Whole exome and targeted deep sequencing identify genome-wide allelic loss and frequent SETDB1 mutations in malignant pleural mesotheliomas

Our plain-English summary of Whole exome and targeted deep sequencing identify genome-wide allelic loss and frequent SETDB1 mutations in malignant pleural mesotheliomas, by H.C. Kang, H.K. Kim, S. Lee, et al (Oncotarget, 2016).

The study

• Authors: H.C. Kang, H.K. Kim, S. Lee, P. Mendez, J.W. Kim, G. Woodard, J.H. Yoon, K.Y. Jen, L.T. Fang, K. Jones, D.M. Jablons, I.J. Kim
• Journal: Oncotarget
• Published: 2016;7(7):8321-31
• Type of article: Case report
• Cited by: 42 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM), a rare malignancy with a poor prognosis, is mainly caused by exposure to asbestos or other organic fibers, but the underlying genetic mechanism is not fully understood. Genetic alterations and causes for multiple primary cancer development including MPM are unknown. We used whole exome sequencing to identify somatic mutations in a patient with MPM and two additional primary cancers who had no evidence of venous, arterial, lymphovascular, or perineural invasion indicating dissemination of a primary lung cancer to the pleura. We found that the MPM had R282W, a key TP53 mutation, and genome-wide allelic loss or loss of heterozygosity, a distinct genomic alteration not previously described in MPM. We identified frequent inactivating SETDB1 mutations in this patient and in 68 additional MPM patients (mutation frequency: 10%, 7/69) by targeted deep sequencing. Our observations suggest the possibility of a new genetic mechanism in the development of either MPM or multiple primary cancers. The frequent SETDB1 inactivating mutations suggest there could be new diagnostic or therapeutic options for MPM.

In plain English

This laboratory genetics study started with one patient: a 62-year-old Caucasian woman with sarcomatoid pleural mesothelioma, a lung adenocarcinoma, and bladder cancer treated eight years earlier. She was a former smoker and had worked for a construction company in her forties. The article describes her asbestos exposure as possible but uncertain. The authors sequenced the genes of her mesothelioma. They found a TP53 mutation (R282W) and genome-wide allelic loss, also called loss of heterozygosity, across most chromosomes, a pattern they said had not, to their knowledge, been described in mesothelioma. They then sequenced the SETDB1 gene in 78 mesothelioma tissue samples from 69 patients. They reported seven mutations, a frequency of 10% (7/69), although the text also says the mutations came from six patients. The mutations were not significantly linked with survival (p=0.351), probably because few patients had them, the authors wrote. The authors concluded that SETDB1 and other histone-related genes may be important in pleural mesothelioma, and that functional studies are needed. The study did not measure asbestos exposure.

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: Case report of one patient with multiple primary cancers, studied by whole exome sequencing, followed by targeted deep sequencing of one gene (SETDB1) in a series of pleural mesothelioma tissue samples
• Who was studied: One 62-year-old Caucasian woman with malignant pleural mesothelioma, lung adenocarcinoma and earlier bladder cancer, plus 78 primary malignant pleural mesothelioma tissues from 69 patients in total, collected under a University of California, San Francisco protocol. Dates of collection are not given.
• Exposure: Asbestos exposure was not measured. The single case patient had worked for a construction company in her forties with possible but uncertain asbestos exposure, and was a former smoker with a 30 pack-year history. No fiber type is named. No exposure information is given in the article text for the other 68 patients.
• Main results:
  • In the case patient's pleural mesothelioma, a TP53 mutation, R282W, was found.
  • The case patient's mesothelioma showed genome-wide allelic loss, or loss of heterozygosity, affecting most variants on all chromosomes except chromosomes 7 and 20. The authors wrote that the high mutant-allele levels suggested either a homozygous alteration or deletion of the wild-type allele.
  • A focus of atypical adenomatous hyperplasia from the same patient showed no evidence of the genome-wide allelic loss seen in the mesothelioma.
  • In the case patient's mesothelioma, a nonsense mutation (Y249X) of the SETDB1 gene was found.
  • Across the 69 mesothelioma patients, seven somatic SETDB1 mutations were identified, a reported mutation frequency of 10% (7/69).
  • The article also states that the four point mutations and three deletions came from a total of six patients.
  • Ten matched normal pleural samples were sequenced, and no SETDB1 variants were found in them.
  • Overall survival was compared between SETDB1 wild-type (n=62) and mutant (n=7) patients. No significant correlation with survival was found (p=0.351).
• The authors' conclusion: The authors concluded that the high frequency of SETDB1 mutations they found suggests that this and other histone-related genes are important in malignant pleural mesothelioma. They wrote that further functional studies are required.
• Limitations the authors state:
  • Karyotyping to confirm the genome-wide allelic loss was not possible because the patient had died and no appropriate samples were available.
  • The patient's lung adenocarcinoma specimen was unavailable for genetic analysis.
  • The allelic loss could not be classified as chromothripsis or a similar event because exome sequencing identified only a limited number of variants.
  • Whether the SETDB1 mutations cause loss of function was not tested; the authors state that functional validation is needed.
  • Few patients had SETDB1 mutations, which the authors give as the probable reason no survival association was found.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Prognosis, Somatic Mutation, Lung Cancer, Pleura.

Related studies

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• Targeted next-generation sequencing of cancer genes in advanced stage malignant pleural mesothelioma: a retrospective study — M. Lo Iacono, V. Monica, et al. (2015)
• Germline and somatic variant identification using BGISEQ-500 and HiSeq X Ten whole genome sequencing — A.M. Patch, K. Nones, et al. (2018)
• Establishment and mutation analysis of a novel malignant peritoneal mesothelioma cell line, TU-MM-1, using whole genome sequencing — N. Oumi, H. Itamochi, et al. (2016)
• Driver Gene and Novel Mutations in Asbestos-Exposed Lung Adenocarcinoma and Malignant Mesothelioma Detected by Exome Sequencing — S. Mäki-Nevala, V.K. Sarhadi, et al. (2016)
• Whole exome sequencing of independent lung adenocarcinoma, lung squamous cell carcinoma, and malignant peritoneal mesothelioma: A case report — I. Vanni, S. Coco, et al. (2016)

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