Although the current study did not find a significant difference in gender distribution or age between BRAF wild-type and mutant patients, the small number of patients in the BRAF mutant group makes it difficult to draw definitive conclusions.
Interestingly, a predominance of BRAF V600E mutation in females has been reported by others14 while we found a non-statistically significant trend towards female predominance. BRAF mutation is also more commonly found in females in colorectal cancer23,24.
This finding is akin to the female predominance of EGFR mutations and may represent a similar underlying mechanism.
An association betweenEGFR mutation and oestrogen receptor has been found, possibly indicating a hormonally driven phenomenon25. However, a clear mechanism has yet to be substantiated.
The BRAF V600E mutation has been previously reported to be associated with the aggressive micropapillary subtype of lung adenocarcinoma14,26.
This finding is supported by the current study as both patients with a micropapillary component showed BRAF V600E mutation. However, it is difficult to be conclusive due to the small number of patients in the current study precluding statistical analysis.
The most common BRAF mutation in melanoma is the V600E mutation, which accounts for more than 90% of mutations6. However, the current study shows that BRAF V600E mutation only accounts for 58% of mutations in NSCLC.
This finding is supported by others who found the non-V600E mutation rate to be between 50-89%16,27. Although the biological significance of this is unknown, this raises the possibility thatBRAF-related oncogenesis in NSCLC arises from a different mechanism compared to melanomas with V600E mutations.
It has been shown that the V600E mutation confers a much higher kinase activity compared to other mutations within the kinase domain7. The G469V mutation found in the current study occurs in the P-loop which is the ATP binding site.
Mutations within the P-loop have been shown to have a lower activity compared to wild-type BRAF7, therefore whether these mutations drive oncogenesis is uncertain. Similarly, rare mutations at codons 439 and 440 (AKT phosphorylation motif) have been reported in NSCLC and they do not increase the oncogenic properties of BRAF28.
This indicates that the genotype of the BRAF mutation may be an important therapeutic consideration. Unfortunately, there is currently only limited phase I clinical trial data for RAF inhibitors in NSCLC19 and the significance of the different mutation spectrum remains uncertain.
In conclusion, the current study confirmed that a small proportion of NSCLC patients harbour BRAF mutations. Their clinicopathological characteristics appear to differ from patients with EGFR mutations and their genotype differs from that found in melanoma.
Further work needs to be done to determine whether this small subset of patients will benefit from BRAF inhibitors.
The authors would like to thank Thang Tran for performing the statistical analysis. WC and SOT have received funding from National Foundation for Medical Research and Innovation.
Disclosure: The authors declare no conflict of interest.
Peter P. Luk1, Bing Yu2,3, Chiu Chin Ng2, Belinda Mercorella2, Christina Selinger1, Trina Lum1, Steven Kao4, Sandra A. O’Toole1,3,5, Wendy A. Cooper1,3,6
1Department of Tissue Pathology and Diagnostic Oncology, 2Department of Medical Genomics, Royal Prince Alfred Hospital, Sydney, Australia; 3Sydney Medical School, University of Sydney, Sydney, Australia; 4Lifehouse Cancer Centre, The Chris O’Brien Lifehouse, Sydney, Australia; 5Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia; 6School of Medicine, University of Western Sydney, Sydney, NSW,Australia
Correspondence to: A/Prof. Wendy Cooper. Department of Tissue Pathology and Diagnostic Oncology, The Royal Prince Alfred Hospital, Camperdown NSW 2050, Australia. Email: [email protected]
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Source: Translational Lung Cancer Research.