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Stage-specific prognostic biomarkers in melanoma.

Cheng Y, Lu J, Chen G, Ardekani GS, Rotte A, Martinka M, Xu X, McElwee KJ, Zhang G, Zhou Y - Oncotarget (2015)

Bottom Line: Thus, additional information, such as that provided by biomarkers is needed to assist in identifying the patients at risk of disease progression.We then verified the results by incorporating an additional independent cohort (87 patients) and in a combined cohort (341 patients).Our data indicate that BRAF and MMP2 are optimal prognostic biomarkers for AJCC Stages I and II, respectively (P = 0.010, 0.000, Log-rank test); whereas p27 emerged as a good marker for AJCC Stages III/IV (0.018, 0.046, respectively, log-rank test).

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology and Skin Science, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.

ABSTRACT
The melanoma staging system proposed by the American Joint Committee on Cancer (AJCC) (which classifies melanoma patients into four clinical stages) is currently the most widely used tool for melanoma prognostication, and clinical management decision making by clinicians. However, multiple studies have shown that melanomas within specific AJCC Stages can exhibit varying progression and clinical outcomes. Thus, additional information, such as that provided by biomarkers is needed to assist in identifying the patients at risk of disease progression. Having previously found six independent prognostic biomarkers in melanoma, including BRAF, MMP2, p27, Dicer, Fbw7 and Tip60, our group has gone on to investigate if these markers are useful in risk stratification of melanoma patients in individual AJCC stages. First, we performed Kaplan-Meier survival and Cox proportional multivariate analyses comparing prognostication power of these markers in 254 melanoma patients for whom the expression levels were known, identifying the best performing markers as candidates for stage-specific melanoma markers. We then verified the results by incorporating an additional independent cohort (87 patients) and in a combined cohort (341 patients). Our data indicate that BRAF and MMP2 are optimal prognostic biomarkers for AJCC Stages I and II, respectively (P = 0.010, 0.000, Log-rank test); whereas p27 emerged as a good marker for AJCC Stages III/IV (0.018, 0.046, respectively, log-rank test). Thus, our study has identified stage-specific biomarkers in melanoma, a finding which may assist clinicians in designing improved personalized therapeutic modalities.

No MeSH data available.


Related in: MedlinePlus

Expression levels of 6 biomarkers are changed across melanoma AJCC Stages(a–x) Representative weak and strong immunohistochesistry stain and related haematoxylin and eosin stain images for BRAF (a–d), MMP2 (e–h), p27 (i–l), Dicer (m–q), Fbw7 (r–u) and Tip60 (v–x); (A–E) Percentage of weak and strong staining in AJCC Stage I, II, III and IV of 6 biomarkers. a-x, bar = 10 μm.
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Figure 1: Expression levels of 6 biomarkers are changed across melanoma AJCC Stages(a–x) Representative weak and strong immunohistochesistry stain and related haematoxylin and eosin stain images for BRAF (a–d), MMP2 (e–h), p27 (i–l), Dicer (m–q), Fbw7 (r–u) and Tip60 (v–x); (A–E) Percentage of weak and strong staining in AJCC Stage I, II, III and IV of 6 biomarkers. a-x, bar = 10 μm.

Mentions: Based on the established tissue microarray (TMA) with 707 biopsies from patients with different stages of melanocytic lesions, our group had previously identified six prognostic biomarkers (Table 1) for cutaneous melanoma [11–16]. To further understand the role of these biomarkers in melanoma progression and to select the best stage-specific prognostic biomarkers, we performed additional analyses on the expression patterns of these six biomarkers in primary and metastatic melanomas. As displayed in Figure 1, BRAF and MMP2 proteins showed a progressive increase from Stage I to Stage IV (Figure 1A, 1B), whereas Tip60 loss is most pronounced in metastatic melanoma (Stage III and IV) as compared to primary melanomas (Stages I and II) (Figure 1F). In contrast, p27, Dicer, and Fbw7 show similar expression changes across different AJCC Stages (Figure 1C, 1D, 1E). Interestingly, alteration of BRAF protein is found to be most dramatic between AJCC Stages I and II (P < 0.001, χ2 test), and strong BRAF expression accounts for only 23.6% in Stage I, as compared to 57.0% in Stage II (Figure 1A). One possible explanation is that the activation of the MAPK signalling pathway caused by BRAF increase promotes tumor cell growth and proliferation [17, 18], thereby influencing melanoma progression from AJCC Stage I to Stage II. Expression of the cell cycle inhibitor p27Kip1 is also negatively regulated by Ras/Raf cascades [19], and we found p27Kip1 to be down-regulated in AJCC Stage II, as compared to Stage I (Figure 1C). This change, however, is not statistically significant (P = 0.103, χ2 test).


Stage-specific prognostic biomarkers in melanoma.

Cheng Y, Lu J, Chen G, Ardekani GS, Rotte A, Martinka M, Xu X, McElwee KJ, Zhang G, Zhou Y - Oncotarget (2015)

Expression levels of 6 biomarkers are changed across melanoma AJCC Stages(a–x) Representative weak and strong immunohistochesistry stain and related haematoxylin and eosin stain images for BRAF (a–d), MMP2 (e–h), p27 (i–l), Dicer (m–q), Fbw7 (r–u) and Tip60 (v–x); (A–E) Percentage of weak and strong staining in AJCC Stage I, II, III and IV of 6 biomarkers. a-x, bar = 10 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4414181&req=5

Figure 1: Expression levels of 6 biomarkers are changed across melanoma AJCC Stages(a–x) Representative weak and strong immunohistochesistry stain and related haematoxylin and eosin stain images for BRAF (a–d), MMP2 (e–h), p27 (i–l), Dicer (m–q), Fbw7 (r–u) and Tip60 (v–x); (A–E) Percentage of weak and strong staining in AJCC Stage I, II, III and IV of 6 biomarkers. a-x, bar = 10 μm.
Mentions: Based on the established tissue microarray (TMA) with 707 biopsies from patients with different stages of melanocytic lesions, our group had previously identified six prognostic biomarkers (Table 1) for cutaneous melanoma [11–16]. To further understand the role of these biomarkers in melanoma progression and to select the best stage-specific prognostic biomarkers, we performed additional analyses on the expression patterns of these six biomarkers in primary and metastatic melanomas. As displayed in Figure 1, BRAF and MMP2 proteins showed a progressive increase from Stage I to Stage IV (Figure 1A, 1B), whereas Tip60 loss is most pronounced in metastatic melanoma (Stage III and IV) as compared to primary melanomas (Stages I and II) (Figure 1F). In contrast, p27, Dicer, and Fbw7 show similar expression changes across different AJCC Stages (Figure 1C, 1D, 1E). Interestingly, alteration of BRAF protein is found to be most dramatic between AJCC Stages I and II (P < 0.001, χ2 test), and strong BRAF expression accounts for only 23.6% in Stage I, as compared to 57.0% in Stage II (Figure 1A). One possible explanation is that the activation of the MAPK signalling pathway caused by BRAF increase promotes tumor cell growth and proliferation [17, 18], thereby influencing melanoma progression from AJCC Stage I to Stage II. Expression of the cell cycle inhibitor p27Kip1 is also negatively regulated by Ras/Raf cascades [19], and we found p27Kip1 to be down-regulated in AJCC Stage II, as compared to Stage I (Figure 1C). This change, however, is not statistically significant (P = 0.103, χ2 test).

Bottom Line: Thus, additional information, such as that provided by biomarkers is needed to assist in identifying the patients at risk of disease progression.We then verified the results by incorporating an additional independent cohort (87 patients) and in a combined cohort (341 patients).Our data indicate that BRAF and MMP2 are optimal prognostic biomarkers for AJCC Stages I and II, respectively (P = 0.010, 0.000, Log-rank test); whereas p27 emerged as a good marker for AJCC Stages III/IV (0.018, 0.046, respectively, log-rank test).

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology and Skin Science, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.

ABSTRACT
The melanoma staging system proposed by the American Joint Committee on Cancer (AJCC) (which classifies melanoma patients into four clinical stages) is currently the most widely used tool for melanoma prognostication, and clinical management decision making by clinicians. However, multiple studies have shown that melanomas within specific AJCC Stages can exhibit varying progression and clinical outcomes. Thus, additional information, such as that provided by biomarkers is needed to assist in identifying the patients at risk of disease progression. Having previously found six independent prognostic biomarkers in melanoma, including BRAF, MMP2, p27, Dicer, Fbw7 and Tip60, our group has gone on to investigate if these markers are useful in risk stratification of melanoma patients in individual AJCC stages. First, we performed Kaplan-Meier survival and Cox proportional multivariate analyses comparing prognostication power of these markers in 254 melanoma patients for whom the expression levels were known, identifying the best performing markers as candidates for stage-specific melanoma markers. We then verified the results by incorporating an additional independent cohort (87 patients) and in a combined cohort (341 patients). Our data indicate that BRAF and MMP2 are optimal prognostic biomarkers for AJCC Stages I and II, respectively (P = 0.010, 0.000, Log-rank test); whereas p27 emerged as a good marker for AJCC Stages III/IV (0.018, 0.046, respectively, log-rank test). Thus, our study has identified stage-specific biomarkers in melanoma, a finding which may assist clinicians in designing improved personalized therapeutic modalities.

No MeSH data available.


Related in: MedlinePlus