Whole exome and targeted deep sequencing identify genome-wide allelic loss and frequentSETDB1mutations in malignant pleural mesotheliomas

// Hio Chung Kang 1, 2, * , Hong Kwan Kim 1, 3, * , Sharon Lee 4 , Pedro Mendez 1 , James Wansoo Kim 4 , Gavitt Woodard 1 , Jun-Hee Yoon 1 , Kuang-Yu Jen 5 , Li Tai Fang 1 , Kirk Jones 5 , David M. Jablons 1, 2 , Il-Jin Kim 1, 2 1 Thoracic Oncology Laboratory, Department of Surgery, University of California San Francisco, San Francisco, CA, USA 2 Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA 3 Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 4 CureSeq Inc, Brisbane, CA, USA 5 Department of Pathology, University of California San Francisco, San Francisco, CA, USA * These authors have contributed equally to this work Correspondence to: Il-Jin Kim, e-mail: Il-Jin.Kim@ucsf.edu David M. Jablons, e-mail: David.Jablons@ucsf.edu Keywords: malignant pleural mesothelioma, multiple primary cancer, genome-wide allelic loss, exome sequencing, SETDB1 Received: October 05, 2015 Accepted: January 15, 2016 Published: January 27, 2016 ABSTRACT Malignant pleural mesothelioma (MPM), a rare malignancy with a poor prognosis, is mainly caused by exposure to asbestos or other organic fibers, but the underlying genetic mechanism is not fully understood. 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. We found that 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 68 additional MPM patients (mutation frequency: 10%, 7/69) by targeted deep sequencing. Our observations suggest the possibility of a new genetic mechanism in the development of either MPM or multiple primary cancers. The frequent SETDB1 inactivating mutations suggest there could be new diagnostic or therapeutic options for MPM.