Genetic profiles of different subsets of Merkel cell carcinoma show links between combined and pure MCPyV-negative tumors

Carter, Michael D.; Gaston, Dan; Huang, Weei‐Yuarn; Greer, Wenda L.; Pasternak, Sylvia; Ly, Thai Yen; Walsh, Noreen

doi:10.1016/j.humpath.2017.10.014

Cited by 58 publications

(59 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Prior to this study, the largest genomic analyses of patients with MCC have been performed in fewer than 50 patients, thus limiting the ability to describe less frequent drivers and to cluster molecular subsets (25)(26)(27)(28)(29). The magnitude of this study provides a more definitive landscape of the disease, demonstrating the distinctive mutational spectra of MCPyV-positive/TMB-low and UV-driven MCC subgroups (25)(26)(27).…”

Section: Discussionmentioning

confidence: 99%

“…For MCPyV-negative patients, NGS and whole exome sequencing have revealed a high tumor mutational burden (TMB), with recurrent mutations in TP53 and RB1. On the other hand, for MCPyV-positive patients a particularly low TMB has been noted, without a pattern of recurrent mutations (25)(26)(27)(28)(29). Because of the rarity of MCC, comprehensive genomic analyses have been limited studies of less than 50 patients.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Genomic Landscape of Merkel Cell Carcinoma and Clinicogenomic Biomarkers of Response to Immune Checkpoint Inhibitor Therapy

Knepper

Montesion

Russell

et al. 2019

Clinical Cancer Research

129

171

View full text Add to dashboard Cite

Purpose: Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous malignancy, which has demonstrated sensitivity to immune checkpoint inhibitor therapy. Here, we perform the largest genomics study in MCC to date to characterize the molecular landscape and evaluate for clinical and molecular correlates to immune checkpoint inhibitor response. Experimental Design: Comprehensive molecular profiling was performed on 317 tumors from patients with MCC, including the evaluation of oncogenic mutations, tumor mutational burden (TMB), mutational signatures, and the Merkel cell polyomavirus (MCPyV). For a subset of 57 patients, a retrospective analysis was conducted to evaluate for clinical and molecular correlates to immune checkpoint inhibitor response and disease survival. Results: Genomic analyses revealed a bimodal distribution in TMB, with 2 molecularly distinct subgroups. Ninety-four percent (n ¼ 110) of TMB-high specimens exhibited an ultraviolet light (UV) mutational signature. MCPyV genomic DNA sequences were not identified in any TMB-high cases (0/117), but were in 63% (110/175) of TMB-low cases. For 36 evaluable patients treated with checkpoint inhibitors, the overall response rate was 44% and response correlated with survival at time of review (100% vs. 20%, P < 0.001). Response rate was 50% in TMB-high/UV-driven and 41% in TMB-low/MCPyV-positive tumors (P ¼ 0.63). Response rate was significantly correlated with line of therapy: 75% in firstline, 39% in second-line, and 18% in third-line or beyond (P ¼ 0.0066). PD-1, but not PD-L1, expression was associated with immunotherapy response (77% vs. 21%, P ¼ 0.00598, for PD-1 positive and negative, respectively). Conclusions: We provide a comprehensive genomic landscape of MCC and demonstrate clinicogenomic associates of immunotherapy response.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Genomic Landscape of Merkel Cell Carcinoma and Clinicogenomic Biomarkers of Response to Immune Checkpoint Inhibitor Therapy

Knepper

Montesion

Russell

et al. 2019

Clinical Cancer Research

129

171

View full text Add to dashboard Cite

show abstract

“…TP53 is the most frequently mutated tumor suppressor gene in cancer. Mutations of TP53 are found in approximately 74% of MCPyV‐negative MCCs, while MCPyV‐positive MCCs more often contain wild‐type TP53 . MCPyV‐negative tumors frequently contain gain‐of‐function (GOF) mutations in TP53 which have been shown to predict death in early‐stage MCC .…”

Section: Discussionmentioning

confidence: 99%

“…Similar to TP53 , approximately 54% of MCPyV‐negative MCCs contain mutations in RB1 , while MCPyV‐positive MCCs contain intact RB1 . The RB1 gene product, pRB, prevents cell‐cycle progression by repressing E2F family transcription factors.…”

Section: Discussionmentioning

confidence: 99%

Molecular and immune targets for Merkel cell carcinoma therapy and prevention

Cohen

Tsai

2019

Molecular Carcinogenesis

View full text Add to dashboard Cite

Merkel cell carcinoma (MCC) is a rare neuroendocrine carcinoma of the skin, for which the exact mechanisms of carcinogenesis remain unknown. Therapeutic options for this highly aggressive malignancy have historically been limited in both their initial response and response durability. Recent improvements in our understanding of MCC tumor biology have expanded therapeutic options for these patients, namely through the use of immunotherapies such as immune checkpoint inhibitors. Further elucidation of the tumor mutational landscape has identified molecular targets for therapies, which have demonstrated success in other cancer types. In this review, we discuss both current and investigational immune and molecular targets of therapy for MCC.

show abstract

“…Despite the currently low (but rapidly increasing) incidence (0.7 per 100,000) [121][122][123], MCC is associated with shorter disease-free and OS and higher cancer-related death rates than melanoma. To date, two main different oncogenic pathways have been identified [124,125]. The first is related to UV exposure with high tumor mutational burden, while the second one is related to a ubiquitous DNA virus, Merkel Cell Polyomavirus (MCPyV).…”

Section: Merkel Cell Carcinomamentioning

confidence: 99%

Clinical Relevance of Liquid Biopsy in Melanoma and Merkel Cell Carcinoma

Boyer¹,

Cayrefourcq²,

Dereure

et al. 2020

Cancers

View full text Add to dashboard Cite

Melanoma and Merkel cell carcinoma are two aggressive skin malignancies with high disease-related mortality and increasing incidence rates. Currently, invasive tumor tissue biopsy is the gold standard for their diagnosis, and no reliable easily accessible biomarker is available to monitor patients with melanoma or Merkel cell carcinoma during the disease course. In these last years, liquid biopsy has emerged as a candidate approach to overcome this limit and to identify biomarkers for early cancer diagnosis, prognosis, therapeutic response prediction, and patient follow-up. Liquid biopsy is a blood-based non-invasive procedure that allows the sequential analysis of circulating tumor cells, circulating cell-free and tumor DNA, and extracellular vesicles. These innovative biosources show similar features as the primary tumor from where they originated and represent an alternative to invasive solid tumor biopsy. In this review, the biology and technical challenges linked to the detection and analysis of the different circulating candidate biomarkers for melanoma and Merkel cell carcinoma are discussed as well as their clinical relevance.

show abstract

Genetic profiles of different subsets of Merkel cell carcinoma show links between combined and pure MCPyV-negative tumors

Cited by 58 publications

References 29 publications

The Genomic Landscape of Merkel Cell Carcinoma and Clinicogenomic Biomarkers of Response to Immune Checkpoint Inhibitor Therapy

The Genomic Landscape of Merkel Cell Carcinoma and Clinicogenomic Biomarkers of Response to Immune Checkpoint Inhibitor Therapy

Molecular and immune targets for Merkel cell carcinoma therapy and prevention

Clinical Relevance of Liquid Biopsy in Melanoma and Merkel Cell Carcinoma

Contact Info

Product

Resources

About