A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Role of variant allele fraction and rare SNP filtering to improve cellular DNA repair endpoint association
Tekijät: David M. Vossen, Caroline V. M. Verhagen, Reidar Grénman, Roelof J. C. Kluin, Marcel Verheij, Michiel W. M. van den Brekel, Lodewyk F. A. Wessels, Conchita Vens
Kustantaja: PUBLIC LIBRARY SCIENCE
Julkaisuvuosi: 2018
Lehti:PLoS ONE
Tietokannassa oleva lehden nimiPLOS ONE
Lehden akronyymi: PLOS ONE
Artikkelin numero: ARTN e0206632
Vuosikerta: 13
Numero: 11
Sivujen määrä: 16
ISSN: 1932-6203
DOI: https://doi.org/10.1371/journal.pone.0206632
Rinnakkaistallenteen osoite: https://research.utu.fi/converis/portal/detail/Publication/36983837
Background
Large cancer genome studies continue to reveal new players in treatment response and tumorigenesis. The discrimination of functional alterations from the abundance of passenger genetic alterations still poses challenges and determines DNA sequence variant selection procedures. Here we evaluate variant selection strategies that select homozygous variants and rare SNPs and assess its value in detecting tumor cells with DNA repair defects.
Methods
To this end we employed a panel of 29 patient-derived head and neck squamous cell carcinoma (HNSCC) cell lines, of which a subset harbors DNA repair defects. Mitomycin C (MMC) sensitivity was used as functional endpoint of DNA crosslink repair deficiency. 556 genes including the Fanconi anemia (FA) and homologous recombination (HR) genes, whose products strongly determine MMC response, were capture-sequenced.
Results
We show a strong association between MMC sensitivity, thus loss of DNA repair function, and the presence of homozygous and rare SNPs in the relevant FA/HR genes. Excluding such selection criteria impedes the discrimination of crosslink repair status by mutation analysis. Applied to all KEGG pathways, we find that the association with MMC sensitivity is strongest in the KEGG FA pathway, therefore also demonstrating the value of such selection strategies for exploratory analyses. Variant analyses in 56 clinical samples demonstrate that homozygous variants occur more frequently in tumor suppressor genes than oncogenes further supporting the role of a homozygosity criterion to improve gene function association or tumor suppressor gene identification studies.
Conclusion
Together our data show that the detection of relevant genes or of repair pathway defected tumor cells can be improved by the consideration of allele zygosity and SNP allele frequencies.
Ladattava julkaisu This is an electronic reprint of the original article. |  |
