Abstract
Melanoma is currently divided on a genetic level according to mutational status. However, this classification does not optimally predict prognosis. In prior studies, we have defined gene expression phenotypes (high-immune, pigmentation, proliferative and normal-like), which are predictive of survival outcome as well as informative of biology. Herein, we employed a population-based metastatic melanoma cohort and external cohorts to determine the prognostic and predictive significance of the gene expression phenotypes. We performed expression profiling on 214 cutaneous melanoma tumors and found an increased risk of developing distant metastases in the pigmentation (HR, 1.9; 95% CI, 1.05-3.28; P=0.03) and proliferative (HR, 2.8; 95% CI, 1.43-5.57; P=0.003) groups as compared to the high-immune response group. Further genetic characterization of melanomas using targeted deep-sequencing revealed similar mutational patterns across these phenotypes. We also used publicly available expression profiling data from melanoma patients treated with targeted or vaccine therapy in order to determine if our signatures predicted therapeutic response. In patients receiving targeted therapy, melanomas resistant to targeted therapy were enriched in the MITF-low proliferative subtype as compared to pre-treatment biopsies (P=0.02). In summary, the melanoma gene expression phenotypes are highly predictive of survival outcome and can further help to discriminate patients responding to targeted therapy.
Highlights
Cutaneous malignant melanoma (CMM) is the most lethal form of skin cancer and its incidence has increased faster than that of any other cancer, rendering it a major public health problem worldwide
When analyzing primary melanoma tumor features we found that histological type and primary site varied between the phenotypes (P=0.01 or P=0.02, respectively, Fisher’s exact test)
This stratification is relevant, controversy exists regarding the prognostic significance of classifying melanomas based only on BRAF and NRAS mutations [18, 19]
Summary
Cutaneous malignant melanoma (CMM) is the most lethal form of skin cancer and its incidence has increased faster than that of any other cancer, rendering it a major public health problem worldwide. In order to www.impactjournals.com/oncotarget provide clinicians and patients with accurate prognostic information about the disease, a correct staging system is fundamental. Several attempts to introduce this approach as a step towards individualized patient management have been made by defining new molecular biomarkers and gene signatures correlating with clinical outcome. Since the initial search for prognostic signatures in melanoma by Winnepenninckx et al [4], several signatures have been proposed. These range from a single-gene signature of osteopontin in primary melanoma, to different multi-gene signatures in stage III and IV metastatic melanoma lesions [5,6,7,8]. At present time there is still no extensively validated prognostic molecular signature in melanoma
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
