Diffuse Pleural Mesotheliomas with Genomic Near-Haploidization: A Newly Recognized Subset with Distinct Clinical, Histologic, and Molecular Features

Our plain-English summary of Diffuse Pleural Mesotheliomas with Genomic Near-Haploidization: A Newly Recognized Subset with Distinct Clinical, Histologic, and Molecular Features, by S.R. Yang, G. Jayakumaran, J. Benhamida, et al (Clinical Cancer Research, 2024).

The study

• Authors: S.R. Yang, G. Jayakumaran, J. Benhamida, C.A. Febres-Aldana, R. Fanaroff, J. Chang, E. Gedvilaite, L.B. Villafania, J.L. Sauter, M. Offin, M.G. Zauderer, M. Ladanyi
• Journal: Clinical Cancer Research
• Published: 2024;30(13):2780-2789
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Purpose: Diffuse pleural mesotheliomas (DPM) with genomic near-haploidization (GNH) represent a novel subtype first recognized by The Cancer Genome Atlas project; however, its clinicopathologic and molecular features remain poorly defined.

Experimental Design: We analyzed clinical genomic profiling data from 290 patients with DPM using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay. Allele-specific copy number analysis was performed using the Fraction and Allele-Specific Copy Number Estimates from Tumor Sequencing (FACETS) algorithm.

Results: A total of 210 patients were evaluable for loss of heterozygosity (LOH) analysis using FACETS from MSK-IMPACT tumor:normal sequencing data. In this cohort, GNH, defined as LOH across >80% of the genome, was detected in 10 cases (4.8%). Compared with non-GNH tumors, GNH DPMs were associated with younger age and less frequent self-reported history of occupational asbestos exposure. Histologically, GNH DPMs were enriched in biphasic subtype (80% vs. 14.5%) and showed abundant tumor-infiltrating lymphocytes (TILs). Genomic analysis revealed a higher frequency of TP53 alterations, whereas SETDB1 mutations were present in nearly all and only in this subset. The clinicopathologic and molecular findings were further validated in a separate cohort. Despite the younger age, patients with GNH DPMs had a shorter overall survival (10.9 vs. 25.4 months, P = 0.004); the poor prognostic impact of GNH remained significant after controlling for biphasic histology. Of three patients with GNH DPMs who received immune checkpoint blockade, two achieved a clinician-assessed partial response.

Conclusions: GNH defines an aggressive subtype of mainly biphasic DPMs in younger patients with recurrent alterations in SETDB1 and TP53. The enrichment in biphasic histology and TILs, together with our preliminary immune checkpoint blockade response data and anecdotal clinical trial data, suggests that further evaluation of immunotherapy may be warranted in this subset.

©2024 American Association for Cancer Research.

In plain English

Researchers at Memorial Sloan Kettering Cancer Center reviewed tumor genetic tests from diffuse pleural mesothelioma patients, 2014 to 2021. Of 290 patients, 210 had samples suitable for analysis. In 10 of these (4.8%), loss of heterozygosity covered more than 80% of the tumor genome, called genomic near-haploidization (GNH). GNH patients were younger at diagnosis than non-GNH patients (median 58 versus 71 years) and less often self-reported classical occupational asbestos exposure (2 of 10 versus 58.3% of those with data: 109 yes, 78 no). Their tumors were more often biphasic (80% versus 15%) and had TP53 changes; among untreated tumors, dense immune-cell infiltrates and necrosis were more common. Eight of 10 GNH tumors had SETDB1 mutations; none of 8 non-GNH tumors tested did. In a second group of 105 patients, all 4 with SETDB1 mutations had GNH. Median overall survival was 10.9 months with GNH versus 25.4 without. Two of three GNH patients given immune checkpoint blockade had a clinician-assessed partial response. The authors raised a possible different cause, cautioning that asbestos data were self-reported and incomplete and survival and immunotherapy findings preliminary.

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: Retrospective genomic and clinicopathologic analysis of patients at a single cancer center whose tumors had been prospectively profiled with the MSK-IMPACT sequencing assay, with a separate validation cohort
• Who was studied: 290 patients with diffuse pleural mesothelioma at Memorial Sloan Kettering Cancer Center, New York, profiled from January 2014 to January 2021. Of these, 210 were evaluable (10 GNH, 200 non-GNH). A separate validation cohort of 105 patients was sequenced with an updated 505-gene panel.
• Exposure: The main variable studied was tumor genomic near-haploidization, defined as loss of heterozygosity across more than 80% of the genome. Asbestos exposure was recorded only as self-reported classic occupational exposure. No fiber types, products or doses are given.
• Main results:
  • GNH, defined as genome-wide loss of heterozygosity affecting more than 80% of the genome, was found in 10 of 210 evaluable cases (4.8%). Half of the GNH cases showed genome duplication.
  • Compared with non-GNH patients, GNH patients were younger at diagnosis (median 58 vs. 71 years, p=0.008). They also less often self-reported classical occupational asbestos exposure, p=0.02. In the GNH group, 2 patients (20%) reported exposure and 8 did not. In the non-GNH group, among those with exposure information, 109 (58.3%) reported exposure and 78 (41.7%) did not (Table 1).
  • Biphasic histology was more common in GNH than in non-GNH tumors (80% vs. 15%, p<0.0001).
  • Among tumors without prior therapy, GNH tumors more often had the highest tumor-infiltrating lymphocyte score (3+: 90% vs. 20.3%, p<0.0001) and tumor necrosis (90% vs. 24.3%, p<0.0001).
  • When GNH tumors were compared only with biphasic non-GNH tumors, GNH was still associated with younger age (p=0.02) and with lack of classical occupational asbestos exposure (p=0.003).
  • NF2 and TP53 alterations were more common in GNH tumors (90% vs. 26.5%, q=0.0007; 60% vs. 14%, q=0.0035). Only the TP53 association remained significant after controlling for biphasic histology (q=0.04).
  • SETDB1 mutations were found in 8 of 10 GNH tumors and in none of the 8 non-GNH tumors re-sequenced (q=0.0035).
  • In the separate validation cohort of 105 patients, 4 (3.8%) had pathogenic SETDB1 mutations, and all 4 had GNH. All 4 tumors were biphasic.
  • Median overall survival was shorter for GNH patients than for non-GNH patients (10.9 vs. 25.4 months, p=0.004). Among biphasic tumors only, the difference remained significant (p=0.016).
  • Of 3 GNH patients given immune checkpoint blockade, 2 had a best response of partial response, as assessed by a thoracic oncologist, and 1 had progression. Of 44 non-GNH patients, 1 (2%) had a partial response. Median progression-free survival (9.2 vs. 2.8 months) was not statistically different (p=0.2).
  • Germline testing found no pathogenic variants in the 4 GNH patients tested. Pathogenic or likely pathogenic variants were found in 9 of 83 non-GNH patients (10.8%), including BAP1 in 3.
• The authors' conclusion: The authors concluded that GNH defines a rare and aggressive subtype of diffuse pleural mesothelioma with recurrent clinicopathologic and molecular features. They suggested that the lower rate of reported occupational asbestos exposure raises the possibility of a different cause, and that immunotherapy may warrant further study in this group.
• Limitations the authors state:
  • Occupational asbestos exposure data were self-reported and not available for all patients, so the authors said the asbestos association should be interpreted with caution and needs validation.
  • The immunotherapy response observation rests on only 3 GNH patients in a small descriptive series.
  • The poor survival associated with GNH is preliminary and needs confirmation in larger cohorts.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Memorial Sloan Kettering, Asbestos Exposure, Biphasic Mesothelioma, Tumor-Infiltrating Lymphocytes, Overall Survival, Histology, Clinical Trial.

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