Ultraviolet radiation and melanoma: a systematic review and analysis of reported sequence variants

Abstract

Despite the large body of mutational data available for melanoma and epidemiological studies linking this cancer to ultraviolet radiation (UVR), the fundamental carcinogenic mechanisms involved in melanoma remain largely unknown. To this end, we systematically reviewed, extracted, and analyzed mutational data from the extant melanoma literature in an effort to gain more insight into its early pathogenic events. We searched PubMed (1966-January 2006) using the words "mutation" AND "melanoma" in the title or abstract. Out of 2,095 returned results, there were 203 eligible studies that were subsequently analyzed. We cataloged 8,201 somatic and cultured melanoma specimens and annotated 2,041 reported somatic sequence variants. The single BRAF c.1799T>A (p.Val600Glu) alteration is the most prevalent variant while other A:T>T:A transversions were uncommon. Four highly-recurrent, non-ultraviolet B (UVB) changes account for most of the NRAS and BRAF variants. CDKN2A, PTEN/MMAC1, and TP53 harbored statistically higher rates of UVB signature changes (64.2%, 52.4%, and 69.2%, respectively) than oncogenic loci (NRAS: 15.3% and BRAF: 2.4%). More specifically, cutaneous melanomas showed a significantly higher proportion of UVB signature mutations at both TP53 and CDKN2A when compared to non-skin cancers using data from their respective locus-specific databases. Superficial spreading and nodular melanomas had the highest rates of BRAF (53.4%) and NRAS (28.0%) mutations. In melanoma, there is sufficient mutational evidence to support a role for direct UVB participation, especially at TP53 and CDKN2A. For oncogenes, the role for UVB is less clear since functionally-activating changes are uncommon and are subject to sequence constraints.

Melanoma Epidemiology and Prevention

“…PTEN, CDKN2A, and P53 harbor higher rates of UVB signature mutations than oncogenic BRAF and NRAS variants, and TP53 and CDKN2A harbor higher rates of UVB signature mutations than non-skin cancers [102]. Furthermore, PTEN mutations occur in approximately 50 % of melanomas from xeroderma pigmentosum patients, who are susceptible to UV mutagenesis, while BRAF, NRAS, and KIT mutation frequencies were lower than PTEN [160].…”

Targeted Therapy for Cutaneous Melanoma: Beyond BRAF...

“…3,13,14 Overall, recurrent hotspot mutations in NRAS are detected in ~20% of cutaneous melanomas. The majority (80%) of these mutations result in substitutions at the Q61 position of the NRAS protein, while the rest (20%) cause substitutions at the G12/G13 positions.…”

“…The majority (80%) of these mutations result in substitutions at the Q61 position of the NRAS protein, while the rest (20%) cause substitutions at the G12/G13 positions. 2,3 These mutations are essentially mutually exclusive with BRAF V600 mutations in treatmentnaïve melanomas. 15 In our study of ~700 melanoma patients who underwent mutation testing, BRAF V600 mutations and NRAS mutations were present concurrently in <1% of the tumors tested.…”

“…Subsequent large single-center studies and meta-analyses of clinical specimens demonstrated that the prevalence of BRAF V600 mutations is ~40-45% in cutaneous melanomas in patients. 2,3 The discovery of the high prevalence of activating BRAF mutations in melanoma strongly implicated activation of the RAS-RAF-MAPK signaling pathway as a critical factor in the pathogenesis of this disease. More importantly, this discovery led to the rapid and successful development of targeted therapies that provide marked clinical benefit in metastatic melanoma patients with BRAF V600 mutations.…”

Comprendre la mutagenèse somatique grâce à la cartographie des dommages à l’ADN

“…L'usage de doses d'irradiation conformes à celles des rayons solaires tend cependant à confirmer le rôle prédominant des UVB dans l'étiologie des cancers non mélanocytiques [11]. Toutefois, un point chaud de mutations au codon 600 du gène BRAF a récem-ment été associé spécifiquement aux cancers mélanocytiques provoqués par le soleil [12]. Même si plusieurs longueurs d'ondes peuvent entraîner ce type de mutation, la capacité des UVA à atteindre des couches plus profondes de la peau suggère que leur responsabilité dans la formation de mélanomes pourrait être plus considérable qu'anticipé initialement [13,37].…”