Distinct Mutation Patterns Reveal Melanoma Subtypes and Influence Immunotherapy Response in Advanced Melanoma Patients

Hilke, Franz J.; Sinnberg, Tobias; Gschwind, Axel; Niessner, Heike; Demidov, German; Amaral, Teresa; Ossowski, Stephan; Bonzheim, Irina; Röcken, Martin; Rieß, Olaf; Garbe, Claus; Schroeder, Christopher; Forschner, Andrea

doi:10.3390/cancers12092359

Cited by 36 publications

(35 citation statements)

References 51 publications

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“…However, we did not observe a significant difference of OS between MYC amplification and MYC non-amplification cohorts. In addition, PDGFRA , CCND3 , KIT amplification and PTEN deletion have been reported in previous studies of MM [ 30 , 38 ], which was consistent with our findings. Deletion of the NRG1 gene was detected in 8.3% (3/36) of RMM patients and was associated with poor prognosis in our cohort.…”

Section: Discussionsupporting

confidence: 94%

Genetic alteration of Chinese patients with rectal mucosal melanoma

Yang

Lai

et al. 2021

BMC Cancer

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Background Rectal mucosal melanoma (RMM) is a rare and highly aggressive disease with a poor prognosis. Due to the rarity of RMM, there are few studies focusing on its genetic mechanism. This retrospective study aimed to analyze the genetic spectrum and prognosis of RMM in China and lay a foundation for targeted therapy. Methods 36 patients with primary RMM from Peking University Cancer Hospital were enrolled in this study. The Next-generation sequencing (NGS) data of the tumor samples were fitted into the TruSight™ Oncology 500 (TSO500) Docker pipeline to detect genomic variants. Then, the univariate and multivariate Cox hazard analysis were performed to evaluate the correlations of the variants with the overall survival (OS), along with Kaplan-Meier and log-rank test to determine their significance. Results BRAF mutations, NRG1 deletions and mitotic index were significant prognostic factors in the univariate analysis. In multivariable analysis of the OS-related prognostic factors in primary RMM patients, it revealed 2 significant alterations: BRAF mutations [HR 7.732 (95%CI: 1.735–34.456), P = 0.007] and NRG1 deletions [HR 14.976 (95%CI: 2.305–97.300), P = 0.005]. Conclusions This is the first study to show genetic alterations exclusively to Chinese patients with RMM. We confirmed genetic alterations of RMM differ from cutaneous melanoma (CM). Our study indicates that BRAF and NRG1 were correlated with a poor prognostic of RMM and may be potential therapeutic targets for RMM treatment.

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Section: Discussionsupporting

confidence: 94%

Genetic alteration of Chinese patients with rectal mucosal melanoma

Yang

Lai

et al. 2021

BMC Cancer

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“…CD274 encoded PD-L1 which was one of the target for ICI and studies had suggested that patients with CD274 amplification would have better immunotherapy outcomes 33 , 34 . Current research also found that deletion of CDKN2A and alteration of PTEN increase the resistance to ICIs 35 , 36 . NOTCH2 was amplified in some patients before and after chemotherapy.…”

Section: Discussionmentioning

confidence: 84%

Genomic and transcriptional alterations in first-line chemotherapy exert a potentially unfavorable influence on subsequent immunotherapy in NSCLC

He¹,

Chen²,

Zhao³

et al. 2021

Theranostics

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Background: Recent studies in non-small cell lung cancer (NSCLC) patients have demonstrated that first-line immunotherapy is associated with better therapeutic response than second-line treatment. So far, the mechanisms need to be explored. It prompted us to evaluate the association between first-line chemotherapy and subsequent immunotherapy in NSCLC as well as its underlying mechanisms at the genomic and transcriptomic level. Methods: We launched a prospective, observational clinical study, paired tumor biopsies before and after chemotherapy were collected from NSCLC patients without tyrosine kinase inhibitor (TKI)-related driver gene mutations. The analyses included genomic and transcriptional changes performed by next-generation sequencing (NGS)-based whole-exome sequencing (WES) and messager ribonucleic acid (mRNA) sequencing. Characteristic mutational alterations in 1574 genes were investigated based on mutational status, clinicopathological factors, and chemotherapy responses. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, neoantigen prediction and intratumoral heterogeneity evaluation were also performed. Results: Samples and information from 32 NSCLC patients without TKI-related driver gene mutations were obtained. We found that the total number of single nucleotide variants (SNV)/insertion-deletion (INDEL) mutations did not change significantly after chemotherapy. The tumor mutation burden (TMB) decreased significantly after chemotherapy in smoking patients and the decreased TMB correlated with a better survival of smoking patients. The change in copy number variations (CNVs) exhibited a decreasing trend during chemotherapy. Subsequent analysis at mRNA level revealed a significant decrease in the expression levels of genes related to antigen processing and presentation as well as other factors relevant for response to immunotherapy. Pathway enrichment analysis confirmed that the immune-related signaling pathways or biological processes were decreased after first-line chemotherapy. Conclusions: Our study presents an explanation for the unsatisfactory results of immunotherapy when given after chemotherapy, and suggests that first-line chemotherapy is able to influence the tumor microenvironment and decrease the efficacy of subsequent immunotherapy. The study was registered at ClinicalTrials.gov, number NCT03764917, and has completed enrolment; patients are still in follow-up.

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“…In addition, genetic alterations in CDK4 pathway components (CDK4, CCND1, and CDKN2A), which are particularly common in Asians, have been associated with innate resistance to PD-1 blockade in patients with acral melanoma (93). Consistently, a recent panel-based next-generation sequencing analysis by Hilke et al (94) showed that CDKN2A deletions or loss of heterozygosity, which are commonly found in non-Caucasian patients with melanoma, were significantly enriched in patients with progressing melanomas after treatment with ICIs (nivolumab, pembrolizumab, or nivolumab plus ipilimumab).…”

Section: Current Treatment Optionsmentioning

confidence: 76%

Immunotherapy in Acral and Mucosal Melanoma: Current Status and Future Directions

Mao

Zhang

et al. 2021

Front. Immunol.

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Acral and mucosal melanomas are extremely rare in Caucasians; however, they are the predominant melanoma subtypes in Asians and other non-Caucasian populations. Acral and mucosal melanomas share many clinicopathological features, including aggressive phenotypes, similar genetic landscapes, and grim prognoses. In spite of advances in melanoma management, patients with acral and mucosal melanomas show limited benefit from current therapies. The rarity of these subtypes of melanoma is a significant factor contributing to the poor understanding of these pathological subtypes and the lack of effective interventions. Furthermore, the mechanisms contributing to disparities between different types of melanoma remain largely unclear. Herein, we comprehensively review current knowledge on the clinicopathological characteristics and mutational landscapes of acral and mucosal melanomas, as well as providing an overview of current therapies for patients with these aggressive melanoma subtypes, focusing on available immunotherapeutic interventions. We also discuss pathological differences between different melanoma subtypes and summarize current knowledge on melanoma disparities between Asians and Caucasians. Finally, we discuss emerging immunotherapeutic strategies for the treatment of acral and mucosal melanomas, focusing on combination therapies with immune checkpoint inhibitors. Unraveling the unique features of acral and mucosal melanomas is key for their early diagnosis and for the development of effective therapies.

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Distinct Mutation Patterns Reveal Melanoma Subtypes and Influence Immunotherapy Response in Advanced Melanoma Patients

Cited by 36 publications

References 51 publications

Genetic alteration of Chinese patients with rectal mucosal melanoma

Genetic alteration of Chinese patients with rectal mucosal melanoma

Genomic and transcriptional alterations in first-line chemotherapy exert a potentially unfavorable influence on subsequent immunotherapy in NSCLC

Immunotherapy in Acral and Mucosal Melanoma: Current Status and Future Directions

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