Genome-wide analysis of allelic imbalances reveals 4q deletions as a poor prognostic factor and MDM4 amplification at 1q32.1 in hepatoblastoma.
In a single-nucleotide polymorphism array-based analysis of 56 hepatoblastoma (HB) tumors, allelic imbalances were detected in 37 tumors (66%). Chromosome gains were found in 1q (28 tumors), 2q (24), 6p (8), 8q (8), 17q (6), and 20pq (10), and losses in 1p (6), 4q (9), and 16q (4). Fine mapping delineated the shortest overlapping region (SOR) of gains at 1q32.1 (1.3 Mb) and 2q24.2-q24.3 (4.8 Mb), and losses at 4q34.3-q35.2 (8.7 Mb) and 4q32.3 (1.6 Mb). Uniparental disomy of 11pter-11p15.4 (IGF2) and loss of 11pter-p14.1 were found in 11 and 2 tumors, respectively. Expression of HTATIP2 (11p15.1) was absent in 9 of 20 tumors. Amplification was identified in four tumors at 1q32.1, where the candidate oncogene MDM4 is located. In the 4q32.3-SRO, ANXA10S, a variant of the candidate tumor suppressor ANXA10, showed no expression in 19 of 24 tumors. Sequence analysis of ANXA10S identified a missense mutation (E36K, c.106G>A) in a HB cell line. Multivariate analysis revealed that both 4q deletion and RASSF1A methylation (relative risks: 4.21 and 7.55, respectively) are independent prognostic factors. Our results indicate that allelic imbalances and gene expression patterns provide possible diagnostic and prognostic markers, as well as therapeutic targets in a subset of HB.
Arai
Yasuhito
Y
Cancer Genomics Project, National Cancer Center Research Institute, Chuo-Ku, Tokyo, Japan.
Honda
Shohei
S
Haruta
Masayuki
M
Kasai
Fumio
F
Fujiwara
Yuiko
Y
Ohshima
Junjiro
J
Sasaki
Fumiaki
F
Nakagawara
Akira
A
Horie
Hiroshi
H
Yamaoka
Hiroyuki
H
Hiyama
Eiso
E
Kaneko
Yasuhiko
Y
D000123:Acetyltransferases; D022981:Allelic Imbalance; D017302:Annexins; D019411:Clinical Laboratory Techniques; D005796:Genes; D016678:Genome; D018197:Hepatoblastoma / Q000235:genetics*; D006801:Humans; D007610:Kallikreins; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins; D012106:Research; D017384:Sequence Deletion; D014157:Transcription Factors; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases
C121387:ANXA10 protein, human; D017302:Annexins; C461497:Mdm4 protein, mouse; D011518:Proto-Oncogene Proteins; C051838:TFF1 protein, human; D014157:Transcription Factors; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; D000123:Acetyltransferases; C111246:HTATIP2 protein, human; D044767:Ubiquitin-Protein Ligases; C501608:KLK15 protein, human; D007610:Kallikreins