PMC:2948432 / 20747-27157 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/2948432","sourcedb":"PMC","sourceid":"2948432","source_url":"https://www.ncbi.nlm.nih.gov/pmc/2948432","text":"Gene Dosage at 9p21\nGene dosage at 9p21 was successfully measured in 75 vertical growth phase primary melanomas (48 relapsers and 27 non-relapsers) using MLPA. Gene dosage ratios for 12 CDKN2A/CDKN2B locus sites and 11 other 9p gene sites were determined. Reduced gene dosage was more frequent in relapsers (Fig. 2). It can be seen that although loss of gene dosage occurred across 9p (especially in relapsers) the most common region of loss was between CDKN2A exon 1α (coding for CDKN2A) and MTAP. The median gene dosage at eight key regions across 9p, and their association with relapse or histological indicators of poor prognosis are presented in Table 1. Relapse was associated with loss at 9p21.3 overall (P = 0.04) and loss in regions coding for CDKN2A (one sided P = 0.03, two sided P = 0.05), and (borderline) associated with loss anywhere in the CDKN2A region (from CDKN2A CpG island probe to CDKN2A exon 3 probe) (one-sided P = 0.05, two-sided P = 0.1) but not elsewhere across 9p.\nFigure 2 Heatmap of gene dosage at chromosome region 9p21 by relapse status. Gene dosage ratios are shown for tumors from 45 relapsed patients (above) compared with tumors from 27 patients who had not relapsed. Blue coloration indicates reduced gene dosage, red coloration indicates increased gene dosage.\nTABLE 1 Median Gene Dosage by Probe Categories and Indicators of Relapse\nY = yes N = no Total numbers CDKN2B CDKN2B (Intron) CDKN2A p14ARF CDKN2A p16 Intron CDKN2A p16 All probes within CDKN2A MTAP Interferon 9p21.3\nRelapse Y 48 0.92 0.74 0.94 0.67 0.76 0.82 0.71 0.86 0.85\nN 27 0.88 0.78 0.98 0.77 0.84 0.91 0.77 0.90 0.90\nP-value (one-sided) 0.47 0.47 0.10 0.06 0.03 0.05 0.26 0.13 0.04\nUlceration Y 29 0.77 0.67 0.82 0.67 0.70 0.77 0.67 0.84 0.81\nN 46 0.96 0.78 0.98 0.73 0.82 0.91 0.77 0.90 0.92\nP-value (one-sided) 0.006 0.04 0.002 0.11 0.02 0.02 0.05 0.03 0.002\nBreslow thickness \u003c2 mm 18 1.04 0.86 0.97 0.75 0.84 0.91 0.8 0.89 0.92\n\u003e2\u003c4 mm 30 0.90 0.74 0.97 0.70 0.84 0.86 0.77 0.90 0.88\n\u003e4mm 27 0.79 0.67 0.84 0.70 0.76 0.77 0.67 0.83 0.81\nrs (P-value)* −0.31 (0.007) −0.14 (0.22) −0.29 (0.01) −0.06 (0.58) −0.28 (0.01) −0.24 (0.04) −0.19 (0.11) −0.11 (0.34) −0.27 (0.02)\nMitotic rate 0/ mm2 3 1.11 0.92 1.01 0.92 0.99 0.99 0.82 0.59 0.96\n1–6/ mm2 52 0.93 0.77 0.97 0.72 0.81 0.91 0.75 0.89 0.89\n\u003e6/ mm2 20 0.59 0.64 0.67 0.57 0.55 0.64 0.69 0.84 0.80\nP-value** 0.02 0.28 0.0006 0.28 0.004 0.005 0.37 0.12 0.02\nTumour site Head/neck/ hand/foot 15 1.06 0.74 1.00 0.85 0.80 0.84 0.69 0.88 0.88\nOther 60 0.90 0.76 0.93 0.69 0.78 0.85 0.76 0.88 0.87\nP-value (one-sided) 0.12 0.21 0.26 0.30 0.49 0.42 0.24 0.08 0.47\nMelanoma type (Wilcoxon two-sample tests were made between nodular and superficial spreading melanomas) Acral Lentiginous 2 0.44 0.37 0.76 0.53 0.61 0.62 0.44 0.67 0.58\nDesmoplastic 1 1.10 0.73 0.82 1.02 0.80 0.83 0.69 0.97 0.97\nIndeterminate 3 1.06 0.11 0.22 0.10 0.18 0.20 0.12 0.97 0.23\nNodular 28 0.88 0.78 0.93 0.72 0.77 0.81 0.67 0.88 0.83\nSuperficial- Spreading 41 0.96 0.77 0.96 0.70 0.82 0.91 0.77 0.87 0.90\nP-value (one-sided) 0.09 0.31 0.15 0.28 0.17 0.59 0.32 0.81 0.09\nBRAF mutation Y 25 0.93 0.75 0.93 0.65 0.82 0.85 0.77 0.87 0.89\nN 33 0.90 0.70 0.93 0.72 0.70 0.82 0.68 0.9 0.82\nP-value (one-sided) 0.13 0.45 0.36 0.44 0.06 0.16 0.04 0.49 0.13\nNRAS mutation Y 6 0.94 0.78 1.01 0.66 0.67 0.91 0.72 1.02 0.85\nN 45 0.94 0.75 0.95 0.75 0.79 0.85 0.71 0.87 0.88\nP-value (one-sided) 0.28 0.40 0.41 0.31 0.38 0.37 0.40 0.05 0.39\nBRAF or NRAS mutation Y 31 0.93 0.75 0.94 0.65 0.82 0.89 0.77 0.90 0.89\nN 19 0.90 0.73 0.93 0.73 0.73 0.82 0.68 0.84 0.83\nP-value (one-sided) 0.37 0.46 0.37 0.49 0.16 0.12 0.02 0.29 0.14\nThe statistical test used was the Wilcoxon two-sample test, unless otherwise stated (*Spearman correlation, **Kruskal-Wallis test). Loss anywhere in the CDKN2A region was associated with ulceration (P = 0.002). However, ulceration of the tumor was most significantly associated with reduced gene dosage at CDKN2B (one sided test P = 0.006, two sided P = 0.01) and regions coding for P14ARF (one sided P = 0.002, two sided P = 0.004). There was some evidence of an association between ulceration and reduced gene dosage at CDKN2A coding for CDKN2A, MTAP, and the interferon gene cluster (Table 1).\nRelative loss across the region was associated with increasing tumor thickness (Fig. 3). Spearman correlation coefficients are given for thickness and reduced gene dosage across the CDKN2A region (Table 1). The most significant correlation was with reduced gene dosage at CDKN2B (P = 0.007 one-sided test) but there was some association across 9p21.3 (P = 0.02). To summarize, at 9p increasing thickness correlated with loss impacting on the coding regions of CDKN2B, CDKN2A, but not with loss in intronic regions of CDKN2A, MTAP or the interferon gene cluster. Increased mitotic rate was associated with reduced gene dosage across CDKN2A and especially in regions coding for P14ARF and CDKN2A (one sided P = 0.0006 and 0.004, respectively). There was no association between reduced gene dosage at 9p and tumor site or melanoma subtype (Table 1).\nFigure 3 Heatmap of gene dosage at chromosome region 9p21 by Breslow thickness. Gene dosage ratios are shown for 18 tumors with Breslow thickness \u003c2 mm (above), 30 tumors with Breslow thickness 2–4 mm (middle) and 27 tumors of thickness \u003e4 mm. Blue coloration indicates reduced gene dosage, red coloration indicates increased gene dosage. There was no significant association between BRAF and NRAS mutation status and reduced gene dosage in the CDKN2A/CDKN2B regions with the Wilcoxon Two-Sample test, but there was a trend toward an association between the presence of BRAF mutations and loss at regions coding for CDKN2A (one sided P = 0.06, two sided P = 0.12). The absence of BRAF mutation was associated with reduced gene dosage at MTAP (one sided P = 0.04, two sided P = 0.09) and the absence of an NRAS mutation was (borderline) associated with reduced gene dosage at the interferon gene cluster (one sided P = 0.05, two sided P = 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