A Subset of Mesotheliomas With Improved Survival Occurring in Carriers of BAP1 and Other Germline Mutations

Our plain-English summary of A Subset of Mesotheliomas With Improved Survival Occurring in Carriers of BAP1 and Other Germline Mutations, by S. Pastorino, Y. Yoshikawa, H.I. Pass, et al (Journal of Clinical Oncology, 2018).

The study

• Authors: S. Pastorino, Y. Yoshikawa, H.I. Pass, M. Emi, M. Nasu, I. Pagano, Y. Takinishi, R. Yamamoto, M. Minaai, T. Hashimoto-Tamaoki, M. Ohmuraya, K. Goto, C. Goparaju, K.Y. Sarin, M. Tanji, A. Bononi, A. Napolitano, G. Gaudino, M. Hesdorffer, H. Yang, M. Carbone
• Journal: Journal of Clinical Oncology
• Published: 2018;36(35):JCO2018790352
• Cited by: 127 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Purpose: We hypothesized that four criteria could help identify malignant mesotheliomas (MMs) most likely linked to germline mutations of BAP1 or of other genes: family history of MM, BAP1-associated cancers, or multiple malignancies; or age younger than 50 years.

Patients And Methods: Over the course of 7 years, 79 patients with MM met the four criteria; 22 of the 79 (28%) reported possible asbestos exposure. They were screened for germline BAP1 mutations by Sanger sequencing and by targeted next-generation sequencing (tNGS) for germline mutations in 55 additional cancer-linked genes. Deleterious mutations detected by tNGS were validated by Sanger sequencing.

Results: Of the 79 patients, 43 (16 probands and 27 relatives) had deleterious germline BAP1 mutations. The median age at diagnosis was 54 years and median survival was 5 years. Among the remaining 36 patients with no BAP1 mutation, median age at diagnosis was 45 years, median survival was 9 years, and 12 had deleterious mutations of additional genes linked to cancer. When compared with patients with MMs in the SEER cohort, median age at diagnosis (72 years), median survival for all MM stages (8 months), and stage I (11 months) were significantly different from the 79 patients with MM in the current study ( P < .0001).

Conclusion: We provide criteria that help identify a subset of patients with MM who had significantly improved survival. Most of these patients were not aware of asbestos exposure and carried either pathogenic germline mutations of BAP1 or of additional genes linked to cancer, some of which may have targeted-therapy options. These patients and their relatives are susceptible to development of additional cancers; therefore, genetic counseling and cancer screening should be considered.

In plain English

The authors studied 79 people with malignant mesothelioma, 52 unrelated patients and 27 affected relatives, who met at least one criterion: relatives with mesothelioma; the patient or a close relative having uveal melanoma, cutaneous melanoma or clear-cell renal cell carcinoma; multiple cancers in most close relatives; or onset before age 50. All 79 had BAP1 testing; 45 also had other cancer-linked genes tested. Sixteen of 52 unrelated patients (30.7%) carried a harmful BAP1 mutation. In relatives, mesothelioma developed in 27 of 66 BAP1 carriers and none of 87 non-carriers. Twelve of 34 tested BAP1 non-carriers had a harmful mutation in another gene. Asbestos exposure was self-reported; 57 of 79 (72%) reported none. Median survival was 5 years in BAP1 carriers and 9 years in non-carriers, a non-significant difference. In SEER statistics, median survival was 8 months for all stages and 11 months for stage I. Among study patients, 33 diagnosed before age 50 had median survival of 10 years, versus 4 years for 44 diagnosed later. The authors concluded that their criteria help identify a subset of patients with significantly improved survival.

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 testing study of selected mesothelioma patients and their relatives, with survival follow-up compared against SEER cancer statistics
• Who was studied: 79 patients with pleural and/or peritoneal malignant mesothelioma (52 unrelated probands and 27 affected relatives), mostly white patients in the United States. Patients met one or more criteria: first- or second-degree relatives with mesothelioma; the proband or a first- or second-degree relative diagnosed with uveal melanoma, cutaneous melanoma or clear-cell renal cell carcinoma; multiple cancers in the majority of first- and second-degree relatives; or mesothelioma onset before age 50. A further 153 relatives of 12 BAP1-carrier probands were also tested.
• Exposure: Inherited (germline) mutations in BAP1 and in 55 other cancer-linked genes. Asbestos exposure was self-reported by questionnaire; no fiber types, products or jobs are given. 22 of 79 patients reported possible asbestos exposure and 57 of 79 (72%) did not.
• Main results:
  • 16 of 52 unrelated patients (30.7%) had harmful germline BAP1 mutations; 36 did not.
  • Among 153 relatives tested, mesothelioma developed in 27 of 66 BAP1 mutation carriers and in none of the 87 relatives without the mutation.
  • Median survival was 5 years among 43 BAP1 carriers, of whom 15% were alive 10 years after diagnosis. It was 9 years among 34 non-carriers, whose 10-year survival was 41%.
  • In the multivariate analysis, the survival difference between BAP1 carriers and non-carriers was not statistically significant (P = .16).
  • Median survival in the SEER cohort was 8 months for all stages and 11 months for stage I. The authors reported that their cohort, both carriers and non-carriers, had significantly better survival than SEER.
  • Within the study cohort and regardless of BAP1 status, the 33 patients diagnosed before age 50 had a median survival of 10 years, against 4 years for the 44 patients diagnosed later (log-rank P = .0006).
  • Targeted sequencing of the gene panel was done for 45 patients: 34 of the 36 non-carriers and 11 BAP1 carriers. 12 of the 34 non-carriers (35%) had one harmful germline mutation in 11 of the 55 additional genes. 5 of the 11 tested BAP1 carriers had one additional germline mutation.
  • Reported asbestos exposure was 7 of 43 (16%) among BAP1 carriers and 15 of 36 (42%) among non-carriers. The table footnote gives P = .02 for mean age at diagnosis and asbestos exposure between the two groups.
  • There was no significant survival difference by mesothelioma site, single versus multiple cancers, or sex in the Kaplan-Meier analysis. In the multivariate analysis, the difference between patients with mesothelioma plus other cancers and those with mesothelioma only reached significance (P = .02), which the authors said needs verification in a larger cohort.
• The authors' conclusion: The authors concluded that their criteria help identify a subset of mesothelioma patients with significantly improved survival. They noted that most of these patients were not aware of asbestos exposure and carried pathogenic germline mutations of BAP1 or other cancer-linked genes. They stated that genetic counseling and cancer screening should be considered for these patients and their relatives.
• Limitations the authors state:
  • Only 22 of 79 patients reported asbestos exposure, which limited statistical power to assess hypotheses about asbestos exposure and germline mutations.
  • Asbestos exposure was self-reported and subject to recall bias.
  • Some patients may have carried mutations in genes not on the 56-gene panel, and the strict criteria may have missed harmful mutations, so the share of cases linked to mutations may be underestimated.
  • Not all detected mutations may have contributed to tumor development; further evidence is needed to prove causality.
  • Patients in this cohort and in SEER were treated at different institutions, and the exact treatments were not known.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, BAP1, Germline Mutation, Malignant Mesothelioma, Asbestos Exposure, BAP1 Tumor Predisposition Syndrome, Next-Generation Sequencing (NGS), Median Survival.

Related studies

• Heterozygous germline BLM mutations increase susceptibility to asbestos and mesothelioma — A. Bononi, K. Goto, et al. (2020)
• Medical and Surgical Care of Patients With Mesothelioma and Their Relatives Carrying Germline BAP1 Mutations — M. Carbone, H.I. Pass, et al. (2022)
• Germline BARD1 variants predispose to mesothelioma by impairing DNA repair and calcium signaling — F. Novelli, Y. Yoshikawa, et al. (2024)
• Germline BAP1 mutations predispose to malignant mesothelioma — J.R. Testa, M. Cheung, et al. (2011)
• Germline BAP1 mutations induce a Warburg effect — A. Bononi, H. Yang, et al. (2017)
• Prevalence and Preliminary Validation of Screening Criteria to Identify Carriers of Germline BAP1 Mutations — M.G. Zauderer, G. Jayakumaran, et al. (2019)

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