Whole exome sequencing of independent lung adenocarcinoma, lung squamous cell carcinoma, and malignant peritoneal mesothelioma: A case report

Our plain-English summary of Whole exome sequencing of independent lung adenocarcinoma, lung squamous cell carcinoma, and malignant peritoneal mesothelioma: A case report, by I. Vanni, S. Coco, S. Bonfiglio, et al (Medicine, 2016).

The study

• Authors: I. Vanni, S. Coco, S. Bonfiglio, D. Cittaro, C. Genova, F. Biello, M. Mora, V. Rossella, M.G. Dal Bello, A. Truini, B. Banelli, D. Lazarevic, A. Alama, E. Rijavec, G. Barletta, F. Grossi
• Journal: Medicine
• Published: 2016;95(48):e5447
• Type of article: Case report
• Cited by: 10 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The presence of multiple primary tumors (MPT) in a single patient has been identified with an increasing frequency. A critical issue is to establish if the second tumor represents an independent primary cancer or a metastasis. Therefore, the assessment of MPT clonal origin might help understand the disease behavior and improve the management/prognosis of the patient.Herein, we report a 73-year-old male smoker who developed 2 primary lung cancers (adenocarcinoma and squamous cell carcinoma) and a malignant peritoneal mesothelioma (PM).Whole exome sequencing (WES) of the 3 tumors and of germline DNA was performed to determine the clonal origin and identify genetic cancer susceptibility.Both lung cancers were characterized by a high mutational rate with distinct mutational profiles and activation of tumor-specific pathways. Conversely, the PM harbored a relative low number of genetic variants and a novel mutation in the WT1 gene that might be involved in the carcinogenesis of nonasbestos-related mesothelioma. Finally, WES of the germinal DNA displayed several single nucleotide polymorphisms in DNA repair genes likely conferring higher cancer susceptibility.Overall, WES did not disclose any somatic genetic variant shared across the 3 tumors, suggesting their clonal independency; however, the carcinogenic effect of smoke combined with a deficiency in DNA repair genes and the patient advanced age might have been responsible for the MPT development. This case highlights the WES importance to define the clonal origin of MPT and susceptibility to cancer.

In plain English

This article is a case report of one Caucasian man who was a heavy smoker (100 pack-years), had chronic obstructive pulmonary disease, and, as the article states, had no exposure to asbestos. Starting at age 73 in 2009, he was diagnosed with a lung adenocarcinoma, then a squamous cell carcinoma of the lung in 2012, then an epithelioid peritoneal mesothelioma in 2015. He died in March 2015. The authors sequenced the protein-coding DNA (whole exome sequencing) of all three tumors and of his blood. Each tumor had its own set of somatic mutations (358, 405 and 28 in the adenocarcinoma, squamous cell carcinoma and mesothelioma, respectively), and none was shared across the three. Both lung cancers showed a mutation pattern linked to tobacco. The mesothelioma had new variants in the BAP1, SETD2 and WT1 genes. His inherited DNA carried 74 variants in 59 genes related to DNA repair or cancer predisposition. The authors concluded that their data supported the three tumors arising independently. They suggested the WT1 mutation may explain the mesothelioma regardless of asbestos exposure. They noted that the sequencing method missed regulatory regions of DNA.

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 with whole exome sequencing of three tumors and germline (blood) DNA
• Who was studied: one Caucasian male patient, aged 73 in January 2009, heavy smoker (100 pack-years) with COPD, treated in part at a lung cancer unit in Genova, Italy; died March 2015
• Exposure: heavy tobacco smoking (100 pack-years); the article states the patient had no exposure to asbestos
• Main results:
  • The patient was diagnosed with epithelioid peritoneal mesothelioma in 2015, after lung adenocarcinoma (2009) and lung squamous cell carcinoma (2012)
  • Each tumor had its own set of somatic variants: 358 in the adenocarcinoma, 405 in the squamous cell carcinoma and 28 in the peritoneal mesothelioma, not shared across the 3 tumors
  • Both lung cancers showed a predominance of C>A changes, a mutation signature the authors relate to tobacco consumption
  • The peritoneal mesothelioma had 3 novel variants: frameshift variants in BAP1 and SETD2 and a missense variant in WT1
  • Germline (inherited) DNA showed 74 variants in 59 genes related to DNA repair or cancer predisposition; 21 of the 74 had been described as conferring high cancer risk, 7 of which were homozygous
  • The patient also carried 5 SNPs involved in nicotine dependence
• The authors' conclusion: The authors concluded that their data support the three tumors having developed independently. They suggested that tobacco smoke, DNA repair deficiency and advanced age may have led to the high mutation rate in the lung cancers, and that the WT1 mutation may explain the peritoneal mesothelioma regardless of asbestos exposure.
• Limitations the authors state:
  • Whole exome sequencing does not cover regulatory regions, so shared mutations there could not be excluded
  • A mutagenic effect of the earlier carboplatin chemotherapy on the squamous cell carcinoma could not be excluded

Topics

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

Medical terms in this study, explained in our Lexicon: Lung Adenocarcinoma, Squamous Cell Carcinoma, Peritoneal Mesothelioma, Metastasis, Prognosis, Lung Cancer, Adenocarcinoma, Carcinogenesis.

Related studies

• 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)
• Next-generation sequencing informs diagnosis and identifies unexpected therapeutic targets in lung squamous cell carcinomas — J.M. Sands, T. Nguyen, et al. (2020)
• Asbestosis, laryngeal carcinoma, and malignant peritoneal mesothelioma in an insulation worker — A. Fischbein, J.C. Luo, et al. (1991)
• Whole-exome sequencing reveals frequent genetic alterations in BAP1, NF2, CDKN2A, and CUL1 in malignant pleural mesothelioma — G. Guo, J. Chmielecki, et al. (2015)
• Whole exome and targeted deep sequencing identify genome-wide allelic loss and frequent SETDB1 mutations in malignant pleural mesotheliomas — H.C. Kang, H.K. Kim, et al. (2016)
• Whole exome sequencing of an asbestos-induced wild-type murine model of malignant mesothelioma — S. Sneddon, A.M. Patch, et al. (2017)

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