Dataset Information

Comprehensive Genomic Characterization of Parathyroid Cancer Identifies Novel Candidate Driver Mutations and Core Pathways.

ABSTRACT: Context:Elucidating the genomic landscape of sporadic parathyroid carcinoma (PC) has been limited by low tumor incidence. Objective:Identify driver mutations of sporadic PC and potential actionable pathways. Methods:Patients undergoing surgical resection for sporadic PC between 1980 and 2016 at MD Anderson Cancer Center were identified. Patients with sporadic PC according to World Health Organization diagnostic criteria and with available formalin-fixed, paraffin-embedded (FFPE) PC tumor tissue were included and their clinical data analyzed to assess extent of disease. Patients with parathyroid tumors of uncertain malignancy or atypical parathyroid neoplasms were excluded. Thirty-one patients meeting diagnostic criteria had available tissue for analysis. FFPE PC tumors were subjected to DNA extraction and next-generation whole-exome sequencing. All variant calls are single-algorithm only. Twenty-nine samples passed quality assurance after DNA extraction. Main Outcome Measures:Somatic or private germline mutations present in sporadic PC and identification of pathways involved in tumorigenesis. Results:We identified 35 genes with considerable mutational load; only eight genes were previously identified in other PC cohorts. These genes mediate critical processes, including chromosome organization, DNA repair, and cell cycle regulations. Gene mutations involved in MAPK signaling and immune response are also heavily implicated. These findings are limited by inherent molecular artifacts in FFPE tissue analysis and the absence of matched germline DNA. Additionally, variant calls are only single algorithm and may include false-positive/negative calls. Conclusion:We identified 33 candidate driver genes of sporadic PC, in addition to previously known driver genes CDC73 and MEN1.

SUBMITTER: Clarke CN

PROVIDER: S-EPMC6372985 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Comprehensive Genomic Characterization of Parathyroid Cancer Identifies Novel Candidate Driver Mutations and Core Pathways.

Clarke Callisia N CN Katsonis Panagiotis P Hsu Teng-Kuei TK Koire Amanda M AM Silva-Figueroa Angelica A Christakis Ioannis I Williams Michelle D MD Kutahyalioglu Merve M Kwatampora Lily L Xi Yuanxin Y Lee Jeffrey E JE Koptez E Scott ES Busaidy Naifa L NL Perrier Nancy D ND Lichtarge Olivier O

Journal of the Endocrine Society 20180903 3

<h4>Context</h4>Elucidating the genomic landscape of sporadic parathyroid carcinoma (PC) has been limited by low tumor incidence.<h4>Objective</h4>Identify driver mutations of sporadic PC and potential actionable pathways.<h4>Methods</h4>Patients undergoing surgical resection for sporadic PC between 1980 and 2016 at MD Anderson Cancer Center were identified. Patients with sporadic PC according to World Health Organization diagnostic criteria and with available formalin-fixed, paraffin-embedded ( ...[more]

PMID: 30788456

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Project description:The carcinogen urethane induces pulmonary tumors in mice initiated by an incredibly specific Q61L/R oncogenic mutation in the proto-oncogene Kras. Previous Whole-Exome Sequencing of urethane-induced tumors revealed a bias towards A➙T/G and G➙A substitutions. Subsequent ultra-sensitive Maximum-Depth Sequencing of Kras shortly after urethane exposure suggest a further refinement to CA➙CT/G substitutions. As C182AA➙C182T/GA substitutions in Kras result in Q61L/R mutations, the extreme bias of urethane towards these genomic driver mutations can be ascribed to the specificity of the carcinogen for CA➙CT/G substitutions. However, we previously found that changing rare codons to common in the Kras gene to increase protein expression shifted mutations in urethane-induced tumors away from Kras, or when detected in Kras, to G12D mutations that are usually rarely detected in such tumors. Moreover, the loss of p53 partially reversed this effect, generating tumors with either Q61L/R or G12D oncogenic Kras mutations, or no Kras mutations, presumably due to other genomic driver mutations. Determining the origin of these G12D and other unknown non-canonical genomic driver mutations would provide critical insight into the extreme bias of carcinogens for specific genomic driver mutations. We thus compared the types of Single Nucleotide Variations detected by previously performed Maximum-Depth Sequencing immediately after urethane exposure to the mutation signatures derived from Whole Exome Sequencing of urethane-induced tumors. This identified two types of non-canonical mutations. First, a V637E oncogenic mutation in the proto-oncogene Braf that conforms to the mutation signature of urethane, suggesting that the mutational bias of the carcinogen may account for this non-canonical mutation, similar to that for canonical Q61L/R mutations in Kras. Second, G12D and Q61H mutations in Kras that did not fit this mutation signature, and instead shared similarity with Single Nucleotide Variations detected by Maximum-Depth Sequencing from normal cells, suggesting that perhaps these mutations were pre-existing. We thus posit that when canonical Kras mutations are selected against that the carcinogen may instead promote the expansion of pre-existing genomic driver mutations, although admittedly we cannot rule out other mechanisms. Interrogating the mutation signatures of human lung cancers similarly identified KRAS genomic driver mutations that failed to match the mutation signature of the tumor. Thus, we also speculate that the selection for non-canonical genomic driver mutations during urethane carcinogenesis may reflect the process by which discordance between genomic driver mutations and mutational signatures arises in human cancers.

Dataset Information

Comprehensive Genomic Characterization of Parathyroid Cancer Identifies Novel Candidate Driver Mutations and Core Pathways.

Publications

Comprehensive Genomic Characterization of Parathyroid Cancer Identifies Novel Candidate Driver Mutations and Core Pathways.

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