Search

Hedgehog pathway inhibitors (HPI) inactivating SMO 1, have become first line treatment for patients with locally advanced BCC (laBCC). HPI safety and efficacy have been shown in clinical trials2,3. Nevertheless, common adverse events lead to treatment discontinuation.

Multifactorial predisposition to melanoma includes genes involved in pigmentation, immunity and DNA repair. Nonetheless, missing heritability in melanoma is still important. We studied the role of 335 candidate SNPs in melanoma susceptibility by using a dedicated chip and investigating 110 genes involved in different pathways. A discovery set was comprised of 1069 melanoma patients and 925 controls from France. Data were replicated using validation phases II (1085 cases and 801 controls from Spain) and III (1808 cases and 1894 controls from Germany and a second set of Spanish samples). In addition, an exome sequencing study was performed in three high-risk French melanoma families. Nineteen SNPs in 17 genes were initially associated with melanoma in the French population. Six SNPs were replicated in phase II, including two new SNPs in the WNT3 (rs199524) and VPS41 (rs11773094) genes. The role of VPS41 and WNT3 was confirmed in a meta-analysis (3940 melanoma cases and 3620 controls) with two-side p values of 0.002, (OR=0.86) and 4.07x10(-10) (OR=0.80), respectively. Exome sequencing revealed a non-synonymous VPS41 variant in one family that was shown to be strongly associated with familial melanoma (OR=4.46, p=0.001) in an independent sample of 178 melanoma families. WNT3 belongs to WNT pathway known to play a crucial role in melanoma, whereas VPS41 regulates vesicular trafficking and is thought to play a role in pigmentation. Our work identified two new pathways involved in melanoma predisposition. These results may be useful in the future for identifying individuals highly predisposed to melanoma. What's New? While our understanding of the molecular pathways that lead to malignant melanoma has increased over the past few years, it is still incomplete. In this study, the authors identified two new pathways: one that involves WNT signaling (involved in melanoblast development), and another that involves vesicular trafficking (involved in changes in pigmentation phenotype). These results may be useful in developing screening tests for people who are genetically susceptible to melanoma. In addition, the whole-exome sequencing techniques used in this study may aid researchers in identifying mutations in unknown disease-candidate genes.

EDNRB gene variants were reported to be associated with melanoma risk in French patients, with the S305N variant showing the highest frequency.To verify the S305N association with melanoma risk in an independent larger French population (378 patients, 389 controls); to investigate the role of EDNRB variants in melanoma risk in an Italian population (133 patients, 118 controls); and to explore the association of CDKN2A or CDK4 mutations with the S305N EDNRB variant in a subgroup of patients (59 French, 12 Italian) with a suspected hereditary predisposition to melanoma (familial melanoma, sporadic multiple primary melanoma or melanoma associated with pancreatic cancer).The S305N variant was genotyped in the French population, while the EDNRB gene in the Italian population was entirely sequenced.Overall, there was no significant difference in the frequency of the S305N variant between patients with sporadic melanoma and controls in either the French or the Italian population. However, a significantly higher S305N allele frequency was detected in French patients with a suspected hereditary predisposition to melanoma compared with controls (P = 0.04). In addition, in this subgroup of patients, the S305N allele was also significantly associated with the presence of CDKN2A mutations (P = 0.04).Our results showed no evidence of association of the S305N EDNRB polymorphism with sporadic melanoma risk in either the French or Italian populations, but there was an indication that EDNRB might be a melanoma-predisposing gene in French patients with a suspected hereditary predisposition to melanoma.

Recent studies on normal and pathological skin have suggested a role of the c-fos proto-oncogene in keratinocyte differentiation. To further elucidate this question we have used keratinocyte and skin culture models to study in vitro regulation of c-fos expression and attempted to correlate it with the keratinocyte maturation process. Our results show that c-fos expression is prolonged in keratinocyte monolayers both at the mRNA and protein level. Extracellular calcium which stimulate keratinocyte differentiation is able to induce c-fos expression in the presence of growth factors. However this c-fos expression cannot be maintained by these factors as seen in normal human skin in vivo. Conversely, spontaneous expression of c-fos can be seen in reconstituted skin when the neo-epidermis has completed its differentiation. All these data strongly support a role of c-fos as a switch between the early and late phases of keratinocyte differentiation allowing them to be definitively committed to their elimination process. Additionally, a differential regulation of c-fos seems to exist between keratinocyte culture and reconstituted epidermis, suggesting that tissular and serum factors are involved in the prolonged c-fos expression observed in human epidermis.

Background No simple staging system has emerged for basal cell carcinomas (BCCs), since they do not follow the TNM process, and practitioners failed to agree on simple clinical or pathological criteria as a basis for a classification. Operational classification of BCCs is required for decision‐making, trials and guidelines. Unsupervised clustering of real cases of difficult‐to‐treat BCCs (DTT‐BCCs; part 1) has demonstrated that experts could blindly agree on a five groups classification of DTT‐BCCs based on five patterns of clinical situations. Objective Using this five patterns to generate an operational and comprehensive classification of BCCs. Method Testing practitioner's agreement, when using the five patterns classification to ensure that it is robust enough to be used in the practice. Generating the first version of a staging system of BCCs based on pattern recognition. Results Sixty‐two physicians, including 48 practitioners and the 14 experts who participated in the generation of the five different patterns of DTT‐BCCs, agreed on 90% of cases when classifying 199 DTT‐BCCs cases using the five patterns classification (part 1) attesting that this classification is understandable and usable in practice. In order to cover the whole field of BCCs, these five groups of DTT‐BCCs were added a group representing the huge number of easy‐to‐treat BCCs, for which sub‐classification has little interest, and a group of very rare metastatic cases, resulting in a four‐stage and seven‐substage staging system of BCCs. Conclusion A practical classification adapted to the specificities of BCCs is proposed. It is the first tumour classification based on pattern recognition of clinical situations, which proves to be consistent and usable. This EADO staging system version 1 will be improved step by step and tested as a decision tool and a prognostic instrument.