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Published on: October 14, 2015
High frequency of BRAF mutations and concomitant KRAS mutations in Taiwanese ovarian clear cell carcinoma
Huang-Pin Shen1, Ming-Yung Lee2, Wan-Ru Chao3
1Department of Obstetrics and Gynecology, Chung-Shan Medical University and Chung-Shan Medical University Hospital, Taichung, Taiwan, Republic of China.
Objectives:
Given encouraging clinical evidence of BRAF inhibitors for melanoma, etc., we investigated BRAF mutation status in ovarian clear cell carcinoma (OCCC) from Taiwanese women and assessed the association of BRAF mutation with KRAS mutation.
Materials And Methods:
DNA was extracted from microdissected tissue samples and analyzed for BRAF mutations in exon 15, around the activation segment (AS), using a highly sensitive BRAF mutant enrichment kit (FemtoPath®) with Sanger sequencing.
Results:
All 17 OCCC cases were evaluated. 16 (94.12 %) harbored BRAF missense mutations, categorized as Class I - p.V600M (n = 3); Class II - p.A598V (n = 8), p.T599I (n = 10); Class III - none; and unclassified (UC) variants - p.A598T (n = 1), p.A598I (n = 1), p.S602A (n = 1), p.S602F (n = 7). These mutations occurred as single-point (n = 6), double-point (n = 5), or triple-point (n = 5) mutations. The most frequent mutation observed was p.T599I (n = 10), followed by p.A598V (n = 8) and p.S602F (n = 7). The p.A598I, p.S602A, and p.S602F are novel BRAF alterations. Merging our previous KRAS data, we found that concurrent KRAS and BRAF mutations in 11 of 17 cases (64.71 %) suggest a possible synergistic effect in OCCC tumorigenesis.
Conclusions:
Activating BRAF mutations are common in OCCC in Ascian Taiwanese, with p.T599I most prevalent. This suggests the potential for reduced response to current BRAF V600 inhibitors but possible sensitivity to dual BRAF/MEK or MEK inhibitors, other multi-targeted approaches, and new avenues for cancer immunotherapy. Further studies are encouraged to investigate the clinical benefits of these approaches for advanced OCCC with various BRAF mutation classes.
Insights
Activating BRAF mutations are frequent in ovarian clear cell carcinoma (OCCC) in Taiwanese women, with p.T599I being the most common. This finding has implications for targeted therapy selection in OCCC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- BRAF inhibitors show clinical promise in melanoma.
- Ovarian clear cell carcinoma (OCCC) is a distinct subtype of ovarian cancer.
- Understanding the genetic landscape of OCCC is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the prevalence and spectrum of BRAF mutations in OCCC among Taiwanese women.
- To assess the association between BRAF mutations and KRAS mutations in OCCC.
- To explore the potential therapeutic implications of identified BRAF alterations.
Main Methods:
- DNA was extracted from microdissected OCCC tissue samples.
- BRAF mutations in exon 15 were analyzed using a sensitive enrichment kit and Sanger sequencing.
- KRAS mutation data was integrated for correlative analysis.
Main Results:
- Activating BRAF missense mutations were detected in 94.12% of the 17 evaluated OCCC cases.
- The most frequent BRAF alteration was p.T599I, followed by p.A598V and p.S602F.
- Novel BRAF alterations (p.A598I, p.S602A, p.S602F) were identified.
- Concurrent BRAF and KRAS mutations were observed in 64.71% of cases, suggesting a synergistic role in tumorigenesis.
Conclusions:
- Activating BRAF mutations are common in OCCC in Taiwanese patients, with p.T599I being the most prevalent.
- The high prevalence of non-V600 BRAF mutations suggests limited efficacy of current BRAF V600 inhibitors.
- Patients may benefit from dual BRAF/MEK inhibitors, MEK inhibitors, or other targeted therapies, warranting further clinical investigation.
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