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Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features.

ABSTRACT: Age-related degenerative and malignant diseases represent major challenges for health care systems. Elucidation of the molecular mechanisms underlying carcinogenesis and age-associated pathologies is thus of growing biomedical relevance. We identified biallelic germline mutations in SPRTN (also called C1orf124 or DVC1) in three patients from two unrelated families. All three patients are affected by a new segmental progeroid syndrome characterized by genomic instability and susceptibility toward early onset hepatocellular carcinoma. SPRTN was recently proposed to have a function in translesional DNA synthesis and the prevention of mutagenesis. Our in vivo and in vitro characterization of identified mutations has uncovered an essential role for SPRTN in the prevention of DNA replication stress during general DNA replication and in replication-related G2/M-checkpoint regulation. In addition to demonstrating the pathogenicity of identified SPRTN mutations, our findings provide a molecular explanation of how SPRTN dysfunction causes accelerated aging and susceptibility toward carcinoma.

SUBMITTER: Lessel D

PROVIDER: S-EPMC4343211 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features.

Lessel Davor D Vaz Bruno B Halder Swagata S Lockhart Paul J PJ Marinovic-Terzic Ivana I Lopez-Mosqueda Jaime J Philipp Melanie M Sim Joe C H JC Smith Katherine R KR Oehler Judith J Cabrera Elisa E Freire Raimundo R Pope Kate K Nahid Amsha A Norris Fiona F Leventer Richard J RJ Delatycki Martin B MB Barbi Gotthold G von Ameln Simon S Högel Josef J Degoricija Marina M Fertig Regina R Burkhalter Martin D MD Hofmann Kay K Thiele Holger H Altmüller Janine J Nürnberg Gudrun G Nürnberg Peter P Bahlo Melanie M Martin George M GM Aalfs Cora M CM Oshima Junko J Terzic Janos J Amor David J DJ Dikic Ivan I Ramadan Kristijan K Kubisch Christian C

Nature genetics 20140928 11

Age-related degenerative and malignant diseases represent major challenges for health care systems. Elucidation of the molecular mechanisms underlying carcinogenesis and age-associated pathologies is thus of growing biomedical relevance. We identified biallelic germline mutations in SPRTN (also called C1orf124 or DVC1) in three patients from two unrelated families. All three patients are affected by a new segmental progeroid syndrome characterized by genomic instability and susceptibility toward ...[more]

PMID: 25261934

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Project description:Background Long noncoding RNAs (lncRNAs) are found to be novel biomarkers for hepatocellular carcinoma (HCC) and play an important role in tumor progression. We established a genomic instability-related long noncoding RNA signature (GIlncSig) as an independent prognosis factor and also investigated its impact on prognosis significance. Method Somatic mutation profiles, clinical characteristics, and RNA sequencing data were obtained from The Cancer Genome Atlas (TCGA) database. Lasso regression was used to construct GIlncSig. KEGG was used to identify the possible biological pathways. ESTIMATE and CIBERSORT algorithms were used to calculate the immune microenvironment scores and proportion of immune cells in HCC patients. The expression of LINC00501 was conducted by qRT-PCR. Cell proliferation was measured by EdU, CCK-8, and colony formation assay, and cell migration and invasion ability were measured by wound healing and transwell assay. Results 135 genomic instability-related lncRNAs were identified, and GIlncSig was constructed using 13 independent lncRNAs with significant prognosis values. Based on the GIlncSig, high-risk group had worse clinical outcomes than low-risk group, while high-risk group also had higher UBQLN4, KRAS, ARID1A, and PIK3CA expression. Moreover, the efficiency of GIlncSig combining single-gene mutation was higher than single-gene mutation alone such as TP53. The results of CIBERSORT and ESTIMATE showed that GS group and GU group had significantly different immune infiltration. In addition, LINC00501 was identified as a potential biomarker in HCC with strong relationship with clinical characteristics. In vitro assays validated that LINC00501 promoted proliferation and migration of HCC cell lines. Conclusion Our results showed that GIlncSig serves as a potential independent prognosis factor to predict HCC patients' prognosis for exploring potential mechanism and therapy strategy. Besides, LINC00501 plays an important role in the progression of HCC, which may be a potential therapy target.

Dataset Information

Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features.

Publications

Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features.

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