title: Loss of tumor suppressors KAI1 and p27 identifies a unique subgroup of primary melanoma patients with poor prognosis.
abstract: Primary melanoma, a highly aggressive malignancy, exhibits heterogeneity in biologic behaviors, clinical characteristics, metastasis potential and mortality. The present study sought to identify the molecular signatures that define a subgroup of primary melanomas with high risks of metastasis and mortality. First, we identified the markers that best differentiated metastatic melanomas from primary melanomas by examining the expression of seven previously reported biomarkers (BRAF, Dicer, Fbw7, KAI1, MMP2, p27 and Tip60) in a training cohort consisting of 145 primary melanomas and 105 metastatic melanomas. KAI1 and p27, both tumor suppressors, emerged as best candidates. Loss of both tumor suppressors occurred in the majority (74.29%) of metastatic melanomas. Further, a subset (metastatic like, or "ML", 33.10%) of primary melanomas also lost these two tumor suppressors. Kaplan-Meier analysis indicated that ML subgroup of primary melanoma patients had much worse 5 year survival compared with other primary melanoma patients (P = 0.002). The result was confirmed in an independent validation cohort with 92 primary melanomas (P = 0.030) and in the combined cohort with 237 melanoma patients (P = 3.00E-4). Additionally, compared to KAI1 and p27 as an individual prognostic marker, the combined signature is more closely associated with melanoma patient survival (P = 0.025, 0.264 and 0.009, respectively). In conclusion, loss of both KAI1 and p27 defines a subgroup of primary melanoma patients with poor prognosis. This molecular signature may help in metastatic melanoma diagnosis and may provide information useful in identifying high-risk primary melanoma patients for more intensive clinical surveillance in the future.
authors.affiliation: Department of Dermatology and Skin Science, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.|Department of Pathology, Shantou University Medical College, Shantou, Guangdong, China.
authors.forename: Guohong
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Dermatology and Skin Science, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Yabin
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Bioelectromagnetics Laboratory, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
authors.forename: Guangdi
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Dermatology and Skin Science, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Yun
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Department of Dermatology and Skin Science, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Gholamreza
authors.initials: G
authors.lastname: Ardekani
authors.affiliation: Department of Dermatology and Skin Science, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Anand
authors.initials: A
authors.lastname: Rotte
authors.affiliation: Department of Pathology, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Martinka
authors.affiliation: Department of Dermatology and Skin Science, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Kevin
authors.initials: K
authors.lastname: McElwee
authors.affiliation: Department of Dermatology, 2nd Affiliated Hospital, Dalian Medical University, Dalian, China.
authors.forename: Xuezhu
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Dermatology, 2nd Affiliated Hospital, Dalian Medical University, Dalian, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Dermatology and Skin Science, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.|Department of Dermatology, 2nd Affiliated Hospital, Dalian Medical University, Dalian, China.|Dermatologic Oncology Program, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Youwen
authors.initials: Y
authors.lastname: Zhou
mesh_terms: D014408:Biomarkers, Tumor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D051861:Kangai-1 Protein / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000145:classification* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D011379:Prognosis; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D000096142:Cutaneous Malignant Melanoma
chemical_list: D014408:Biomarkers, Tumor; C497688:CD82 protein, human; C436291:CDKN1B protein, human; D051861:Kangai-1 Protein; D050760:Cyclin-Dependent Kinase Inhibitor p27
keywords: KAI1; p27; primary melanoma; prognostic marker; subgroup