Lack of association between CDKN2A germline mutations and survival in patients with melanoma: A retrospective cohort study

Ipenburg, Norbertus A.; Sharouni, Mary‐Ann El; Doorn, Remco van; Diest, Paul J. van; Leerdam, Monique E. van; Rhee, Jasper I. van der; Goeman, Jelle J.; Kukutsch, Nicole A.; Snels, Dyon G.C.T.M.; Dekker, Sybren K.; Leeuwen, Robert L. van; Rijssen, Tondo van; Honig, E.; Vink, Jacqueline; Crijns, Marianne B.; Bruynzeel, Ineke; Wu, F.; Zupan-Kajcovski, Biljana; Schuur, Jacqueline

doi:10.1016/j.jaad.2021.10.024

Cited by 7 publications

(13 citation statements)

References 5 publications

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“…In addition, the results help to explain discordant findings on the association between pathogenic CDKN2A gene variants and melanoma survival from previous studies performed in Sweden, Italy and the Netherlands. [6][7][8] The present study provides support for surveillance of patients with familial melanoma and for the identification of patients carrying pathogenic CDKN2A gene variants who might benefit most from periodic skin examinations.…”

Section: On F L Ic T Of I N T E R E S Tmentioning

confidence: 65%

Surveillance, CDKN2A and survival of familial melanoma

Doorn

2023

Acad Dermatol Venereol

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Section: On F L Ic T Of I N T E R E S Tmentioning

confidence: 65%

Surveillance, CDKN2A and survival of familial melanoma

Doorn

2023

Acad Dermatol Venereol

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“…Loss-of-function mutations or homozygous deletions of CDKN2A resulted in the loss of both proteins, releasing the G1–S and G2–M cell cycle checkpoints and resulting in uninhibited cell proliferation and tumor formation[ 16 ]. A literature database search revealed that CDKN2A has been extensively researched in the context of melanoma, pancreatic cancer and other tumor types, but the findings are controversial[ 15 , 17 ].…”

Section: Discussionmentioning

confidence: 99%

Comprehensive proteomic signature and identification of CDKN2A as a promising prognostic biomarker and therapeutic target of colorectal cancer

Wang¹,

Zhou²,

Ge³

et al. 2022

WJCC

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BACKGROUND The carcinogenesis of colorectal cancer (CRC) involves many different molecules and multiple pathways, and the specific mechanism has not been elucidated until now. Existing studies on the proteomic signature profiles of CRC are relatively limited. Therefore, we herein aimed to provide a more comprehensive proteomic signature profile and discover new prognostic markers and therapeutic targets by performing proteomic analysis of CRC and paired normal tissues. AIM To investigate the proteomic signature and identify novel protein prognostic biomarkers of CRC. METHODS Cancer tissues and paired normal tissues were collected from 48 patients who underwent surgical removal at the China-Japan Friendship Hospital from January 2020 to June 2021. Data independent acquisition (DIA) quantitative proteomic analysis was performed using high-performance liquid chromatography–mass spectrometry/mass spectrometry (nano-UHPLC–MS/MS) to identify differentially expressed proteins, among which those with a P adj value ( t test, BH correction) < 0.05 and an absolute fold change (|log 2 FC|) > 2 were identified as potential markers. Differentially expressed proteins were selected by bioinformatics analysis and validated by immunohistochemical tissue microarrays, and their association with prognosis was further analyzed with the Gene Expression Profiling Interactive Analysis database to identify prognostic protein biomarkers of CRC. RESULTS Significantly differential protein expression was observed between cancer tissues and normal tissues. Compared with normal tissues, 1115 proteins were upregulated and 705 proteins were downregulated in CRC based on P adj < 0.05 and |log 2 FC| > 2, and bioinformatics analysis revealed that the differentially expressed proteins were involved in multiple biological processes associated with tumorigenesis, including ribosome biogenesis in eukaryotes, focal adhesion, extracellular matrix-receptor interactions and other tumor metabolism processes. Moreover, cyclin-dependent kinase inhibitor 2A (CDKN2A) expression was markedly upregulated in CRC, as validated by immunohistochemistry (0.228 vs 0.364, P = 0.0044), and was significantly enriched in tumor proliferation and signal transduction pathways such as the cell cycle and p53 signaling pathways. High CDKN2A expression was significantly correlated with poor prognosis ( P = 0.021). These results demonstrated that CDKN2A functions as a driver of CRC. CONCLUSION Our study provides a comprehensive proteomic signature of CRC and highlights CDKN2A as a potential powerful prognostic marker and precision therapeutic target.

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“…In reports from two other European centres, no significant survival difference was seen in carrier melanoma cases compared with genotyped non‐carrier cases (Italy) or compared with population melanoma controls (Netherlands). 27 , 28 However, our study is the first to specifically assess the survival in melanoma cases diagnosed before or after inclusion in a dermatologic surveillance program, where comprehensive data on family members, diagnosis and survival outcomes were retrieved from national registries, including the Multigeneration Registry and Swedish Cancer Registry going back to 1958. In this setting, a significantly worse melanoma‐specific survival was noted in the CDKN2A mutation carriers compared with non‐carriers if the melanomas had been diagnosed before, but importantly not after inclusion.…”

Section: Discussionmentioning

confidence: 99%

“… 26 Additionally, in one study from Italy and one study from Holland, no survival differences were found, but these studies involved melanoma cases that were diagnosed after the families had been enrolled in a dermatologic surveillance program. 27 , 28 As a result of the novel immunotherapy and targeted therapy regimens, melanoma survival has improved significantly. 29 , 30 Moreover, metastatic melanoma cases with germline CDKN2A mutations have been reported to respond well to both immune checkpoint inhibitors and BRAF and MEK inhibitors.…”

Section: Introductionmentioning

confidence: 99%

“…In another Swedish study, involving a different set of patients, it was found that when comparing pedigrees retrospectively, at the timepoint when their family is identified, the mortality among melanoma cases was significantly higher in the families that carried CDKN2A mutations 26 . Additionally, in one study from Italy and one study from Holland, no survival differences were found, but these studies involved melanoma cases that were diagnosed after the families had been enrolled in a dermatologic surveillance program 27,28 . As a result of the novel immunotherapy and targeted therapy regimens, melanoma survival has improved significantly 29,30 .…”

Section: Introductionmentioning

confidence: 99%

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Melanoma‐specific survival before and after inclusion in a familial melanoma dermatologic surveillance program in CDKN2A mutation carriers and non‐carriers

Pissa

Lapins

Sköldmark

et al. 2022

Acad Dermatol Venereol

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Background Inherited mutations in the CDKN2A gene are among the strongest known risk factors for cutaneous melanoma. Further, previous studies have reported inferior melanoma‐specific survival in CDKN2A mutation carriers. Objectives Here, the melanoma‐specific survival was studied, depending on CDKN2A carrier status and if the melanomas had been diagnosed before or after families were included in a surveillance program. Methods Melanoma‐prone families participating in this study were identified through a nationwide preventive program starting in 1987. Information on melanoma tumours and deaths was obtained through the Swedish Cancer Registry and Cause of Death Registry. Kaplan–Meier and Cox proportional hazards regression models were used to assess melanoma‐specific survival in four defined cohorts, CDKN2A mutation (MUT) carriers with first invasive melanoma before or after inclusion [MUT‐pre (n = 53) and MUT‐post (n = 43)] and likewise in CDKN2A wild type (WT) cases [WT‐pre (n = 255) and WT‐post (n = 122)]. Results The MUT‐pre and MUT‐post cases were diagnosed with their first invasive melanoma at a significantly younger ages (38 and 42 years, respectively) than the WT‐pre and WT‐post cases (48 and 57 years, respectively). The melanomas in the MUT‐pre had significantly higher T stage compared with MUT‐post (p = 0.006), whereas no such difference was seen comparing WT‐pre with WT‐post (p = 0.849). MUT‐pre had compared with WT‐pre, significantly worse melanoma‐specific survival, unadjusted (HR 2.33, 95% CI 1.33–4.08, p = 0.003) adjusted (HR 2.70, 95% CI 1.46–5.00, p = 0.001). However, the MUT‐post cases had compared with the WT‐post cases, no significant survival differences. Conclusion This study is the first to address the impact on survival from introducing a dermatologic surveillance program to familial melanoma cases with or without CDKN2A mutations. The CDKN2A‐mut carriers appeared to have a clear benefit with less advanced melanomas diagnosed and better melanoma‐specific survival after inclusion. Among the CDKN2A‐wt cases, the effect of the inclusion on the studied outcomes was less evident.

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Lack of association between CDKN2A germline mutations and survival in patients with melanoma: A retrospective cohort study

Cited by 7 publications

References 5 publications

Surveillance, CDKN2A and survival of familial melanoma

Surveillance, CDKN2A and survival of familial melanoma

Comprehensive proteomic signature and identification of CDKN2A as a promising prognostic biomarker and therapeutic target of colorectal cancer

Melanoma‐specific survival before and after inclusion in a familial melanoma dermatologic surveillance program in CDKN2A mutation carriers and non‐carriers

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