Novel LRRK2 mutations and other rare, non-BAP1-related candidate tumor predisposition gene variants in high-risk cancer families with mesothelioma and other tumors

Our plain-English summary of Novel LRRK2 mutations and other rare, non-BAP1-related candidate tumor predisposition gene variants in high-risk cancer families with mesothelioma and other tumors, by M. Cheung, Y. Kadariya, E. Sementino, et al (Human Molecular Genetics, 2021).

The study

• Authors: M. Cheung, Y. Kadariya, E. Sementino, M.J. Hall, I. Cozzi, V. Ascoli, J.A. Ohar, J.R. Testa
• Journal: Human Molecular Genetics
• Published: 2021;30(18):1750-1761
• Cited by: 16 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

There is irrefutable evidence that germline BRCA1-associated protein 1 gene (BAP1) mutations contribute to malignant mesothelioma (MM) susceptibility. However, BAP1 mutations are not found in all cases with evidence of familial MM or in other high-risk cancer families affected by various cancers, including MM. The goal of this study was to use whole genome sequencing (WGS) to determine the frequency and types of germline gene variants occurring in 12 MM patients who were selected from a series of 141 asbestos-exposed MM patients with a family history of cancer but without a germline BAP1 mutation. WGS was also performed on two MM cases, a proband and sibling, from a previously reported family with multiple cases of MM without the inheritance of a predisposing BAP1 mutation. Altogether, germline DNA sequencing variants were identified in 21 cancer-related genes in 10 of the 13 probands. Germline indel, splice site and missense mutations and two large deletions were identified. Among the 13 MM index cases, 6 (46%) exhibited one or more predicted pathogenic mutations. Affected genes encode proteins involved in DNA repair (ATM, ATR, BRCA2, BRIP1, CHEK2, MLH3, MUTYH, POLE, POLE4, POLQ and XRCC1), chromatin modification (ARID1B, DNMT3A, JARID2 and SETD1B) or other cellular pathways: leucine-rich repeat kinase 2 gene (LRRK2) (two cases) and MSH4. Notably, somatic truncating mutation or deletions of LRRK2 were occasionally found in MMs in The Cancer Genome Atlas, and the expression of LRRK2 was undetectable or downregulated in a majority of primary MMs and MM cell lines we examined, implying that loss of LRRK2 expression is a newly recognized tumor suppressor alteration in MM.

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In plain English

This study used whole genome sequencing to look for inherited (germline) gene variants in people with malignant mesothelioma who did not carry a germline BAP1 mutation. The authors sequenced 12 U.S. or Canadian patients, chosen from 141 asbestos-exposed mesothelioma patients with a family history of cancer. They also sequenced two members of an Italian family with several pleural mesothelioma cases and domestic crocidolite exposure. Of 13 index cases, 10 had germline variants in cancer-related genes, and 6 had one or more variants predicted to be harmful. Three had no candidate variants. In the Italian family, a new LRRK2 splice-site deletion was found in three relatives with mesothelioma but not in one relative without it. One tumor had lost the normal copy of the gene. LRRK2 protein was undetectable or substantially reduced in 10 of 16 mesothelioma cell lines and 7 of 12 primary tumors. The authors concluded that their data suggest loss of LRRK2 expression is a newly recognized tumor suppressor alteration in mesothelioma. They noted that samples from relatives of most patients were lacking. Because of this, they could not confirm whether most candidate genes played a part in other tumors in those families.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Genetic study: whole genome sequencing of germline DNA from mesothelioma patients in high-risk cancer families without germline BAP1 mutations, with follow-up Sanger sequencing, a search of The Cancer Genome Atlas (TCGA) data, and protein (immunoblot) testing of LRRK2 in tumors and cell lines
• Who was studied: 12 U.S. or Canadian mesothelioma patients selected from a series of 141 asbestos-exposed mesothelioma patients with a family history of cancer and no germline BAP1 mutation. Also 3 members with mesothelioma from one Italian family with multiple pleural mesothelioma cases: 2 by whole genome sequencing and 1 by Sanger sequencing. In that family, 8 confirmed pleural mesotheliomas occurred in one generation between 1987 and 2012.
• Exposure: The study examined inherited gene variants rather than asbestos doses. All participants had asbestos exposure, and the Italian family had documented domestic exposure to crocidolite asbestos.
• Main results:
  • Among the 13 probands, 10 had germline variants in cancer-related genes, and 6 of these had one or more predicted pathogenic mutations.
  • Three genes were mutated in more than one proband: CHEK2, LRRK2 and POLQ.
  • In three of the families, no candidate gene variants were found in the proband's germline DNA. In four others, only missense variants not predicted to be pathogenic were found.
  • In the Italian family, a germline LRRK2 splice-site deletion was found in family member III-5 and in tumor DNA from III-2. A macrodissected tumor from III-1 carried the mutation in a homozygous or hemizygous state, indicating loss of heterozygosity. The mutation was not present in III-3, who did not have mesothelioma.
  • In the Italian family, a germline BRCA2 mutation was found in only 2 of the 4 members with mesothelioma who were tested. The authors said it is unclear whether this mutation contributes to mesothelioma susceptibility in the family.
  • In TCGA data on 82 pleural mesothelioma patients, no germline mutations were found in the candidate genes. Somatic alterations in BRIP1, LRRK2 and RHBDF2 occurred in 3-6% of cases.
  • LRRK2 protein was undetectable or substantially downregulated in 10 of 16 (62.5%) mesothelioma cell lines and 7 of 12 (58%) primary mesothelioma tumors, compared with immortalized LP9 mesothelial cells.
• The authors' conclusion: The authors concluded that their data suggest LRRK2 is a candidate mesothelioma susceptibility gene, and that loss of LRRK2 expression is a newly recognized common tumor suppressor alteration in mesothelioma. They also stated that other genes besides BAP1 are likely associated with mesothelioma susceptibility.
• Limitations the authors state:
  • Blood or tumor samples from relatives were lacking for most probands. As a result, the authors could not confirm whether most candidate genes were involved in other tumors in the probands' families.
  • It is not known how germline DNMT3A mutations might predispose to mesothelioma.
  • It is unknown what product, if any, the LRRK2 mutation found in the Italian family would produce.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: BAP1, Mesothelioma, Malignant Mesothelioma, BAP1 Tumor Predisposition Syndrome.

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• Malignant Peripheral Nerve Sheath Tumor in a Patient With BAP1 Tumor Predisposition Syndrome — M.C. Kaszuba, J.S. Pulido, et al. (2018)
• Intrahepatic cholangiocarcinoma development in a patient with a novel BAP1 germline mutation and low exposure to asbestos — G. Brandi, M. Deserti, et al. (2020)
• An asbestos-exposed family with multiple cases of pleural malignant mesothelioma without inheritance of a predisposing BAP1 mutation — M. Cheung, Y. Kadariya, et al. (2015)

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