title: DLC1 expression is reduced in human cutaneous melanoma and correlates with patient survival.
abstract: Deleted in Liver Cancer-1 (DLC1) is a Rho-GTPase-activating protein known to be downregulated and function as a tumor suppressor in numerous solid and hematological cancers. Its expression status in melanoma is currently unknown however, prompting us to examine this. Using immunohistochemistry and tissue microarrays containing a large set of melanocytic lesions (n=539), we examined the expression profile of DLC1 in melanoma progression, as well as the association between DLC1 and patient survival. We detected both cytoplasmic and nuclear DLC1 expression, and found that whereas cytoplasmic DLC1 was significantly downregulated in metastatic melanoma compared with nevi and primary melanoma, nuclear DLC1 expression was significantly down in primary melanoma compared with nevi, and then further down in metastatic melanoma. Loss of cytoplasmic DLC1 was significantly associated with poorer overall and disease-specific 5-year survival rates of all melanoma (P<0.001 and P=0.001, respectively) and metastatic melanoma patients (P=0.020 and 0.008, respectively), and similar results were seen for nuclear DLC1 (P<0.001 for both overall and disease-specific survival for all melanoma patients, and P=0.004 for metastatic melanoma patients). Next, we examined the correlation between cytoplasmic and nuclear DLC1 and found that concomitant loss of both forms was associated with the worst outcome for metastatic melanoma patients (P=0.013 and P=0.008 for overall and disease-specific 5-year survival, respectively). Finally, multivariate Cox regression analysis determined that strong cytoplasmic and nuclear DLC1 expression was a favorable independent prognostic factor for all melanoma (HR, 0.61; 95% CI, 0.42-0.88; P=0.008) and metastatic melanoma patients (HR, 0.42; 95% CI, 0.23-0.77; P=0.005). Although more research still needs to be done on the topic, these preliminary results support the hypothesis that DLC1 is a tumor suppressor in melanoma.
authors.affiliation: Department of Dermatology and Skin Science, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Sjoestroem
authors.affiliation: Department of Dermatology and Skin Science, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Shahram
authors.initials: S
authors.lastname: Khosravi
authors.affiliation: Department of Dermatology and Skin Science, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Yabin
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Dermatology and Skin Science, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Gholamreza
authors.initials: G
authors.lastname: Safaee Ardekani
authors.affiliation: Department of Pathology, Vancouver General Hospital, Vancouver, BC, 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, BC, Canada.
authors.forename: Gang
authors.initials: G
authors.lastname: Li
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D005260:Female; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008545:Melanoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D012878:Skin Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D015996:Survival Rate; D046888:Tissue Array Analysis; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C112352:DLC1 protein, human; D020690:GTPase-Activating Proteins; D025521:Tumor Suppressor Proteins