Dataset Information

Familial Melanoma Phenotype With Xeroderma Pigmentosum Group C (XP-C) Genotype - The Putative Role of MC1R Polymorphism as Modifier.

ABSTRACT:

Introduction

Xeroderma pigmentosum (XP), a rare inherited condition, hallmarked by extreme sensitivity to sun exposure resulting in multiple skin cancers and non-malignant skin alterations is attributed to homozygous inactivating pathogenic variants (PVs) in DNA repair genes, predominantly the XPC gene.

Objectives

Report a unique phenotypic expression of mutant XPC allele that may be compatible with a putative modifier role for MC1R polymorphism.

Methods

A family of 13 siblings, seven of whom were diagnosed with at least one cutaneous melanoma (N = 53) and non-melanoma skin cancers (N = 9) was studied. Of seven melanoma-affected cases, five consented for genetic analysis. CDKN2A revealed no PV in any case and subsequent whole-exome sequencing (WES) identified a rare homozygous missense PV (c.919C>T; p.Arg307Trp) in exon 8 of the XPC gene in all affected individuals. Notably, XPC PV carriers who co-harbored the p.I155T MC1R variant (N = 3) exhibited larger number of tumors, deeper Breslow indexes, higher rates of invasive melanomas and earlier age at diagnosis compared with non MC1R variant carriers (N = 2).

Conclusions

Familial malignant melanoma phenotype may, in fact, be an unusual clinical presentation of XPC, and MC1R may be a genetic modifier of penetrance and phenotype of mutant XPC alleles.

SUBMITTER: Leidenz FAB

PROVIDER: S-EPMC10868875 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Publications

Familial Melanoma Phenotype With Xeroderma Pigmentosum Group C (XP-C) Genotype - The Putative Role of MC1R Polymorphism as Modifier.

Leidenz Franciele Antonieta Bianchi FAB Bittencourt Flavia Vasques FV Braga Williana Garcia WG de Sá Araújo Elio Magno EM Gomes Carolina Cavalieri CC de Fatima Bernardes Vanessa V Friedman Eitan E De Marco Luiz L

Dermatology practical & conceptual 20240101 1

<h4>Introduction</h4>Xeroderma pigmentosum (XP), a rare inherited condition, hallmarked by extreme sensitivity to sun exposure resulting in multiple skin cancers and non-malignant skin alterations is attributed to homozygous inactivating pathogenic variants (PVs) in DNA repair genes, predominantly the XPC gene.<h4>Objectives</h4>Report a unique phenotypic expression of mutant XPC allele that may be compatible with a putative modifier role for MC1R polymorphism.<h4>Methods</h4>A family of 13 sibl ...[more]

PMID: 38364385

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Project description:BackgroundAssessment of immune-specific markers is a well-established approach for predicting the response to immune checkpoint inhibitors (ICIs). Promising candidates as ICI predictive biomarkers are the DNA damage response pathway genes. One of those pathways, which are mainly responsible for the repair of DNA damage caused by ultraviolet radiation, is the nucleotide excision repair (NER) pathway. Xeroderma pigmentosum (XP) is a hereditary disease caused by mutations of eight different genes of the NER pathway, or POLH, here together named the nine XP genes. Anecdotal evidence indicated that XP patients with melanoma or other skin tumors responded impressively well to anti-PD-1 ICIs. Hence, we analyzed the expression of the nine XP genes as prognostic and anti-PD-1 ICI predictive biomarkers in melanoma.MethodsWe assessed mRNA gene expression in the TCGA-SKCM dataset (n = 445) and two pooled clinical melanoma cohorts of anti-PD-1 ICI (n = 75). In TCGA-SKCM, we applied hierarchical clustering on XP genes to reveal clusters, further utilized as XP cluster scores. In addition, out of 18 predefined genes representative of a T cell inflamed tumor microenvironment, the TIS score was calculated. Besides these scores, the XP genes, immune-specific single genes (CD8A, CXCL9, CD274, and CXCL13) and tumor mutational burden (TMB) were cross-correlated. Survival analysis in TCGA-SKCM was conducted for the selected parameters. Lastly, the XP response prediction value was calculated for the two pooled anti-PD-1 cohorts by classification models.ResultsIn TCGA-SKCM, expression of the XP genes was divided into two clusters, inversely correlated with immune-specific markers. A higher ERCC3 expression was associated with improved survival, particularly in younger patients. The constructed models utilizing XP genes, and the XP cluster scores outperformed the immune-specific gene-based models in predicting response to anti-PD-1 ICI in the pooled clinical cohorts. However, the best prediction was achieved by combining the immune-specific gene CD274 with three XP genes from both clusters.ConclusionOur results suggest pre-therapeutic XP gene expression as a potential marker to improve the prediction of anti-PD-1 response in melanoma.

Project description:IntroductionPoor adherence to photoprotection for people with xeroderma pigmentosum (XP) can be life-threatening. A randomised controlled trial (RCT) is being conducted to test the efficacy of a personalised adherence intervention (XPAND) to reduce the level of ultraviolet radiation (UVR) reaching the face, by improving photoprotection activities in adults with XP.Methods and analysisA two-armed parallel groups RCT, where we randomised 24 patients with suboptimal adherence to either an intervention group who received XPAND in 2018 or a delayed intervention group who will receive XPAND in 2019. XPAND involves seven sessions, one-to-one with a facilitator, using behaviour change techniques and specially designed materials to target barriers to photoprotection. Following baseline assessment in April 2018 (t0) and intervention, the primary outcome will be measured across 21 consecutive days in June and July 2018 (t1). The primary outcome is the average daily UVR dose to the face (D-to-F), calculated by combining objective UVR exposure at the wrist (measured by a dosimeter) with face photoprotection activities recorded on a daily UVR protection diary. Secondary outcomes include average daily UVR D-to-F across 21 days in August (t2); psychosocial process variables measured by daily questions (t0, t1, t2) and self-report questionnaires (t0, t1, t2, December 2018 (t3)). Intervention cost-utility is assessed by service use and personal cost questionnaires (t0, t3). The delayed intervention control arm participants will complete three further assessments in April 2019 (t4) and June-July 2019 (t5), and December 2019 (t6) with dosimetry and UVR protection diary completed for 21 days at t4 and t5. A process evaluation will be conducted using mixed methods.Ethics and disseminationEthical approval has been received from West London & GTAC REC 17/LO/2110. Results will be disseminated in peer-reviewed journals and at conferences. This study tests a novel intervention, which, if successful, will be integrated into routine care.Trial registration numberNCT03445052; Pre-results.

Dataset Information

Familial Melanoma Phenotype With Xeroderma Pigmentosum Group C (XP-C) Genotype - The Putative Role of MC1R Polymorphism as Modifier.

Introduction

Objectives

Methods

Conclusions

Publications

Familial Melanoma Phenotype With Xeroderma Pigmentosum Group C (XP-C) Genotype - The Putative Role of MC1R Polymorphism as Modifier.

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