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Mutational Analysis of BRAF Inhibitor-Associated Squamoproliferative Lesions
Britt Clynick1, Tania Tabone1, Kathryn Fuller1
1Translational Cancer Pathology Laboratory, School of Pathology and Laboratory Medicine, The University of Western Australia, Crawley, Western Australia, Australia.
Abstract:
In recent years, there has been increasing use of BRAF-inhibiting drugs for the treatment of various malignancies, including melanoma. However, these agents are associated with the development of other nonmelanoma skin lesions, in particular squamoproliferative lesions such as keratoacanthomas (KAs), squamous cell carcinomas, and BRAF inhibitor-associated verrucous keratoses. The molecular pathogenesis of these lesions is of interest, not only for therapeutic reasons, but also for the insight it might provide into the development of similar lesions in a sporadic setting. We used next-generation sequencing to compare the mutational profiles of lesions after treatment with a BRAF inhibitor, with similar lesions arising sporadically. HRAS mutations were common among the BRAF inhibitor-induced lesions, being identified in 56%, compared with 14% of lesions in the sporadic group (P = 0.002). Thus, despite similar histomorphological appearances, the underlying molecular mechanisms may be different. In addition, within the BRAF inhibitor-associated group, the lesions designated as KAs and BRAF inhibitor-associated verrucous keratoses had a similar mutational profile (mutations in PIK3CA, APC, and HRAS), which was distinct to that seen in squamous cell carcinomas (FGFR3, CDKN2A, and STK11). We have previously noted histological overlap between KAs and BRAF inhibitor-associated verrucous keratoses, and this finding supports the notion that they may represent morphological or temporal variants of a single lesion type.
Insights
BRAF inhibitor drugs can cause skin lesions like keratoacanthomas. Next-generation sequencing revealed HRAS mutations are common in drug-induced lesions, unlike sporadic ones, suggesting different molecular causes for similar-looking skin conditions.
Area of Science:
- Oncology
- Dermatology
- Genetics
Background:
- BRAF inhibitors are increasingly used for cancers like melanoma.
- These drugs can induce nonmelanoma skin lesions, including keratoacanthomas (KAs) and squamous cell carcinomas.
- Understanding the molecular basis of these lesions is crucial for treatment and insights into sporadic lesion development.
Purpose of the Study:
- To compare the mutational profiles of BRAF inhibitor-induced skin lesions with those arising sporadically.
- To investigate the molecular pathogenesis of squamoproliferative lesions associated with BRAF inhibitor therapy.
Main Methods:
- Next-generation sequencing was employed to analyze the mutational landscape of skin lesions.
- Lesions from patients treated with BRAF inhibitors were compared to sporadically occurring lesions.
Main Results:
- HRAS mutations were significantly more frequent in BRAF inhibitor-induced lesions (56%) compared to sporadic lesions (14%).
- BRAF inhibitor-associated keratoacanthomas (KAs) and verrucous keratoses shared a similar mutational profile (PIK3CA, APC, HRAS).
- Squamous cell carcinomas exhibited distinct mutations (FGFR3, CDKN2A, STK11) compared to KAs and verrucous keratoses.
Conclusions:
- BRAF inhibitor-induced and sporadic squamoproliferative lesions may arise from different molecular pathways despite similar histology.
- Keratoacanthomas and BRAF inhibitor-associated verrucous keratoses might represent variants of the same lesion type based on shared mutational profiles.
- Distinct molecular profiles differentiate BRAF inhibitor-associated squamous cell carcinomas from keratoacanthomas and verrucous keratoses.
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