Gene Expression Profiling of Primary Cutaneous Melanoma and Clinical Outcome

Winnepenninckx, Véronique; Lazar, Vladimir; Michiels, Stefan; Dessen, Philippe; Stas, Marguerite; Alonso, Soledad; Avril, Marie-Françoise; Romero, Pablo Luis Ortiz; Robert, Thomas; Bălăcescu, Ovidiu; Eggermont, Alexander; Lenoir, Gilbert; Sarasin, Alain; Tursz, Thomas; Oord, Joost J. van den; Spatz, Alan

doi:10.1093/jnci/djj103

Cited by 456 publications

(459 citation statements)

References 36 publications

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“…To understand melanoma progression, we analysed the gene expression profiles of primary melanoma giving rise to metastasis (M þ ; n ¼ 26) versus the melanoma where no metastasis (MÀ; n ¼ 34) was documented after a 4-year follow-up period (Winnepenninckx et al, 2006) (Supplementary Table 1). By applying searching for a biological interpretation of microarray experiments (SBIME) to the entire data set with Gene Ontology (GO) annotations, we found that two biological processes, that is, replication and repair, are especially overrepresented among the genes that are significantly differentially expressed between M þ and MÀ (Supplementary Table 2).…”

Section: Resultsmentioning

confidence: 99%

“…It shows, moreover, that our experimental approach allows us to detect gene underexpression as well as overexpression between M þ and MÀ tumors. Because the direct relationship between the risk of metastasis and the expression of some replication factors has already been discussed in a previous paper (Winnepenninckx et al, 2006), we are only discussing here the role of DNA repair genes for metastasis formation.…”

Section: Resultsmentioning

confidence: 99%

“…The same analysis has been performed on the validation set of melanomas derived from another hospital (IGR) also described in Winnepenninckx et al (2006) (Supplementary Table 1). The 8 MÀ primary tumors were compared with those of the 9 M þ primary tumors.…”

Section: Dna Repair and Melanoma Metastasismentioning

confidence: 99%

“…To understand the progression of primary melanoma to distant metastasis, we used a large bank of frozen primary melanomas in order to correlate gene expression profiles with distant metastasis-free survival at 4 years (Winnepenninckx et al, 2006). We identified 254 genes that allowed us to differentiate between primary tumors that will metastasize within 4 years (M þ ) versus those that will not (MÀ) (Winnepenninckx et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…We identified 254 genes that allowed us to differentiate between primary tumors that will metastasize within 4 years (M þ ) versus those that will not (MÀ) (Winnepenninckx et al, 2006). This kind of analysis is not only useful at the single gene level but is also extremely informative to characterize the pathways that are altered as a consequence of the neoplastic process as well as on the pathways that ensure tumor growth and invasiveness.…”

Section: Introductionmentioning

confidence: 99%

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High expression of DNA repair pathways is associated with metastasis in melanoma patients

et al. 2007

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We have identified a gene-profile signature for human primary malignant melanoma associated with metastasis to distant sites and poor prognosis. We analyse the differential gene expression by looking at whole biological pathways rather than individual genes. Among the most significant pathways associated with progression to metastasis, we found the DNA replication (P ¼ 10 À14 ) and the DNA repair pathways (P ¼ 10 À16 ). We concentrated our analysis on DNA repair and found that 48 genes of this category, among a list of 234 genes, are associated with metastatic progression. These genes belong essentially to the pathways allowing recovery of stalled replication forks due to spontaneous blockage or induced DNA lesions. Because almost all these differentially expressed repair genes were overexpressed in primary tumors with bad prognosis, we speculate that primary melanoma cells that will metastasize try to replicate in a fast and errorfree mode. In contrast to the progression from melanocytes to primary melanoma, genetic stability appears to be necessary for a melanoma cell to give rise to distant metastasis. This overexpression of repair genes explains nicely the extraordinary resistance of metastatic melanoma to chemo-and radio-therapy. Our results may open a new avenue for the discovery of drugs active on human metastatic melanoma.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Dna Repair and Melanoma Metastasismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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High expression of DNA repair pathways is associated with metastasis in melanoma patients

et al. 2007

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The Changing Kinetics of Advanced Melanoma

Coit

2019

JAMA Dermatol

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The current issue of JAMA Dermatology contains 3 articles that attempt to describe some aspect of disease kinetics of selected subsets of patients with melanoma.The first of these studies, from von Schuckmann and colleagues 1 in Australia, attempts to describe factors predictive of early recurrence (within 2 years) among patients who presented for treatment of clinically localized T1b to T4b melanoma in Queensland.Patients were recruited prospectively from a number of hospital and private clinic sources. Of 1245 patients identified and invited to participate, 700 (56%) were included in the analysis. Most of the follow-up was obtained as a patient-reported binary recurrence status (yes/no) every 6 months. In the event of patients lost to follow-up, local hospital records and Queensland Cancer Registry data were reviewed. All recurrences were verified insofar as possible by medical record review. Factors identified predicting recurrence within 2 years were not surprising and included the presence of ulceration, an increased mitotic index, increasing T stage, and head and neck location. Descriptive statistics were provided comparing outcomes by the seventh and eighth editions of the AJCC Staging Manual, and describing the initial sites of recurrence.The biggest challenge in interpreting the significance of this study is the heterogeneity of the patient data set, a data set that included 442 patients with clinical T1b to T4b who did not undergo sentinel lymph node biopsy (SLNB), 213 patients with pathologic T1b to T4b who had a negative SLNB result, and 38 patients with at least stage IIIa after a positive SLNB result (the SLNB numbers do not quite add up to 700 in Table 1). This heterogeneity recalls that of the AJCC7 data set, where pathologic staging of clinically localized melanomas was not required. The A JCC8 has addressed this shortcoming by including only patients who underwent SLNB, 2 thus describing more homogeneous T-stage subsets. Excluding the patients with T1a disease, the AJCC8 data set depicted describes the dynamic kinetics of outcome in 10 466 patients with pathologic T1b to T4b melanomas. As expected, more advanced tumors generally recur more frequently and earlier. Importantly, the AJCC8 data set demonstrated that most events in this cohort of patients are expected to occur after the 2-year threshold described in the study by von Schuckmann et al, 1 with continued attrition out to at least 10 years. Thus, the second concern: the 2-year interval, although entirely practical for a prospective study such as this, may not be entirely reflective of the true biology of this heterogeneous cohort.

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Prognostic Gene Expression Profiling in Cutaneous Melanoma

et al. 2020

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gene expression profile (GEP) testing in cutaneous melanoma (CM) is rising despite a lack of endorsement as standard of care.OBJECTIVE To develop guidelines within the national Melanoma Prevention Working Group (MPWG) on integration of GEP testing into the management of patients with CM, including (1) review of published data using GEP tests, (2) definition of acceptable performance criteria, (3) current recommendations for use of GEP testing in clinical practice, and (4) considerations for future studies. EVIDENCE REVIEWThe MPWG members and other international melanoma specialists participated in 2 online surveys and then convened a summit meeting. Published data and meeting abstracts from 2015 to 2019 were reviewed.FINDINGS The MPWG members are optimistic about the future use of prognostic GEP testing to improve risk stratification and enhance clinical decision-making but acknowledge that current utility is limited by test performance in patients with stage I disease. Published studies of GEP testing have not evaluated results in the context of all relevant clinicopathologic factors or as predictors of regional nodal metastasis to replace sentinel lymph node biopsy (SLNB). The performance of GEP tests has generally been reported for small groups of patients representing particular tumor stages or in aggregate form, such that stage-specific performance cannot be ascertained, and without survival outcomes compared with data from the American Joint Committee on Cancer 8th edition melanoma staging system international database. There are significant challenges to performing clinical trials incorporating GEP testing with SLNB and adjuvant therapy. The MPWG members favor conducting retrospective studies that evaluate multiple GEP testing platforms on fully annotated archived samples before embarking on costly prospective studies and recommend avoiding routine use of GEP testing to direct patient management until prospective studies support their clinical utility.CONCLUSIONS AND RELEVANCE More evidence is needed to support using GEP testing to inform recommendations regarding SLNB, intensity of follow-up or imaging surveillance, and postoperative adjuvant therapy. The MPWG recommends further research to assess the validity and clinical applicability of existing and emerging GEP tests. Decisions on performing GEP testing and patient management based on these results should only be made in the context of discussion of testing limitations with the patient or within a multidisciplinary group.

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Gene Expression Profiling of Primary Cutaneous Melanoma and Clinical Outcome

Abstract: We identified 254 genes whose expression was associated with metastatic dissemination of cutaneous melanomas. These genes may shed light on the molecular mechanisms underlying poor prognosis in melanoma patients.

Cited by 456 publications

References 36 publications

High expression of DNA repair pathways is associated with metastasis in melanoma patients

High expression of DNA repair pathways is associated with metastasis in melanoma patients

The Changing Kinetics of Advanced Melanoma

Prognostic Gene Expression Profiling in Cutaneous Melanoma

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