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

Abstract

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/mm2. 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.

IMP dehydrogenase rod/ring structures in acral melanomas

“…Heterogeneity within and between tumors has been described in different tumor types and organs (Bonin & Stanta, ; Burrell, McGranahan, Bartek, & Swanton, ; Carapeto et al, ; Comodo‐Navarro et al, ; Harbst et al, ; de Souza et al, ). We have recently reported that acral melanomas are heterogeneous at the level of gene mutation ( BRAF mutation and KIT mutation) and regarding immune‐expression of several cell‐cycle proteins (Carapeto et al, ; Comodo‐Navarro et al, ; Fernandes et al, ). Using a TMA collection of well‐characterized ALM specimens, we now demonstrate that IMPDH RR structures are present increased in ALM, but there is heterogeneity in the frequency of RR‐positive cells across different sections of a given ALM specimen.…”

The tumor genetics of acral melanoma: What should a dermatologist know?

“…3,22,40 KIT mutations activate both the mitogen-activated protein kinase and PI3K/AKT pathways. 41 Most KIT mutations described in acral Activated in more than 90% of melanomas 7 Stimulated by activating BRAF and NRAS mutations and inactivating NF1 mutations 5 Stimulated by upstream receptor tyrosine kinases (eg, KIT ) 8 Collateral effects allow tumor to evade immune system 5 Constitutive activation of this pathway demonstrated in ALM (in situ and invasive) and the AM group as a whole 5,9 PI3K/AKT/PTEN 5 Permits cellular survival (antiapoptotic) 10 PTEN antagonizes the PI3K/AKT/mTOR pathway, acts as a tumor suppressor 10 Stimulated by upstream receptor tyrosine kinases (eg, KIT ) 8 JAK/STAT3 5 Regulates cellular proliferation, differentiation, migration, and survival (context dependent) 11 Regulates the PD-1 immune checkpoint, a mechanism of immune escape for melanomas 12 May correlate with more advanced AM 5 TERT 5 Regulates telomere maintenance 13 TERT activation essential in tumor development Confers immortality to melanoma cells by maintaining telomere length 13 Abnormally activated in 37% of AM patients in 1 study 14 CDK4/CDKN2A 5 Directs the cell cycle CDK4 = an oncogene CDKN2A = a tumor suppressor gene that encodes p16 RB1 and p53 also involved in this pathway Also stimulated by the MAPK pathway via cyclin D1 15…”

“…Analysis of a single clone of tumor cells may disregard important driver mutations in other tumor clones. 7 , 29 , 30 Molecular alterations leading to tumor progression and metastases are poorly understood.…”

“… 30 This is a possible mechanism for failure of targeted therapy, including the development of recurrences. 7 It was detected in acral melanoma during assessment of BRAF and KIT mutations. 7 , 63 It is an extensive and early event in acral melanoma development.…”

“… 7 It was detected in acral melanoma during assessment of BRAF and KIT mutations. 7 , 63 It is an extensive and early event in acral melanoma development. 64 Thus, the concept of “treating a single mutation” is an oversimplification.…”