MicroRNA signatures differentiate melanoma subtypes.

Melanoma is an aggressive cancer that is highly resistance to therapies once metastasized. We studied microRNA (miRNA) expression in clinical melanoma subtypes and evaluated different miRNA signatures in the background of gain of function somatic and inherited mutations associated with melanoma. Total RNA from 42 patient derived primary melanoma cell lines and three independent normal primary melanocyte cell cultures was evaluated by miRNA array. MiRNA expression was then analyzed comparing subtypes and additional clinicopathologic criteria including somatic mutations. The prevalence and association of an inherited variant in a miRNA binding site in the 3'UTR of the KRAS oncogene, referred to as the KRAS-variant, was also evaluated. We show that seven miRNAs, miR-142-3p, miR-486, miR-214, miR-218, miR-362, miR-650 and miR-31, were significantly correlated with acral as compared to non-acral melanomas (p < 0.04). In addition, we discovered that the KRAS-variant was enriched in non-acral melanoma (25%), and that miR-137 under expression was significantly associated with melanomas with the KRAS-variant. Our findings indicate that miRNAs are differentially expressed in melanoma subtypes and that their misregulation can be impacted by inherited gene variants, supporting the hypothesis that miRNA misregulation reflects biological differences in melanoma.

MicroRNA signatures differentiate uterine cancer tumor subtypes.

OBJECTIVE: Endometrial cancer (EC) is the most common gynecologic malignancy. Type I EC has a favorable prognosis, while type II ECs account for half of all treatment failures. Little knowledge of the biological differences is available to predict EC outcomes besides their pathological distinctions. MicroRNAs (miRNA) are a family of non-translated RNAs important in regulating oncogenic pathways. Mis-expression patterns of miRNAs in EC, as well as differences in miRNA expression patterns between the subtypes of EC, has not been previously evaluated. Our purpose was to identify miRNA profiles of EC subtypes, and to identify miRNAs associated with these subtypes to ultimately understand the different biological behavior between these subtypes. METHODS: Ninety-five fresh/frozen and paraffin-embedded samples of endometrial type I and II cancer, carcinosarcomas and benign endometrial samples were collected. MiRNA expression profiles were evaluated by microarray analysis. Statistical analysis was performed. RESULTS: Distinct miRNA signatures in tumor versus normal samples and in endometrioid vs. uterine papillary serous carcinomas exist. Additionally, carcinosarcomas have a unique miRNA signature from either the type I or II epithelial tumors. CONCLUSIONS: We hypothesize that further understanding the miRNAs that separate these subtypes of EC will lead to biological insights into the different behavior of these tumors.

A SNP in a let-7 microRNA complementary site in the KRAS 3' untranslated region increases non-small cell lung cancer risk.

Lung cancer is the leading cause of cancer deaths worldwide, yet few genetic markers of lung cancer risk useful for screening exist. The let-7 family-of-microRNAs (miRNA) are global genetic regulators important in controlling lung cancer oncogene expression by binding to the 3' untranslated regions of their target mRNAs. The purpose of this study was to identify single nucleotide polymorphisms (SNP) that could modify let-7 binding and to assess the effect of such SNPs on target gene regulation and risk for non-small cell lung cancer (NSCLC). let-7 complementary sites (LCS) were sequenced in the KRAS 3' untranslated region from 74 NSCLC cases to identify mutations and SNPs that correlated with NSCLC. The allele frequency of a previously unidentified SNP at LCS6 was characterized in 2,433 people (representing 46 human populations). The frequency of the variant allele is 18.1% to 20.3% in NSCLC patients and 5.8% in world populations. The association between the SNP and the risk for NSCLC was defined in two independent case-control studies. A case-control study of lung cancer from New Mexico showed a 2.3-fold increased risk (confidence interval, 1.1-4.6; P = 0.02) for NSCLC cancer in patients who smoked <40 pack-years. This association was validated in a second independent case-control study. Functionally, the variant allele results in KRAS overexpression in vitro. The LCS6 variant allele in a KRAS miRANA complementary site is significantly associated with increased risk for NSCLC among moderate smokers and represents a new paradigm for let-7 miRNAs in lung cancer susceptibility.