Frequency of Germline Mutations in Cancer Susceptibility Genes in Malignant Mesothelioma

Abstract

Purpose: The aim of the current study was to determine the prevalence and clinical predictors of germline cancer susceptibility mutations in patients with malignant mesothelioma (MM).

Methods: We performed targeted capture and next-generation sequencing of 85 cancer susceptibility genes on germline DNA from 198 patients with pleural, peritoneal, and tunica vaginalis MM.

Results: Twenty-four germline mutations were identified in 13 genes in 23 (12%) of 198 patients. BAP1 mutations were the most common (n = 6; 25%). The remaining were in genes involved in DNA damage sensing and repair (n = 14), oxygen sensing (n = 2), endosome trafficking (n = 1), and cell growth (n = 1). Pleural site (odds ratio [OR], 0.23; 95% CI, 0.10 to 0.58; P < .01), asbestos exposure (OR, 0.28; 95% CI, 0.11 to 0.72; P < .01), and older age (OR, 0.95; 95% CI, 0.92 to 0.99; P = .01) were associated with decreased odds of carrying a germline mutation, whereas having a second cancer diagnosis (OR, 3.33; 95% CI, 1.22 to 9.07; P = .02) significantly increased the odds. The odds of carrying a mutation in BAP1 (OR, 1,658; 95% CI, 199 to 76,224; P < .001), BRCA2 (OR, 5; 95% CI, 1.0 to 14.7; P = .03), CDKN2A (OR, 53; 95% CI, 6 to 249; P < .001), TMEM127 (OR, 88; 95% CI, 1.7 to 1,105; P = .01), VHL (OR, 51; 95% CI, 1.1 to 453; P = .02), and WT1 (OR, 20; 95% CI, 0.5 to 135; P = .049) were significantly higher in MM cases than in a noncancer control population. Tumor sequencing identified mutations in a homologous recombination pathway gene in 52% (n = 29 of 54).

Conclusion: A significant proportion of patients with MM carry germline mutations in cancer susceptibility genes, especially those with peritoneal MM, minimal asbestos exposure, young age, and a second cancer diagnosis. These data support clinical germline genetic testing for patients with MM and provide a rationale for additional investigation of the homologous recombination pathway in MM.

Fig 1.

Germline cancer susceptibility gene mutations identified in patients with malignant mesothelioma. (A) Distribution of the 24 mutations identified in 23 patients among 13 genes. (B) Proportions of patients with a germline mutation by specific clinical characteristics.

Fig 2.

Genetic variants identified by site of origin and histology in 54 malignant mesothelioma specimens. Transcript numbers: ATM [NM_000051.3], AKT2 [ NM_001626]; ASXL1 [NM_015338]; ATR [NM_001184.3]; BAP1 [NM_004656.3]; BRCA2 [NM_000059.3]; CARD11 [NM_032415]; CDKN2A [NM_000077]; CSF1R [NM_001288705.1]; CTNNB1 [NM_001904]; DDX3X [NM_001356.4]; DNMT3A [NM_022552]; EPHA5 [NM_004439]; EPHB1 [NM_004441]; FANCA [NM_000135]; FBXW7 [NM033632.3]; FOXP1 [NM_032682]; KDM6A [NM_021140]; KDR [NM_002253.2]; MDM4 [NM_002393]; MLH3 [NM_001040108.1]; MSH6 [NM_00179.2]; NF1 [NM_001042492]; NF2 [NM_000268]; NOTCH1 [NM_017617.4]; NRAS [NM_002524]; PIK3CA [ NM_006218]; PTEN [NM_000314.6]; PTPN11 [NM_002834]; RB1 [NM_000321]; SETD2 [NM_014159]; SMARCA4 [NM_003072]; TERT [NM_198253.2]; TP53 [NM_000546.5]; WT1 [NM_24426.4 ]. Mutation types: loss, large deletion or duplication, nonsense, frameshift, splice site (dark gray); missense, in-frame deletion, promoter mutation (green); amplification (blue). VUS, variant of uncertain significance. (*) Origin: Dark blue, pleural; light blue, peritoneal. (†) Histology: Dark red, epithelioid; pink, biphasic; green, sarcomatoid. Germline variants are notated by ★. Tumors with multiple variants in the same gene are notated with the number of unique variants identified.