Melanocytic nevi and melanoma: unraveling a complex relationship

Abstract

Approximately 33% of melanomas are derived directly from benign, melanocytic nevi. Despite this, the vast majority of melanocytic nevi, which typically form as a result of BRAFV600E-activating mutations, will never progress to melanoma. Herein, we synthesize basic scientific insights and data from mouse models with common observations from clinical practice to comprehensively review melanocytic nevus biology. In particular, we focus on the mechanisms by which growth arrest is established after BRAFV600E mutation. Means by which growth arrest can be overcome and how melanocytic nevi relate to melanoma are also considered. Finally, we present a new conceptual paradigm for understanding the growth arrest of melanocytic nevi in vivo termed stable clonal expansion. This review builds upon the canonical hypothesis of oncogene-induced senescence in growth arrest and tumor suppression in melanocytic nevi and melanoma.

Melanoma: What do all the mutations mean?

“…Melanomagenesis requires cooperation between mutant BRAF and other pathways. Mouse models have demonstrated that concurrent BRAF activating mutations and PTEN inactivating mutations result in melanomagenesis 46–48 . Also, mice with BRAF V600E mutations as well as CDKN2A loss develop larger melanomcytic nevi with a very small proportion progressing to melanoma.…”

“…Also, mice with BRAF V600E mutations as well as CDKN2A loss develop larger melanomcytic nevi with a very small proportion progressing to melanoma. However, when BRAF / CDKN2A mutant mice also have loss of Lkb1, they demonstrate marked activation of mTORC2/Akt resulting in rapidly progressive melanomas 46, 49 . These findings demonstrate some of the complexities underlying melanomagenesis and the need for further understanding of the relationship between BRAF and other mutations.…”

“…Mouse models have demonstrated that concurrent BRAF-activating mutations and PTEN-inactivating mutations result in melanomagenesis. [45][46][47] In addition, mice with BRAF V600E mutations as well as CDKN2A loss develop larger melanocytic nevi, with a very small percentage progressing to melanoma. However, when BRAF/ CDKN2A-mutant mice also have loss of Lkb1, they demonstrate marked activation of mTORC2/Akt, resulting in rapidly progressive melanomas.…”

TERT promoter mutation subtypes and survival in stage I and II melanoma patients

“…Mutations affecting the MAP‐kinase pathway are the earliest somatic genetic alterations that affect mainly the BRAF gene or to a lesser extent NRAS . Activating BRAF mutations arise early and play a role in the formation of melanocytic nevi that represent the oncogene induced senescence stage in melanocyte transformation . Conversion of nevus into lesions with malignant potential includes escape from oncogene‐induce senescence through inactivation of checkpoint inhibitors like CDKN2A .…”

“…4,5 Activating BRAF mutations arise early and play a role in the formation of melanocytic nevi that represent the oncogene induced senescence stage in melanocyte transformation. 6 Conversion of nevus into lesions with malignant potential includes escape from oncogeneinduce senescence through inactivation of checkpoint inhibitors like CDKN2A. 7 Acquisition of unlimited replication capabilityone of the major cancer hallmarks-surmounts the telomere crisis through rejuvenation of telomerase.…”