A genome-wide association study of germline variation and melanoma prognosis
BackgroundThe high mortality of cutaneous melanoma (CM) is partly due to unpredictable patterns of disease progression in patients with early-stage lesions. The reliable prediction of advanced disease risk from early-stage CM, is an urgent clinical need, especially given the recent expansion of immu...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-01-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.1050741/full |
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| author | Vylyny Chat Vylyny Chat Vylyny Chat Sasha Dagayev Sasha Dagayev Sasha Dagayev Una Moran Una Moran Matija Snuderl Jeffrey Weber Jeffrey Weber Robert Ferguson Robert Ferguson Robert Ferguson Iman Osman Iman Osman Iman Osman Tomas Kirchhoff Tomas Kirchhoff Tomas Kirchhoff |
| author_facet | Vylyny Chat Vylyny Chat Vylyny Chat Sasha Dagayev Sasha Dagayev Sasha Dagayev Una Moran Una Moran Matija Snuderl Jeffrey Weber Jeffrey Weber Robert Ferguson Robert Ferguson Robert Ferguson Iman Osman Iman Osman Iman Osman Tomas Kirchhoff Tomas Kirchhoff Tomas Kirchhoff |
| author_sort | Vylyny Chat |
| collection | DOAJ |
| description | BackgroundThe high mortality of cutaneous melanoma (CM) is partly due to unpredictable patterns of disease progression in patients with early-stage lesions. The reliable prediction of advanced disease risk from early-stage CM, is an urgent clinical need, especially given the recent expansion of immune checkpoint inhibitor therapy to the adjuvant setting. In our study, we comprehensively investigated the role of germline variants as CM prognostic markers.MethodsWe performed a genome-wide association analysis in two independent cohorts of N=551 (discovery), and N=550 (validation) early-stage immunotherapy-naïve melanoma patients. A multivariable Cox proportional hazard regression model was used to identify associations with overall survival in the discovery group, followed by a validation analysis. Transcriptomic profiling and survival analysis were used to elucidate the biological relevance of candidate genes associated with CM progression.ResultsWe found two independent associations of germline variants with melanoma prognosis. The alternate alleles of these two SNPs were both associated with an increased risk of death [rs60970102 in MELK: HR=3.14 (2.05–4.81), p=1.48×10-7; and rs77480547 in SH3BP4: HR=3.02 (2.02–4.52), p=7.58×10-8, both in the pooled cohort]. The addition of the combined risk alleles (CRA) of the identified variants into the prognostic model improved the predictive power, as opposed to a model of clinical covariates alone.ConclusionsOur study provides suggestive evidence of novel melanoma germline prognostic markers, implicating two candidate genes: an oncogene MELK and a tumor suppressor SH3BP4, both previously suggested to affect CM progression. Pending further validation, these findings suggest that the genetic factors may improve the prognostic stratification of high-risk early-stage CM patients, and propose putative biological insights for potential therapeutic investigation of these targets to prevent aggressive outcome from early-stage melanoma. |
| first_indexed | 2024-04-10T21:37:48Z |
| format | Article |
| id | doaj.art-23f7ffd3958041eaab2c425ef73c39b6 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-10T21:37:48Z |
| publishDate | 2023-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-23f7ffd3958041eaab2c425ef73c39b62023-01-19T08:53:56ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2023-01-011210.3389/fonc.2022.10507411050741A genome-wide association study of germline variation and melanoma prognosisVylyny Chat0Vylyny Chat1Vylyny Chat2Sasha Dagayev3Sasha Dagayev4Sasha Dagayev5Una Moran6Una Moran7Matija Snuderl8Jeffrey Weber9Jeffrey Weber10Robert Ferguson11Robert Ferguson12Robert Ferguson13Iman Osman14Iman Osman15Iman Osman16Tomas Kirchhoff17Tomas Kirchhoff18Tomas Kirchhoff19Perlmutter Cancer Center, New York University School of Medicine, New York, NY, United StatesDepartment of Population Health and Environmental Medicine, New York University School of Medicine, New York, NY, United StatesThe Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, NY, United StatesPerlmutter Cancer Center, New York University School of Medicine, New York, NY, United StatesDepartment of Population Health and Environmental Medicine, New York University School of Medicine, New York, NY, United StatesThe Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, NY, United StatesPerlmutter Cancer Center, New York University School of Medicine, New York, NY, United StatesThe Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, NY, United StatesDepartment of Pathology, New York University School of Medicine, New York, NY, United StatesPerlmutter Cancer Center, New York University School of Medicine, New York, NY, United StatesThe Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, NY, United StatesPerlmutter Cancer Center, New York University School of Medicine, New York, NY, United StatesDepartment of Population Health and Environmental Medicine, New York University School of Medicine, New York, NY, United StatesThe Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, NY, United StatesPerlmutter Cancer Center, New York University School of Medicine, New York, NY, United StatesThe Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, NY, United StatesRonald O. Perelman Department of Dermatology, NYU Grossman School of Medicine, New York, NY, United StatesPerlmutter Cancer Center, New York University School of Medicine, New York, NY, United StatesDepartment of Population Health and Environmental Medicine, New York University School of Medicine, New York, NY, United StatesThe Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, NY, United StatesBackgroundThe high mortality of cutaneous melanoma (CM) is partly due to unpredictable patterns of disease progression in patients with early-stage lesions. The reliable prediction of advanced disease risk from early-stage CM, is an urgent clinical need, especially given the recent expansion of immune checkpoint inhibitor therapy to the adjuvant setting. In our study, we comprehensively investigated the role of germline variants as CM prognostic markers.MethodsWe performed a genome-wide association analysis in two independent cohorts of N=551 (discovery), and N=550 (validation) early-stage immunotherapy-naïve melanoma patients. A multivariable Cox proportional hazard regression model was used to identify associations with overall survival in the discovery group, followed by a validation analysis. Transcriptomic profiling and survival analysis were used to elucidate the biological relevance of candidate genes associated with CM progression.ResultsWe found two independent associations of germline variants with melanoma prognosis. The alternate alleles of these two SNPs were both associated with an increased risk of death [rs60970102 in MELK: HR=3.14 (2.05–4.81), p=1.48×10-7; and rs77480547 in SH3BP4: HR=3.02 (2.02–4.52), p=7.58×10-8, both in the pooled cohort]. The addition of the combined risk alleles (CRA) of the identified variants into the prognostic model improved the predictive power, as opposed to a model of clinical covariates alone.ConclusionsOur study provides suggestive evidence of novel melanoma germline prognostic markers, implicating two candidate genes: an oncogene MELK and a tumor suppressor SH3BP4, both previously suggested to affect CM progression. Pending further validation, these findings suggest that the genetic factors may improve the prognostic stratification of high-risk early-stage CM patients, and propose putative biological insights for potential therapeutic investigation of these targets to prevent aggressive outcome from early-stage melanoma.https://www.frontiersin.org/articles/10.3389/fonc.2022.1050741/fullcutaneous melanomagenome-wide association studysingle nucleotid polymorphismscancer survivalprognostic biomarkers |
| spellingShingle | Vylyny Chat Vylyny Chat Vylyny Chat Sasha Dagayev Sasha Dagayev Sasha Dagayev Una Moran Una Moran Matija Snuderl Jeffrey Weber Jeffrey Weber Robert Ferguson Robert Ferguson Robert Ferguson Iman Osman Iman Osman Iman Osman Tomas Kirchhoff Tomas Kirchhoff Tomas Kirchhoff A genome-wide association study of germline variation and melanoma prognosis Frontiers in Oncology cutaneous melanoma genome-wide association study single nucleotid polymorphisms cancer survival prognostic biomarkers |
| title | A genome-wide association study of germline variation and melanoma prognosis |
| title_full | A genome-wide association study of germline variation and melanoma prognosis |
| title_fullStr | A genome-wide association study of germline variation and melanoma prognosis |
| title_full_unstemmed | A genome-wide association study of germline variation and melanoma prognosis |
| title_short | A genome-wide association study of germline variation and melanoma prognosis |
| title_sort | genome wide association study of germline variation and melanoma prognosis |
| topic | cutaneous melanoma genome-wide association study single nucleotid polymorphisms cancer survival prognostic biomarkers |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.1050741/full |
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