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Updated: Mar 9, 2026
A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
Published on: December 7, 2014
Mutation screening of ACKR3 and COPS8 in kidney cancer cases from the CONFIRM study
Maryam Mahmoodi1, Tu Nguyen-Dumont2, Fleur Hammet1
1Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Melbourne, VIC, 3010, Australia.
Abstract:
An apparently balanced t(2;3)(q37.3;q13.2) translocation that appears to segregate with renal cell carcinoma (RCC) has indicated potential areas to search for the elusive genetic basis of clear cell RCC. We applied Hi-Plex targeted sequencing to analyse germline DNA from 479 individuals affected with clear cell RCC for this breakpoint translocation and genetic variants in neighbouring genes on chromosome 2, ACKR3 and COPS8. While only synonymous variants were found in COPS8, one of the missense variants in ACKR3:c.892C>T, observed in 4/479 individuals screened (0.8%), was predicted likely to damage ACKR3 function. Identification of causal genes for RCC has potential clinical utility, where risk assessment and risk management can offer better outcomes, with surveillance for at-risk relatives and nephron sparing surgery through earlier intervention.
Insights
A balanced translocation linked to clear cell renal cell carcinoma (RCC) was investigated. A potentially damaging variant in the ACKR3 gene was identified in 0.8% of patients, offering insights into RCC genetics.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- The genetic underpinnings of clear cell renal cell carcinoma (ccRCC) remain incompletely understood.
- A specific translocation, t(2;3)(q37.3;q13.2), has been observed to segregate with ccRCC, suggesting its potential role.
Purpose of the Study:
- To investigate the t(2;3)(q37.3;q13.2) translocation and its associated genetic variants in the germline DNA of ccRCC patients.
- To identify potential causal genes for ccRCC, focusing on ACKR3 and COPS8.
Main Methods:
- Hi-Plex targeted sequencing was employed to analyze germline DNA from 479 individuals with ccRCC.
- Analysis focused on the breakpoint translocation and genetic variants in neighboring genes ACKR3 and COPS8 on chromosome 2.
Main Results:
- No pathogenic variants were found in COPS8, with only synonymous variants identified.
- A missense variant in ACKR3 (c.892C>T) was detected in 4 out of 479 individuals (0.8%) and predicted to likely impair ACKR3 function.
Conclusions:
- The identified ACKR3 variant represents a potential genetic contributor to ccRCC.
- Understanding these genetic factors can aid in risk assessment, early intervention, and improved patient outcomes for renal cell carcinoma.
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