Abstract 108: Whole exome and targeted deep sequencing identify genome-wide allelic loss and frequent SETDB1 mutations in malignant pleural mesotheliomas

Abstract

Abstract Malignant pleural mesothelioma (MPM) is a rare malignancy with a highly unfavorable prognosis. A strong link has been established between increased risk for MPM and exposure to asbestos or erionite. As asbestos had widely been used in different industries, the incidence of MPM in the United States is expected to steadily rise and peak with about 70,000 new MPM cases over the next 20 years. Median survival has ranged from 10-17 months. But the underlying genetic mechanism is not fully understood. Moreover, genetic alterations and causes for multiple primary cancer development including MPM are unknown. We used whole exome sequencing to identify somatic mutations in a patient with MPM and two additional primary cancers who had no evidence of venous, arterial, lymphovascular, or perineural invasion indicating dissemination of a primary lung cancer to the pleura. The development of multiple primary malignancies including a rare MPM led us to search for underlying genetic alterations. Interestingly, most mutations identified in the MPM patient were highly enriched for the mutant allele, suggesting a homozygous alteration or deletion of wild-type allele when minimal contamination of normal pleura in the MPM is taken into consideration. We found that most variants identified showed a high frequency of mutant alleles, except variants on chromosomes 7, 16 and 20. Analysis of tumor allelic ratio to normal using all variants in exome sequencing revealed that this mesothelioma showed genome-wide allelic loss or loss of heterozygosity (LOH), which appears to be distinct from other cancers that have many genetic alterations with focal allelic loss. To the best of our knowledge, this type of extensive genome-wide allelic loss has not been described in MPM. Whole exome sequencing analysis revealed the MPM had R282W, a key TP53 mutation, and genome-wide allelic loss or loss of heterozygosity, a distinct genomic alteration not previously described in MPM. We identified frequent inactivating SETDB1 mutations in this patient and in 77 additional MPM patients (mutation frequency: 9%, 7/78) by targeted deep sequencing. In summary, we identified genome-wide allelic loss in a patient who had MPM and two additional primary cancers, results which suggest that careful analysis in exome sequencing is needed to detect genome-wide deletion in MPM samples with or without multiple primary cancers. The high frequency of mutations in SETDB1 that we found suggests that this and other histone-related genes are important in MPM. Citation Format: Hio Chung Kang, Hong Kwan Kim, Sharon Lee, Pedro Mendez, James Kim, Gavitt Woodard, Kuang-Yu Jen, Li Tai Fang, Kirk Jones, David Jablons, Il Jin Kim. Whole exome and targeted deep sequencing identify genome-wide allelic loss and frequent SETDB1 mutations in malignant pleural mesotheliomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 108.