Dados do Resumo

Título

Mutational spectrum revealed in hepatoblastomas by genome sequencing

Introdução

Pediatric cancers is a complex multifactorial group of diseases with a global incidence of approximately 400 000 new cases each year. Hepatoblastoma (HB) is a rare type of liver embryonal tumor accounting for 1% of all pediatric cancers. Several risk factors were associated with HB etiology, such preterm/low birth weight), parental smoking, congenital anomalies, and genetic predisposition. Due to its rarity, a comprehensive catalogue of germline and somatic mutations remains to be obtained.

Objetivo

The aim of this study was to unveil deleterious germline and somatic variants in HB cases using genome sequencing (GS) of paired blood/tumor samples.

Métodos

Genomic DNA was obtained from paired blood/tumor samples of six unrelated children who developed HB. GS was performed by BGI GenomicsⒸ through the BGI DNBSEQTM sequencing technology. Variant analysis was based on the Franklin Genoox platform and VarSeq software 2.2.1 (Golden Helix®). Variant prioritization parameters were read depth (≥10), Phred score (≥20), alternative variant allele frequency (≥15%), very low frequencies (<1% for germline and <0.0005% for somatic variants) in population databases, variant type (Loss-of-Function and missense for coding; mapped to regulatory regions for non-coding), in silico pathogenicity scores , and disease association (cancer predisposition, hepatoblastoma and liver function gene panels). This study was approved by the Research Ethics Committee of the Clinical Hospital - Faculty of Medicine of the University of São Paulo (CAAE 47277115.0.0000.0068) AC Camargo Câncer Center (1987/14) and Institute of Biosciences (CAAE 75570423.3.0000.5464). Informed consent was obtained from the parents.

Resultados

After quality filtering, we identified 9,099 germline variants and 570 somatic coding/ 15,328 somatic non-coding variants among six tumor-germline pairs. We prioritized 44 germline and 18 somatic variants based on scores of pathogenicity and function. Among germline variants, CYP21A2, ALDOB, and TRIM71 genes were highlighted since they were reported to be associated with liver function and poor prognosis in liver cancer. The pathogenic missense variants (p.G34V and p.G34E) in CTNNB1 were detected; variants in EXT1 and CANT1, previously associated with poor prognosis in bile duct cancer, breast cancer, leukemia, and hepatocellular carcinoma; and the pathogenic p.A16V missense variant in PRSS1 (two tumors), which is a bona fide predisposition gene in pancreatic cancer. Furthermore, 723 non-coding variants have been already reported in COSMIC in several cancer types. Querying non-coding mutations against liver cancer variants deposited in the LncBook 2.0 database, a 3’UTR variant with a significant FATHMM-MKL Score (0.9833) was detected in PABPC1, a hepatocellular carcinoma oncogene.

Conclusões

The reccurently mutated HB gene was detected (CTNNB1), and germline, somatic mutations in genes associated with liver function or poor prognosis in liver cancer were highlighted. A recurrent somatic deleterious missense variant was disclosed in PRSS1 in two samples, suggesting this gene as a new candidate for hepatoblastoma development. Regarding non-coding somatic variants, a 3’UTR variant at PABPC1, a gene associated with hepatocellular carcinoma, can be of potential relevance.

Financiador do resumo

FAPESP (2013/08028-1, 2018/21047-9, 2023/17465-8); CNPq (grant number 305101/2022-6); CAPES (88887.903185/2023-00).

Palavras Chave

hepatoblastoma; genome sequencing; somatic and germline mutations