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Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
Published on: June 7, 2019
BRAF gene is somatically mutated but does not make a major contribution to malignant melanoma susceptibility: the
Milena Casula1, Maria Colombino, Maria P Satta
1Istituto di Chimica Biomolecolare-Sezione di Sassari, CNR, Località Tramariglio-Alghero, 07040 Santa Maria La Palma (Sassari), Italy.
Purpose:
Ocogenic activation of the BRAF gene has been demonstrated to be involved in the pathogenesis of malignant melanoma (MM). In this study, we investigated the contribution of BRAF to melanoma susceptibility, also making a comparison with frequency of CDKN2A germline mutations in MM patients from different areas in Italy.
Patients And Methods:
sing a combination of denaturing high-performance liquid chromatography analysis and automated sequencing on genomic DNA from peripheral blood or tumor tissue samples, 569 MM patients (211 from northern Italy and 358 from southern Italy) were screened for BRAF mutations.
Results:
Three BRAF germline sequence variants (M116R, V599E, and G608H) were identified in four (0.7%) of 569 MM patients. The most common BRAF mutation, V599E, was detected in one germline DNA sample only; M116R and G608H were newly described mutations. A high frequency (59%) of BRAF mutations was instead observed in tumor samples from patients also undergoing germline DNA analysis; at the somatic level, substitution of valine 599 was found to account for the majority (88%) of BRAF mutations. We then estimated the germline mutation rates in BRAF and CDKN2A among 358 consecutively collected patient samples originating in southern Italy; a low (2.5%) or very low (0.29%) prevalence of CDKN2A and BRAF mutations, respectively, was detected.
Conclusion:
utation analysis of either blood DNA from a large collection of MM patients or matched MM tissues from a subset of such patients revealed that BRAF is somatically mutated and does not play a major role in melanoma susceptibility. The present study further suggests that patient origin may account for different mutation rates in candidate genes.
Insights
BRAF mutations are common in malignant melanoma tumors but rare in patient germline DNA, indicating BRAF does not significantly contribute to melanoma susceptibility. Patient origin may influence mutation rates in genes like BRAF and CDKN2A.
Area of Science:
- Oncology
- Genetics
- Dermatology
Background:
- BRAF gene mutations are implicated in malignant melanoma (MM) pathogenesis.
- Understanding the role of BRAF in melanoma susceptibility is crucial.
Purpose of the Study:
- Investigate BRAF's contribution to melanoma susceptibility.
- Compare BRAF and CDKN2A germline mutation frequencies in Italian MM patients.
- Differentiate between germline and somatic BRAF mutations in MM.
Main Methods:
- Screened 569 MM patients (211 North Italy, 358 South Italy) for BRAF mutations using DHPLC and automated sequencing.
- Analyzed genomic DNA from peripheral blood or tumor tissue.
- Estimated germline mutation rates for BRAF and CDKN2A in 358 Southern Italian MM patients.
Main Results:
- Identified three BRAF germline variants (M116R, V599E, G608H) in 0.7% of MM patients.
- Observed a high frequency (59%) of BRAF mutations in tumor samples; V599E accounted for 88% of somatic mutations.
- Found low prevalence of CDKN2A (2.5%) and BRAF (0.29%) germline mutations in Southern Italian patients.
Conclusions:
- BRAF is somatically mutated in malignant melanoma but does not play a major role in melanoma susceptibility.
- Germline BRAF mutations are rare in the studied MM population.
- Patient geographic origin may influence mutation rates in candidate melanoma susceptibility genes like BRAF and CDKN2A.
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