Progression in Cutaneous Malignant Melanoma Is Associated with Distinct Expression Profiles

Abstract

Cutaneous malignant melanoma remains the leading cause of skin cancer death in industrialized countries. Clinical and histological variables that predict survival, such as Breslow's index, tumor size, ulceration, or vascular invasion have been identified in malignant melanoma. Nevertheless, the potential relevance of biological variables still awaits an in-depth exploration. Using tissue microarrays (TMAs), we retrospectively analyzed 165 malignant melanoma samples from 88 patients corresponding to distinct histological progression phases, radial, vertical, and metastases. A panel of 39 different antibodies for cell cycle, apoptosis, melanoma antigens, transcription factors, DNA mismatch repair, and other proteins was used. Integrating the information, the study has identified expression profiles distinguishing specific melanoma progression stages. Most of the detected alterations were linked to the control of cell cycle G1/S transition; cyclin D1 was expressed in radial cases 48% (12 of 25) with significant lost of expression in vertical cases 14% (9 of 65), P = 0.002; whereas p16(INK4a) (89% in vertical versus 71% in metastatic cases, P = 0.009) and p27(KIP1) (76% in radial versus 45% in vertical cases, P = 0.010) were diminished in advanced stages. The study also defines a combination of biological markers associated with shorter overall survival in patients with vertical growth phase melanoma, that provided a predictor model with four antibodies (Ki67, p16(INK4a), p21(CIP1), and Bcl-6). This predictor model was validated using an independent series of 72 vertical growth phase melanoma patients.

Immunohistochemical Expression of p16, p21, p27 and Cyclin D1 in Oral Nevi and Melanoma

“…These data are in accord with literature reports of negative or weak expression of cyclin D1 in benign melanocytic lesions and high levels in cutaneous melanomas [22][23][24][25]. Besides cutaneous melanomas, increased expression of cyclin D1 has been reported in uveal melanomas, and now we also confirm in oral melanomas, suggesting that it has an oncogenic role in the pathogenesis of this aggressive neoplasm [13,24,26]. Some studies have also shown that cyclin D1 is associated with unfavorable outcomes in cutaneous melanomas and is an independent risk factor for the development of metastases [25,26].…”

“…In agreement with these results, cutaneous nevi have been shown to be uniformly positive for p16 in more than 70% of cells [7,15]. On the other hand, loss of p16 expression has also been demonstrated in almost 50% of primary cutaneous and oral melanomas, similarly to many other cancers, including pancreatic, esophageal, lung, head and neck, breast, bladder, brain and ovarian [1,5,13,14]. Although there is general consensus regarding the loss of p16 expression in cutaneous melanomas, it is suggested that this occurs in later stages of the disease, as it is not altered in melanoma in situ [16].…”

“…Melanoma is known to exhibit aberrant expression of cell cycle-regulating genes, and these abnormalities at the G1/S checkpoint are considered crucial steps in the genesis and progression of melanoma [12,13]. In this study, we evaluated the immunohistochemical expression of the cell cycle regulators p16, p21, p27, and cyclin D1 in 38 intramucosal nevi and 13 primary oral melanomas.…”

“…In oral nevi, expression of p16 was not altered, indicating that in the mouth, nevi do not precede melanoma formation [5]. Reduced expression of p16 in cutaneous melanomas is also associated with a significant risk of recurrence and it is considered an independent predictor for decreased patient survival [13,17,18]. p27 was strongly expressed in all nevi cells, in contrast to oral melanomas where six out of 13 cases were weakly or moderately positive.…”

“…High expression of p27 is a feature of benign lesions, and it can be used to distinguish benign and malignant tumors [5]. Strong p27 nuclear staining has been shown in cutaneous nevi, including Spitz nevi [9,19], and its expression is progressively lost during the development of melanomas [9,13,19]. There are few studies reporting the association of p27 with clinical outcome in melanoma patients.…”