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Cancer Lett. 2017 Oct 1;405:38-45. doi: 10.1016/j.canlet.2017.06.028. Epub 2017 Jul 4.

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

Author information

1
Department of Health Sciences, University of Piemonte Orientale, Novara, Italy.
2
Department of Medical Sciences, University of Turin, Turin, Italy; Human Genetics Foundation, HuGeF, Turin, Italy.
3
CPO-Piemonte and Unit of Medical Statistics and Epidemiology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.
4
Department of Health Sciences, Section of Pathological Anatomy, University of Piemonte Orientale, Novara, Italy.
5
Department of Oncology, University of Turin at San Luigi Hospital, Orbassano, Turin, Italy.
6
Division of Medical Oncology, SS. Antonio e Biagio General Hospital, Alessandria, Italy.
7
Pathology Unit, SS. Antonio e Biagio General Hospital, Alessandria, Italy.
8
Pathological Anatomy Unit, Santo Spirito Hospital, Casale Monferrato, Italy.
9
Pathological Anatomy Unit, SS. Antonio e Biagio General Hospital, Alessandria, Italy.
10
Thoracic Surgery Unit, AOU Maggiore Della Carità, Novara, Italy.
11
Unit of Cancer Epidemiology, CPO-Piemonte and University of Turin, Turin, Italy; Interdepartmental Center for Studies on Asbestos and Other Toxic Particulates "G. Scansetti", University of Turin, Turin, Italy.
12
Department of Medical Sciences, University of Turin, Turin, Italy; Medical Genetics Unit, AOU Città Della Salute e Della Scienza, Turin, Italy.
13
CPO-Piemonte and Unit of Medical Statistics and Epidemiology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy; Interdepartmental Center for Studies on Asbestos and Other Toxic Particulates "G. Scansetti", University of Turin, Turin, Italy. Electronic address: corrado.magnani@med.uniupo.it.
14
Department of Health Sciences, University of Piemonte Orientale, Novara, Italy; Interdepartmental Center for Studies on Asbestos and Other Toxic Particulates "G. Scansetti", University of Turin, Turin, Italy.

Abstract

Malignant pleural mesothelioma (MPM) is a rare, aggressive cancer caused by asbestos exposure. An inherited predisposition has been suggested to explain multiple cases in the same family and the observation that not all individuals highly exposed to asbestos develop the tumor. Germline mutations in BAP1 are responsible for a rare cancer predisposition syndrome that includes predisposition to mesothelioma. We hypothesized that other genes involved in hereditary cancer syndromes could be responsible for the inherited mesothelioma predisposition. We investigated the prevalence of germline variants in 94 cancer-predisposing genes in 93 MPM patients with a quantified asbestos exposure. Ten pathogenic truncating variants (PTVs) were identified in PALB2, BRCA1, FANCI, ATM, SLX4, BRCA2, FANCC, FANCF, PMS1 and XPC. All these genes are involved in DNA repair pathways, mostly in homologous recombination repair. Patients carrying PTVs represented 9.7% of the panel and showed lower asbestos exposure than did all the other patients (p = 0.0015). This suggests that they did not efficiently repair the DNA damage induced by asbestos and leading to carcinogenesis. This study shows that germline variants in several genes may increase MPM susceptibility in the presence of asbestos exposure and may be important for specific treatment.

KEYWORDS:

Asbestos exposure; DNA repair genes; Germline mutation; Homologous recombination repair; Mesothelioma

PMID:
28687356
DOI:
10.1016/j.canlet.2017.06.028
[Indexed for MEDLINE]
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