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Mutations in LRRC50 predispose zebrafish and humans to seminomas
Sander G Basten1, Erica E Davis, Ad J M Gillis
1Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.
Plos Genetics
|April 20, 2013
Summary
Researchers identified a new gene, Leucine-Rich Repeat Containing protein 50 (LRRC50), linked to seminoma development. Mutations in LRRC50 predispose individuals to this testicular cancer, suggesting it acts as a tumor suppressor.
Area of Science:
- Oncology
- Genetics
- Developmental Biology
Background:
- Seminoma, a type of testicular germ cell tumor (TGCT), is the most common cancer in young men.
- The incidence of TGCT is increasing, highlighting the need for new insights into its pathogenesis.
Purpose of the Study:
- To identify novel genes predisposing to seminoma formation.
- To establish a vertebrate model for studying seminoma development.
- To investigate the role of Leucine-Rich Repeat Containing protein 50 (LRRC50) in seminoma.
Main Methods:
- Utilized a zebrafish model with a heterozygous nonsense mutation in lrrc50 (Leucine-Rich Repeat Containing protein 50).
- Analyzed tumor samples for loss of heterozygosity (LOH) of the wild-type lrrc50 allele.
- Screened human pedigrees and seminoma patient cohorts for germline and somatic LRRC50 mutations.
Main Results:
- Zebrafish with lrrc50 mutations exhibited high susceptibility to seminoma formation.
- Loss of heterozygosity (LOH) of lrrc50 was observed in 44.4% of zebrafish tumors, correlating with progression.
- Identified pathogenic LRRC50 mutations (nonsense and missense) in human seminoma patients, with some mutations showing loss-of-function.
- A specific pathogenic variant (Gln307Glu) was significantly enriched in seminoma patients (13% of cohort).
Conclusions:
- LRRC50 is implicated as a novel tumor suppressor gene in human seminoma pathogenesis.
- The study introduces a valuable zebrafish model for investigating seminoma.
- Genetic alterations in LRRC50 contribute to seminoma development.
