Intratumor Heterogeneity of KIT Gene Mutations in Acral Lentiginous Melanoma.

Melanoma is an aggressive skin malignancy, and the acral lentiginous melanoma (ALM) subtype affects non-sun-exposed sites such as the volar surface of the hands and feet and the subungual region and is most common in Asians, Hispanics, and Afro-descendants. The presence of different clones within the same tumor seems to influence the aggressiveness of tumors. Patients with mutations in the KIT gene have shown a good response to tyrosine kinase inhibitor therapy. We tested the hypothesis of intratumor heterogeneity through analysis of KIT gene mutations in ALM and determined the correlation between KIT mutations and demographic, clinical, and histopathological variables. Twenty-five ALM samples were examined. We selected up to four different regions per tumor for sequencing by the Sanger method for analysis of KIT gene exon 11 and exon 13 mutations. Advanced lesions were predominant, and the main histopathological characteristics of lesions were Breslow index >4.0 mm (17/25, 68%), Clark level IV/V (21/25, 84%), ulceration (16/25, 64%), and >3 mitoses/mm (8/25, 32%). KIT gene mutations were detected in 11/25 cases (44%), and all these 11 cases displayed intratumor heterogeneity, that is, at least 2 tumor regions had different mutational profiles. The predicted effect of most mutations detected was detrimental to protein function. No significant correlations between histopathological variables and either KIT mutations or intratumor heterogeneity were observed. The hypothesis of intratumor heterogeneity of KIT gene mutations in acral lentiginous melanoma was supported.

Acral Lentiginous Melanomas Harbour Intratumor Heterogeneity in BRAF Exon 15, With Mutations Distinct From V600E/V600K.

The choice of appropriate therapeutic strategies may be influenced by intratumor heterogeneity and makes cancer treatment considerably more challenging. We aimed to evaluate the heterogeneity of BRAF exon 15 mutations in different areas of acral lentiginous melanoma (ALM). The entire exon 15 was sequenced in 4 different areas of paraffin-embedded samples from 26 patients with ALM. A total of 26 of 49 cases of ≥1 mm in depth of ALM identified by clinical, anatomical, and pathological data fulfilled the inclusion and exclusion criteria for this study. Tumors had a mean Breslow depth of 7.2 mm and an average mitotic index of 3 mitosis/mm. Mutations distinct from the common V600E and V600K were detected in 31%, and intratumor heterogeneity was observed in 31% of samples. Interestingly, 63.5% of all mutations had been previously associated with cancer. Most (62.5%) of the missense BRAF exon 15 mutations found in the ALM samples examined here were deemed "detrimental" for protein function according to at least 2 functional prediction programs, and 3 mutations (37.5%) were predicted to be "neutral," with no effect on protein function. BRAF exon 15 mutations were detected frequently in ALM and displayed heterogeneity, a finding to be further investigated.