Abstract 3294: Clonal evolution and integral analysis of hepatoblastoma
Authors: Hoshino Noriko , Seki Masafumi , Kato Motohiro , Yoshida Kenichi , Sato Yusuke , Nakazawa Atsuko , Miyano Satoru , Oka Akira , Iwanaka Tadashi , Hayashi Yasuhide , Ogawa Seishi , Takita Junko 
Published: August 2015

[Background]

Hepatoblastoma (HB) is a rare and heterogeneous childhood malignancy of liver. It is mainly affecting young children in the first 2 years of life, underscoring the unique sensitivity of the immature liver to tumorigenesis. The unique age range affected by this embryonal tumor suggests that developmental factors contribute to the tumor development. On the other hands it is well recognized activation of Wnt/β-catenin signaling pathway was frequently occurred in HB through somatic mutation of CTNNB1 and germline mutation of APC; however, the exact mechanism that normal hepatic developmental processes are altered by mutational events is an area of current research and the definitive contribution to tumorigenesis is unclear mainly due to its rarity.

[Methods]

To elucidate the genetic aberration underlying development and progression of HB, we performed whole exome sequencing and RNA sequencing using Illumina HiSeq 2000 on 14 HB specimens. In addition, we employed detailed genomic analysis on 5 multiple samples obtained from primary, post-chemotherapy and relapsed HB with familial adenomatous polyposis (FAP). All the candidates for mutations and fusions were validated by target and Sanger sequencing. Detected genetic alterations were sequenced in additional 53 HB samples.

[Results]

The somatic mutation rate was 8.1 (range of 1-41) per tumor with median of 0.16 non-silent mutations per Mb. It is statistically significant that number of somatic mutations is correlated with age. Consistent with the previous reports, most frequent mutated gene in our cohort was CTNNB1 with frequency of 71.4%. Overall, HBs have low mutation rates in concordance with other pediatric solid tumors. In our cohort, recurrent somatic mutations with high frequency was not detected, but overlapping germline mutations in Wnt signaling pathway were found, even if they were not affected with FAP. In total, 42 (79.2%) of 53 HB had mutations in genes regulating WNT/β-catenin signaling pathway. In multisampling sequencing analysis based on 5 different sites of HB specimens, progression from normal hepatocyte to HB seemed to be accompanied by few trancal events including only APC mutation in Wnt/β-catenin signaling pathway and gain of 1q and loss of 4q in copy number analysis.

The major clone of relapsed tumors derived from minor clone of the primary tumor after chemotherapy getting additional genomic aberrations.

[Conclusion]

Our results revealed that mutations in Wnt/βcatenin-signaling pathway were truncal and significant mutations. In addition, even if only one cases multisampling sequencing, it is useful for revealing clonal evolution of HB. This study disclosed comprehensive genetic features of HB and identified potentially important therapeutic targets, as well as insight into possible cancer predisposition genes.

Citation Format: Noriko Hoshino, Masafumi Seki, Motohiro Kato, Kenichi Yoshida, Yusuke Sato, Atsuko Nakazawa, Satoru Miyano, Akira Oka, Tadashi Iwanaka, Yasuhide Hayashi, Seishi Ogawa, Junko Takita. Clonal evolution and integral analysis of hepatoblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3294. doi:10.1158/1538-7445.AM2015-3294