Abstract 3803: Genome-wide approach to identify gene targets of pleuropulmonary blastoma.
Authors: Seki Masafumi , Nisimura Riki , Okuno Yusuke , Yoshida Kenichi , Shiraishi Yuichi , Sanada Masashi , Kato Keisuke , Koh Katsuyoshi , Hanada Ryoji , Hayashi Yasuhide , Miyano Satoru , Ogawa Seishi , Takita Junko 
Published: August 2014

Abstract
Pleuropulmonary blastoma (PPB) is an extremely rare and highly aggressive pediatric pulmonary malignancy that is often part of inherited cancer syndrome. Recently, germline mutations of DICER1, a gene encoding an endoribonuclease type III critical to the generation of small noncoding regulatory RNAs were reported in the majority of familial PPB. However, little is known about other genetic changes than DICER1 mutations that are responsible for the development and/or progression of PPB. Therefore, to assess the genetic alterations underlying the pathogenesis of PPB, genome-wide analyses using whole-exome sequencing and 250K SNP array were performed in total of ten cases with non-familial PPB. Whole-exome sequencing was performed in two cases which primary tumor-relapse tumor pairs were available.
Although most mutations were commonly detected in both the primary and relapse tumors, several alterations were private to either of both samples, suggesting that clonal evolution derives genetic divergence in relapsed/metastatic tumors of PPB. In accordance with this, SNP array analysis also revealed several shared or private copy change variations, the most common finding was gain of the long arm of chromosome 8 in 7 cases, which was previously reported common in PPB.
Whole-exome sequencing disclosed that DICER1 mutation, major cause of familial PPB, was recurrently found in the primary and relapse tumors of one case, but not detected in the another case. In the validation cohort of 8 cases of non-familial PPB, all of them had DICER1 mutations, and 6 cases had compound heterozygous mutations of DICER1. Notably, homozygous DICER1 mutation was observed in one case, and subsequent SNP array analysis revealed uniparental disomy of 14q lesion harboring DICER1 in this case. Somatic origins of missense changes were confirmed in 2 of 10 cases, for which DNA was obtained from peripheral blood.
Meanwhile, whole-exome sequencing identified 13 candidate genes including the cadherin-related gene and a negative regulator of cell cycle in one case without DICER1 mutation. These gene mutations shared in primary and relapse samples, suggests that these are driver mutations rather than passenger mutations or non-functional SNPs.
In conclusion, DICER1 mutation might be a driver mutation not only in familial PPB, but also in non-familial PPB. While DICER1 mutation was reported only germline heterozygous mutation in familial PPB, we notably found compound heterozygous or homozygous DICER1 mutations in non-familial PPB. Furthermore, there were different clones between primary and relapse samples, suggests that clonal evolution contributes to relapse tumor progression.
Citation Format: Masafumi Seki, Riki Nisimura, Yusuke Okuno, Kenichi Yoshida, Yuichi Shiraishi, Masashi Sanada, Keisuke Kato, Katsuyoshi Koh, Ryoji Hanada, Yasuhide Hayashi, Satoru Miyano, Seishi Ogawa, Junko Takita. Genome-wide approach to identify gene targets of pleuropulmonary blastoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3803. doi:10.1158/1538-7445.AM2013-3803