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. 2018 Aug 16;36(28):2863–2871. doi: 10.1200/JCO.2018.78.5204

Frequency of Germline Mutations in Cancer Susceptibility Genes in Malignant Mesothelioma

Vasiliki Panou 1, Meghana Gadiraju 1, Arthur Wolin 1, Caroline M Weipert 1, Emily Skarda 1, Aliya N Husain 1, Jyoti D Patel 1, Buerkley Rose 1, Shannon R Zhang 1, Madison Weatherly 1, Viswateja Nelakuditi 1, Amy Knight Johnson 1, Maria Helgeson 1, David Fischer 1, Arpita Desai 1, Nanna Sulai 1, Lauren Ritterhouse 1, Oluf D Røe 1, Kiran K Turaga 1, Dezheng Huo 1, Jeremy Segal 1, Sabah Kadri 1, Zejuan Li 1, Hedy L Kindler 1, Jane E Churpek 1,✉
PMCID: PMC6804864  PMID: 30113886

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.

INTRODUCTION

Malignant mesothelioma (MM) is an aggressive malignancy with poor survival.1,2 MM develops in the pleura (MPM; 80% to 95%), the peritoneum (MPeM; 5% to 20%), and, rarely, the pericardium and tunica vaginalis of the testis.3,4 Globally, MM mortality has been estimated at 9.9 per million with large regional variations that correlate with asbestos use.5 Both MPM and MPeM are strongly associated with prior asbestos exposure.2 Heavy occupational exposure or long-standing, low-level environmental exposure increases the risk, yet only a fraction of exposed individuals develop MM.6,7 Other patients with MM have no identifiable history of exposure to asbestos or asbestiform minerals. These data suggest that individuals who are not resistant to the carcinogenic effects of asbestos and those who develop MM with minimal or no asbestos exposure may have an underlying inherited susceptibility.

Identification of germline mutations in BAP1 in families with multiple relatives with MM8 and studies that have demonstrated more frequent and accelerated MM development in mice that carry one abnormal copy of Bap1 exposed to even low levels of asbestos compared with wild-type mice9,10 provide a proof of principle that germline genetics contribute to MM risk. More recently, germline mutations in other cancer susceptibility genes, including ATM, CDKN2A, BRCA1, BRCA2, MSH6, MLH1, PALB2, and TP53, have been reported in individual patients11-16; however, the prevalence and causative role of germline mutations in known cancer susceptibility genes in MM remain unknown.

In the current study, we screened patients with MPM, MPeM, or tunica vaginalis mesothelioma for germline mutations in 85 cancer susceptibility genes. We describe the prevalence and spectrum of germline mutations in MM, report disease features that predict the presence of a germline mutation, and compare the prevalence of germline mutations with that of a control population.

METHODS

Study Population

Unrelated patients with MM who attended The University of Chicago Medicine (UCM) MM clinic from April 2016 to August 2017 were prospectively consented. Saliva, peripheral blood, and tumor specimens were collected. A detailed personal and family history of malignancy and asbestos exposure were obtained in person by trained interviewers using a standardized questionnaire. Asbestos exposure was self-reported as definite, probable, possible, or no known exposure and categorized as primary for those with known occupational or environmental exposure and as secondary for those exposed through family members’ exposures. Deceased patients who had previously consented to an historical tumor banking protocol from whom germline DNA was available were also included. Clinical information was abstracted from the medical record. The UCM Institutional Review Board approved this study.

Germline Mutation Detection and Interpretation

Germline variants were identified in DNA that was extracted from saliva or peripheral blood using a customized, Clinical Laboratory Improvement Amendments–certified targeted gene panel designed by The University of Chicago Genetic Services Laboratory to capture and sequence the coding and flanking intronic regions of 85 cancer susceptibility genes17 (Data Supplement). All variants were analyzed by two independent reviewers and interpreted according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology consensus guidelines (Data Supplement).18 Pathogenic and likely pathogenic variants—hereafter termed germline mutations—including nonsense, frameshift, splice site, and missense variants, in genes with known moderate-to-high penetrance cancer susceptibility were reported. For missense variants, only those with published evidence of a damaging effect on protein function were included. All germline mutations were validated by Sanger sequencing, correlated with clinical and family history, and segregated in family members when possible.

Population Frequency Estimates

We estimated the population frequency of germline mutations in each gene using the publicly available noncancer exome sequencing data set from the Exome Aggregation Consortium19 (ExAC; Data Supplement). Individual variant data for each gene were analyzed and interpreted according to American College of Medical Genetics guidelines.18

Somatic Mutation Detection

Somatic mutations were identified in DNA that was extracted from fresh-frozen, paraffin-embedded MM specimens using one of two next-generation sequencing platforms, UCM-OncoPlus20 (n = 147 gene panel; Data Supplement) and Foundation Medicine21,22 (n = 315 gene panel).

Functional Tumor Studies

Microsatellite instability was assessed using a polymerase chain reaction–based assay with fluorescently labeled primers to five DNA mononucleotide repeat markers, and/or a clinically validated method using 336 loci on UCM-OncoPlus. We performed immunohistochemistry (IHC) on fresh-frozen, paraffin-embedded tumor sections to assess for the presence of BAP1, MLH1, MSH6, MSH2, and PMS2 proteins (Data Supplement).

Statistical Analysis

Two-sided Fisher’s exact tests and Wilcoxon rank-sum tests were used to test the difference between categorical and continuous variables, respectively. We used logistic regression to assess associations between clinical characteristics and the presence of a germline mutation. Nested models were compared using likelihood ratio tests. Two-sided exact binomial tests were used to compare the frequencies of germline mutations in genes that were identified in our patients with MM versus those in the noncancer population in ExAC. P values < .05 were considered significant. Statistical analyses were performed with STATA software (version 15; STATA, College Station, TX; Computing Resource Center, Santa Monica, CA).

RESULTS

Study Population

Of 250 unrelated, eligible patients, 186 prospectively consented and 12 historical patients had sufficient germline DNA available for sequencing and were included (Data Supplement). Among these 198 patients, median age at MM diagnosis was 67 years (range, 24 to 88 years). The majority of patients were male (n = 136; 69%), had pleural disease (n = 148; 75%), epithelioid histology (n = 157; 79%), a history of occupational asbestos exposure (n = 129; 65%), and were never smokers (n = 106; 54%; Table 1). Twenty-seven patients (14%) had additional primary cancer diagnoses, with hematologic (n = 8; 4%), breast (n = 7; 4%), prostate (n = 5; 3%), and melanoma (n = 4; 2%) as the most frequent. Most had a family history of first-degree relatives (FDRs) and/or second-degree relatives (SDRs; n = 173; 87%) with cancer. Breast, lung, colorectal, and prostate cancers accounted for the majority of cancers in FDRs or SDRs (n = 67, 53, 46, 40 relatives, respectively), but hematologic malignancies (n = 34) were also frequent (Data Supplement). Thirteen probands had one or more FDR or SDR with MM (Data Supplement).

Table 1.

Patient Characteristics

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Germline Mutations

Twenty-three (12%) of 198 patients with MM carried a germline mutation, including one patient (UC049) who carried two mutations, one in BAP1 and one in TMEM127 (Fig 1A, Table 2, and Data Supplement). The 24 mutations were distributed among 13 genes. BAP1 mutations were the most common, accounting for 25% (n = 6). The remaining were in genes involved in cell-cycle and DNA repair (n = 14), oxygen sensing (n = 2), endosome trafficking (n = 1), and cell growth and development (n = 1).

Fig 1.

Fig 1.

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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.

Table 2.

Detailed Clinical Characteristics of Patients With Malignant Mesothelioma and a Germline Cancer Predisposition Mutation

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Germline Mutations and Clinical Characteristics

Germline mutation frequency was highest in patients with peritoneal MM (n = 11 [25%] of 44 v n = 11 [7%] of 148 for pleural), no known asbestos exposure (n = 9 [26%] of 35 v n = 7 [7%] of 104 for those with definite exposure), those with a second cancer diagnosis (n = 7 [26%] of 27 v n = 16 [9%] of 171 in those without), and epithelioid histology (n = 21 [13%] of 157 v n = 1 [4%] of 23 [biphasic] and n = 0 [0%] of 13 [sarcomatoid]; Fig 1B). The proportion of patients who carried a germline mutation significantly increased with decreasing age from 4% of those older than 75 years to 20% of those age 55 years or younger at diagnosis (test of trend; P = .01). Sex, histology, FDR with cancer, FDR/SDR with MM, and smoking status did not significantly differ between those patients with a germline mutation and those without (Table 3). In univariable analysis, 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 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 (Data Supplement). In multivariable analysis, adjusting for age, asbestos exposure, and a second cancer diagnosis, all three remained significant predictors. The addition of the site of origin did not improve model fit (likelihood ratio test, P = .13), and OR estimates remained similar.

Table 3.

Comparison of Clinical Characteristics Between Germline Mutation Carriers and Nonmutation Carriers

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Of 23 patients with a germline mutation, seven (30%) had a personal and/or family history that met clinical genetic testing criteria for hereditary breast and ovarian cancer (n = 6) or colon cancer23,24 (n = 1; Table 2). Of these, three patients had undergone prior clinical genetic testing that identified the germline mutation confirmed in this study in two patients. The third patient had prior negative clinical testing via a panel that did not include SDHA in which a mutation was identified in this study. Only one (10%) of 10 patients found to carry mutations in hereditary breast cancer genes met clinical genetic testing criteria.23 Three (50%) of six patients who were found to carry a germline BAP1 mutation met clinical recommendations for BAP1 genetic testing25,26 (Table 2 and Data Supplement). The familial BAP1 mutation segregated with BAP1 syndrome-related tumors in two of two families tested. Among 13 total families with more than one case of MM, three carried a germline mutation, all in BAP1 (Data Supplement).

Germline Mutation Frequency in MM Cases Versus Controls

Compared with the noncancer ExAC population, 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 our study population (Table 4).

Table 4.

Mutation Frequencies in Patients With Malignant Mesothelioma Versus a Noncancer Population Estimate

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Somatic Mutations

Fifty-four patients had adequate specimens available for tumor sequencing, including 37 MPM and 17 MPeM specimens. Thirty-two specimens were sequenced using UCM-OncoPlus and 22 had been sequenced as part of clinical care using Foundation Medicine (Fig 2 and Data Supplement). Acquired pathogenic mutations in BAP1 were the most common, found in 13 MPM (43%) and 11 MPeM (65%) specimens. Only two (6%) of 31 BAP1 mutations were germline. Rare BAP1 variants of uncertain significance were common, found in six (22%) of 27 tumors with a known pathogenic BAP1 variant and eight (30%) of 27 of those without a pathogenic BAP1 variant. CDKN2A (n = 10 [19%] of 54), NF2 (n = 10 [19%] of 54), SETD2 (n = 6 [11%] of 54), DDX3X (n = 4 [7%] of 54), and FBXW7 (n = 4 [7%] of 54) were also commonly mutated in both MPM and MPeM. TP53 mutations were only found in MPM (n = 7 [19%] of 37). In total, 52% (29 of 54) of tumors tested had one or more germline or acquired mutation in a homologous recombination (HR) DNA repair pathway gene. Twelve (38%) of 32 MM tested on UCM-OncoPlus had 10 or more copy number changes.

Fig 2.

Fig 2.

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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.

Among the five patients with germline mutations whose tumor was also sequenced (Fig 2 and Table 2; UC016, 059, 041, 102, and 170), the tumors acquired zero to three additional pathogenic mutations. Both individuals with germline BAP1 mutations (UPIN041 and 102) acquired a second pathogenic BAP1 mutation in the tumor, with one confirmed in trans configuration (Data Supplement). Patient UPIN059, who developed MPeM in the radiation field post-treatment of Wilms tumor, had a germline WT1 mutation and acquired a pathogenic BAP1 mutation in the context of a complex karyotype that was detected by conventional karyotyping. Patient UPIN081 carried a germline MSH6 mutation. His MPM, as well as a colon cancer sample from an unrelated patient with Lynch syndrome that carried the exact same germline MSH6 mutation, were both microsatellite stable and demonstrated the presence of all four mismatch repair (MMR) proteins on IHC (Data Supplement), which suggests that this specific mutation may not cause the usual microsatellite instability (MSI) phenotype. An additional five MM specimens that were tested by polymerase chain reaction and IHC and 32 tested by UCM-OncoPlus were all microsatellite stable.

DISCUSSION

We found that 12% of patients with MM carry germline cancer susceptibility gene mutations. This prevalence is strikingly similar to the proportion found in other solid tumors, including ovarian, colon, metastatic prostate cancer, and diverse advanced solid tumors.16,27-29 The recognized MM susceptibility gene, BAP1, accounted for only one quarter of mutations identified. This may help explain why many patients with MM who have a strong personal or family cancer history reported in the literature tested negative for germline mutations in BAP1.8,30,31 We demonstrate that 13 genes, including genes that were previously identified in single MM cases,11-16 as well as genes that have not been previously linked to MM, including TMEM127, CHEK2, MRE11A, VHL, WT1, and SDHA, contribute to MM and other cancer susceptibility in these patients and their families. Our finding that pathogenic mutations in BAP1, CDKN2A, BRCA2, TMEM127, VHL, and WT1 are overrepresented in patients with MM compared with a control population provides additional evidence that supports the association of cancer susceptibility genes with MM carcinogenesis.

Specific clinical characteristics predict the presence of germline mutations and provide insight into differences in subset-specific MM etiology. First, we found that minimal-to-no asbestos exposure was the most significant predictor of the presence of a germline cancer susceptibility mutation, which confirmed an observation made for germline BAP1 mutations8 and similar observations in patients with MPM.12 Two other important predictors—younger age and having had a second cancer—are not surprising given the known association of cancer susceptibility gene mutations and earlier onset and multiple cancers. Second, although the spectrum of mutations is similar across MPM and MPeM, the overall proportion of patients with mutations was significantly different (7% v 25%; P < .01, respectively), which implies that inherited susceptibility may play a larger role in MPeM than in MPM. This is an interesting observation given the overlap in site and cisplatin sensitivity of MPeM and ovarian cancer, a cancer for which 18% to 24%27,32 of patients will carry a germline mutation in some of the same genes identified here. Furthermore, although MPeM is also associated with asbestos exposure, the strength of this association is weaker than for pleural site of origin.33 Our data suggest that genetic susceptibility and/or a gene by environment interaction effect, as previously demonstrated for asbestos exposure in Bap1-deficient mouse models,9,10 may contribute to these differences.

Our findings add to the accumulating evidence of the importance of deficits in DNA damage response pathways in MM.12 Six of the genes with germline mutations in this series—BAP1, BRCA1, BRCA2, CHEK2, ATM, and MRE11A—have a well-established role in the HR DNA repair pathway.34-38 WT1 may also be involved in HR-mediated repair.39,40 We found acquired mutations in additional HR pathway genes, including FANCA and ATR, in MM tumors. In total, 52% of MM tumors sequenced had an HR pathway defect either as a result of a germline or acquired event, and 12 (38%) of 32 tested had multiple copy number rearrangements. These observations are consistent with prior data that demonstrate multiple chromosomal rearrangements in the majority of MM cases,41 with the genomic instability pattern observed in other tumors with HR defects, and with the observation of the loss of BRCA1 expression in 39% of MM tumors.42

These data are immediately relevant for potential prognostic biomarkers and chemotherapeutic targets for MM. In other cancers that are commonly caused by HR defects, such as ovarian cancer, the subset of patients who carry germline BRCA1 or BRCA2 mutations is more likely to respond to cisplatin and have a better prognosis.43 Our study’s findings may help explain the cisplatin sensitivity of a substantial subset of MM and the observed improvement in prognosis in patients with MM who carry a germline BAP1 mutation.44 Furthermore, poly (ADP-ribose) polymerase inhibitors (PARPi) have demonstrated improved efficacy in ovarian, breast, and prostate cancers with HR defects.45-47 MM cells lines, regardless of BAP1 status, have been demonstrated to be sensitive to PARPi,38,48,49 which supports the hypothesis that PARPi could be effective in MM.12,48,50 Taken together, PARPi trials in patients with MM, especially those not refractory to platinum-based chemotherapy, are justified and already in development. Active investigation of HR deficits in MM is warranted to identify biomarkers of prognosis and chemotherapy responsiveness as well as novel drug targets.

We also identified germline (MSH6) and acquired mutations (MSH6, MLH3) in the MMR pathway. Similar to two other germline MMR gene-mutated MPeM in the literature,14,15 none of these tumors featured the MSI pattern typical of other cancers with MMR deficits.51 We did not observe an MSI pattern in 32 total MM examined. The role of these genes and the MMR pathway in MM remains to be determined. Finally, the identification of germline mutations in VHL and SDHA, genes that induce tumorigenesis through impaired hypoxia-inducible factor expression,52,53 and in TMEM127, which negatively regulates the mammalian target of rapamycin signaling pathway,54 highlight additional pathways that warrant investigation.

Our data support clinical panel-based genetic testing for all patients with MM. Clinical genetic testing guidelines23-26 would identify only 12 (52%) of 23 germline mutation carriers in this study, which suggests a need for a universal testing strategy. This testing would allow primary cancer prevention and early detection in at-risk close relatives and in patients with MM with disease features that portend extended survival. Lastly, BRCA1 or BRCA2 germline mutation status has been incorporated into US Food and Drug Administration approvals of specific PARPi for the treatment of advanced ovarian and breast cancer and is expected for prostate cancer. Whether a similar paradigm will hold in MM awaits investigations of the effect of germline mutation status on the response to established and novel therapies.

Our study has limitations. First, our germline genetic testing assay cannot detect copy number variants, and our variant interpretation approach was conservative, including only proven pathogenic or likely pathogenic mutations. Thus, the proportion of patients with MM in our study who carried a pathogenic mutation may be underestimated. Similarly, the UCM-OncoPlus genes analyzed in tumors in this study did not include all HR pathway genes and, similar to other next-generation sequencing–based assays, may miss small copy number changes.55 Second, UCM is a tertiary referral center, which makes our study population subject to referral bias. Third, insufficient tumor tissue for many of the patients who carried a germline mutation and the lack of germline mutations other than BAP1 in families with more than one MM case to allow segregation with MM cases limited our ability to provide more direct evidence of causation. Finally, family history of malignancy and prior asbestos exposure were self-reported, which may limit accuracy; however, our observation that lower self-reported asbestos exposure is a significant predictor of carrying a germline mutation is concordant with prior work.12 Furthermore, a strong family cancer signal has been previously reported in patients with MM.8,31,56-61 Our data confirm these observations and provide a rationale for broader investigations of inherited genomics in patients with MM.

In conclusion, we found that 12% of patients with MM carry germline mutations in cancer susceptibility genes; especially those with peritoneal disease, a second cancer diagnosis, young age at onset, and minimal known asbestos exposure. These data support the inclusion of clinical germline genetic testing in the evaluation of all patients with MM. We found additional evidence of an HR pathway DNA repair defect in a substantial subset of patients with MM, providing a rationale for PARPi clinical trials and additional research into this pathway in MM etiology.

ACKNOWLEDGMENT

We thank all of the patients and their family members who participated in this study. At the time of publication, we are aware of data with similar findings presented by Dr. Raffit Hassan at the Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 1-5, 2018.

Footnotes

Supported by a Pilot Research Grant, awarded by The University of Chicago Comprehensive Cancer Center and supported with funds from John D. Cooney and the firm of Cooney and Conway (J.E.C.), National Institute of Diabetes and Digestive and Kidney Diseases (Grant No. T35DK062719-29) (E.S.), and the Pritzker School of Medicine (S.R.Z.).

Presented at the Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 1-5, 2018.

AUTHOR CONTRIBUTIONS

Conception and design: Hedy L. Kindler, Jane E. Churpek

Financial support: Jane E. Churpek

Provision of study materials or patients: Jyoti D. Patel, Buerkley Rose

Collection and assembly of data: Vasiliki Panou, Meghana Gadiraju, Emily Skarda, Aliya N. Husain, Jyoti D. Patel, Buerkley Rose, Shannon R. Zhang, Madison Weatherly, Arpita Desai, Nanna Sulai, Jeremy Segal, Jane E. Churpek

Data analysis and interpretation: Vasiliki Panou, Meghana Gadiraju, Arthur Wolin, Caroline M. Weipert, Viswateja Nelakuditi, Amy Knight Johnson, Maria Helgeson, David Fischer, Lauren Ritterhouse, Oluf D. Røe, Kiran K. Turaga, Dezheng Huo, Jeremy Segal, Sabah Kadri, Zejuan Li, Jane E. Churpek

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Frequency of Germline Mutations in Cancer Susceptibility Genes in Malignant Mesothelioma

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.

Vasiliki Panou

No relationship to disclose

Meghana Gadiraju

No relationship to disclose

Arthur Wolin

Employment: Regeneron (I)

Stock or Other Ownership: Regeneron (I)

Caroline M. Weipert

Consulting or Advisory Role: Myriad Genetics

Emily Skarda

No relationship to disclose

Aliya N. Husain

No relationship to disclose

Jyoti D. Patel

Consulting or Advisory Role: Ariad Pharmaceuticals, AbbVie, AstraZeneca

Buerkley Rose

No relationship to disclose

Shannon R. Zhang

No relationship to disclose

Madison Weatherly

No relationship to disclose

Viswateja Nelakuditi

No relationship to disclose

Amy Knight Johnson

No relationship to disclose

Maria Helgeson

No relationship to disclose

David Fischer

No relationship to disclose

Arpita Desai

No relationship to disclose

Nanna Sulai

Honoraria: Agendia

Travel, Accommodations, Expenses: Agendia

Lauren Ritterhouse

Honoraria: Bristol-Myers Squibb, AbbVie, Personal Genome Diagnostics

Consulting or Advisory Role: Bristol-Myers Squibb, PGDx, AbbVie

Oluf D. Røe

No relationship to disclose

Kiran K. Turaga

Honoraria: Castle Biosciences, Caris Life Sciences

Dezheng Huo

No relationship to disclose

Jeremy Segal

Honoraria: Bristol-Myers Squibb, AbbVie

Research Funding: AbbVie

Sabah Kadri

Research Funding: AbbVie (Inst)

Zejuan Li

No relationship to disclose

Hedy L. Kindler

Consulting or Advisory Role: Aduro Biotech, MedImmune, Bayer, Celgene, GlaxoSmithKline, AstraZeneca, Merck, Bristol-Myers Squibb, Boehringer Ingelheim, Ipsen, Erytech Pharma, Five Prime Therapeutics, Paredox Therapeutics

Research Funding: Aduro Biotech, AstraZeneca, Bayer, GlaxoSmithKline, Merck, MedImmune, Verastem, Bristol-Myers Squibb, Eli Lilly, Polaris, Deciphera

Jane E. Churpek

Honoraria: UpToDate

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