In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 2223-2223
Abstract:
Introduction and Objective Testicular germ cell cancer (TGCC) is the most common solid malignancy among young adult males. Cure could be obtained by intensive chemotherapy combined with retroperitoneal lymph node dissection, but often with substantially compromised quality of life. As for the common genetic lesions, somatic mutations and amplifications of KIT are found in about 20%-30% of cases with TGCCs. However, the molecular pathogenesis of TGCC is still poorly understood. In this study, to obtain a better understanding of the genetic basis of TGCC and to identify druggable molecular targets, we performed whole exome sequencing as well as SNP array-based copy number analysis in TGCC. Methods All cases underwent high orchiectomy and were histologically diagnosed as TGCC. Genomic DNA was extracted from fresh frozen specimens of TGCC. Whole exome sequencing was performed for paired tumor/normal DNA from 10 TGCC patients, in which target exomes were captured using SureSelect Human All Exon V5 (Agilent Technologies) and subjected to massively parallel sequencing on the Illumina platform (HiSeq2000). Copy number variants were also interrogated in 40 TGCCs (25 seminomas and 15 non-seminomas) using Affymetrix 250K NspI array. Results TGCC genome was triploid in most cases with high level amplification in12p. Loss of heterozygosity (LOH) of chromosome 4 was frequently observed in both seminoma and non-seminoma, whereas 11q deletion was found predominantly in cases with seminoma. In addition, we identified recurrent focal amplifications involving 4q12 and 22q11, from which KIT and MAPK1 were identified, respectively. In whole exome sequencing, 15 somatic mutations were detected per sample on average, which was relatively lower than other solid malignancies. When combined the results of copy number analysis with those of whole-exome sequencing, genes involved in RAS signaling pathway and chromatin modification were frequently altered in TGCC. Conclusions Our comprehensive analyses revealed genomic aberrations of TGCC in terms of copy number alterations and gene mutations. Mutated/amplified KIT and MAPK1 and other RAS pathway gene could be potential targets of small molecule inhibitors for therapeutics. Citation Format: Yusuke Sato, Aiko Sato-Otsubo, Yasunobu Nagata, Kenichi Yoshida, Yuichi Shiraishi, Hiromichi Suzuki, Masashi Sanada, Haruki Kume, Satoru Miyano, Yukio Homma, Seishi Ogawa. Genome-wide analysis of copy number alterations and gene mutations in testicular germ cell cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2223. doi:10.1158/1538-7445.AM2014-2223
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2014-2223
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2014
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
