In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 4592-4592
Abstract:
Hepatoblastoma (HB), the most common malignant liver tumor in children, is a biologically and clinically heterogeneous embryonal malignancy. Activation of the Wnt pathway is known to occur in the vast majority of HBs, most frequently through somatic mutation of CTNNB1 and less often from germline mutation of APC, but knowledge of other gene alterations is scant. To identify critical genes and pathways in the pathogenesis of HB and provide insight into potential clinically-relevant targets, we performed whole exome sequencing on 35 clinically-annotated tumor-normal pairs. Putative mutations identified through exome sequencing on Illumina-based instruments were confirmed on a second sequencing platform. A total of 130 somatic mutations were identified in 24 patients (3.7 mutations per tumor; range of 0 to 22 mutations), resulting in a somatic mutation rate of & lt; 0.2 mutations per Mb. CTNNB1 mutations were identified in 13 HBs (37%), confirming the central role of the Wnt pathway in HB. Somatic mutations were also found in other cancer genes, including the chromatin-remodeling genes MLL2 and ARID1A. Frequent somatic mutations were identified in genes related to regulation of oxidative stress, including recurrent point mutations in NFE2L2 (NRF2) and inactivating mutations in the thioredoxin-domain containing genes TXNDC15 and TXNDC16. An additional 27 HBs were sequenced for NFE2L2 mutations, revealing a mutation frequency of 6.5% (4 of 62 tumors). Mutations of NFE2L2 are known to occur in 5-10% of adult hepatocellular carcinomas (HCC) as well as in other tumor types: as in those tumors, the NFE2L2 mutations identified in HB (p.D29N in one patient and p.R34G in three patients) are clustered within the Neh2 domain and are expected to inhibit KEAP1-mediated degradation of NRF2, resulting in stabilization and nuclear accumulation of NRF2 and activation of downstream oxidative stress response genes. Most NFE2L2-mutated adult HCCs also contain mutations in CTNNB1 or other Wnt pathway genes, suggesting a biological link between NFE2L2-mutated HB and HCC. In addition, whole exome and SNP array data (Affymetrix 6.0 SNPChip) have revealed copy number alterations in previously-described regions of the HB genome, including 1q, 4q and 11p15, as well as novel focal alterations. Finally, germline variants in APC and other Wnt pathway genes have also been identified in this HB patient cohort. In summary, next-generation sequencing of HB has provided an unprecedented view of the genetic landscape of HB, confirmed the primary importance of dysregulation of Wnt signaling in this tumor type, and revealed recurrent hotspot mutations in NFE2L2, a potential therapeutic target. Supported by the Cancer Prevention & Research Institute of Texas (RP101195) and the National Institutes of Health (CA098543). Citation Format: Lisa R. Trevino, David A. Wheeler, Milton J. Finegold, Murali Chintagumpala, Kayuri U. Patel, Stephen F. Sarabia, Sarah A. Comerford, Robert E. Hammer, Dinesh Rakheja, Rebecka L. Meyers, Yidong Chen, Bradley H. Pollock, Gail E. Tomlinson, Dolores H. López-Terrada, D. Williams Parsons. Exome sequencing of hepatoblastoma reveals recurrent mutations in NFE2L2. [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 4592. doi:10.1158/1538-7445.AM2013-4592
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2013-4592
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2013
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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