes that, when mutated, accelerate the accumulation of DNA damage and/or the percentage of cells carrying DNA damage . Inherited mutations may also increase susceptibility to environmental carcinogens (GxE interaction) . Thus, the previous hypothesis, which focused almost exclusively on identifying human carcinogens to understand why cancer developed in some individuals, is now being integrated with studies aimed at including GxE interactions, which may better account for the observation that many are exposed but only few get cancer and that some cancers occur in unexposed individuals …”

Section: Carcinogenic Mechanismsmentioning

confidence: 99%

“…Inherited mutations may also increase susceptibility to environmental carcinogens (GxE interaction) . Thus, the previous hypothesis, which focused almost exclusively on identifying human carcinogens to understand why cancer developed in some individuals, is now being integrated with studies aimed at including GxE interactions, which may better account for the observation that many are exposed but only few get cancer and that some cancers occur in unexposed individuals …”

Section: Carcinogenic Mechanismsmentioning

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

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377

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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“…A variety of factors, such as environmental or occupational exposure to tobacco and biological infection by Schistosoma haematobium, were proved to be associated with the onset of bladder cancer [4,5]. Some hereditary genetic alterations that are involved in carcinogen bioactivation and detoxification may possibly make an individual more susceptible to extrinsic carcinogens [6,7]. Moreover, the accumulation of genetic changes and epigenetic alterations may contribute to the initiation and progression of human cancers, including bladder cancer [8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Development of a novel prognostic signature for predicting the overall survival of bladder cancer patients

Tang

Kan

et al. 2020

Bioscience Reports

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Background: Bladder cancer is one of the most common malignancies. So far, no effective biomarker for bladder cancer prognosis has been identified. Aberrant DNA methylation is frequently observed in the bladder cancer and holds considerable promise as a biomarker for predicting the overall survival (OS) of patients. Materials and methods: We downloaded the DNA methylation and transcriptome data for bladder cancer from The Cancer Genome Atlas (TCGA), a public database, screened hypo-methylated and up-regulated genes, similarly, hyper-methylation with low expression genes, then retrieved the relevant methylation sites. Cox regression analysis was used to identify a nine-methylation site signature of a training group. Predictive ability was validated in a test group by receiver operating characteristic (ROC) analysis. Results: We identified nine bladder cancer-specific methylation sites as potential prognostic biomarkers and established a risk score system based on the methylation site signature to evaluate the OS. The performance of the signature was accurate, with area under curve was 0.73 in the training group and 0.71 in the test group. Taking clinical features into consideration, we constructed a nomogram consisting of the nine-methylation site signature and patients’ clinical variables, and found that the signature was an independent risk factor. Conclusions: Overall, the significant nine methylation sites could be novel prediction biomarkers, which could aid in treatment and also predict the overall survival likelihoods of bladder cancer patients.

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Consensus report of the 8 and 9th Weinman Symposia on Gene x Environment Interaction in carcinogenesis: novel opportunities for precision medicine

Cited by 31 publications

References 213 publications

P53-regulated miR-320a targets PDL1 and is downregulated in malignant mesothelioma

P53-regulated miR-320a targets PDL1 and is downregulated in malignant mesothelioma

Mesothelioma: Scientific clues for prevention, diagnosis, and therapy

Development of a novel prognostic signature for predicting the overall survival of bladder cancer patients

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