The functional roles of SNPs within the 8q24 gene desert in the cancer phenotype are not yet well understood. Here, we report that CCAT2, a novel long noncoding RNA transcript (lncRNA) encompassing the rs6983267 SNP, is highly overexpressed in microsatellite-stable colorectal cancer and promotes tumor growth, metastasis, and chromosomal instability. We demonstrate that MYC, miR-17-5p, and miR-20a are up-regulated by CCAT2 through TCF7L2-mediated transcriptional regulation. We further identify the physical interaction between CCAT2 and TCF7L2 resulting in an enhancement of WNT signaling activity. We show that CCAT2 is itself a WNT downstream target, which suggests the existence of a feedback loop. Finally, we demonstrate that the SNP status affects CCAT2 expression and the risk allele G produces more CCAT2 transcript. Our results support a new mechanism of MYC and WNT regulation by the novel lncRNA CCAT2 in colorectal cancer pathogenesis, and provide an alternative explanation of the SNP-conferred cancer risk.[Supplemental material is available for this article.]Notwithstanding the considerable advancements in our understanding of the molecular genetic basis of cancer, in the majority of cancer-associated genomic regions, the responsible protein-coding genes have not been identified yet. The discovery of short (19-22 nt), noncoding RNAs (ncRNAs)-called microRNAs (miRNAs) (Ambros 2001)-not only revealed a novel mechanism of gene regulation but also led to the identification of miRNAs directly involved in cancer development (Spizzo et al. 2009). It is therefore plausible that as-yet-unidentified members of the broader category of ncRNA mapping to cancer-associated genomic regions play ratelimiting roles in tumor initiation and/or progression (Rinn and Chang 2012). For instance, we previously reported that highly conserved genomic regions (ultraconserved regions, or UCRs) (Bejerano et al. 2004) are frequently transcribed as long (>200 bp) ncRNAs (lncRNAs) in both normal and tumor tissues (Calin et al. 2007). Furthermore, germline mutations, as well as single nucleotide polymorphisms (SNPs) in ultraconserved ncRNAs, were found to occur more frequently in patients with colon cancer and chronic leukemia than in the general population (Wojcik et al. 2010).The rs6983267 SNP, mapping to the 8q24.21 chromosomal region, has been consistently associated with an increased risk of colorectal cancer (CRC) (Haiman et al. 2007): The G allele was associated with greater predisposition to CRC than the T allele (odds ratios of 1.27 and 1.47 for heterozygotes and homozygotes, respectively; P = 1.27 3 10 À14 ) (Tomlinson et al. 2007). The increased cancer risk from this SNP variant was also observed in other cancer types, including prostate, ovarian, and inflammatory breast cancer (Ghoussaini et al. 2008;Bertucci et al. 2012). Despite the consistent association between rs6983267 and cancer risk, the underlying molecular and cellular mechanisms remain largely unknown. The genomic region spanning rs6983267 was found to contain DNA (Pom...

Dominant transmission of multiple uterine and cutaneous smooth-muscle tumors is seen in the disorder multiple leiomyomatosis (ML). We undertook a genomewide screen of 11 families segregating ML and found evidence for linkage to chromosome 1q42.3-q43 (maximum multipoint LOD score 5.40). Haplotype construction and analysis of recombinations permitted the minimal interval containing the locus, which we have designated "MCUL1," to be refined to an approximately 14-cM region flanked by markers D1S517 and D1S2842. Allelic-loss studies of tumors indicated that MCUL1 may act as a tumor suppressor. Identification of MCUL1 should have wide interest, since this gene may harbor low-penetrance variants predisposing to the common form of uterine fibroids and/or may undergo somatic mutation in sporadic leiomyomata.

The role of transforming growth factor β receptor type 1 (TGFBR1) polymorphisms, particularly a coding CGC insertion (rs11466445, TGFBR1*6A/9A) in exon 1, has been extensively investigated in regard to colorectal cancer (CRC) risk. These investigations have generated conflicting results. More recently, allele-specific expression (ASE) of TGFBR1 mRNA has been suggested as predisposing to CRC, with a relative risk of nearly 10-fold and a population attributable risk of ∼10%. Owing to the potential importance of TGFBR1 variants in CRC, we performed a comprehensive examination of tagging SNPs at and around the gene in 3,101 CRC cases and 3,334 controls of northern European ancestry. To test whether rare or subpolymorphic TGFBR1 variants were associated with CRC risk, we sequenced the gene's exons in a subset of patients. We also evaluated TGFBR1 ASE in a panel of CRC cases and controls. Overall, we found no association between TGFBR1 polymorphisms and CRC risk. The rare variant screen did not identify any changes of potentially pathogenic effects. No evidence of greater ASE in cases than controls was detected, and no haplotype around TGFBR1 could account for the ASE reported in other studies. We conclude that neither genetic variation nor ASE at TGFBR1 is likely to be a major CRC risk factor. genetic susceptibility | transforming growth factor β receptor type 1 *6A/ 9A | candidate gene | low penetrance | TGF signaling T ransforming growth factor β receptor type 1 (TGFBR1) is a serine-threonine kinase that mediates growth-inhibiting signals from TGFB1 through a complex with TGFBR2. The TGFB pathway and the related bone morphogenetic protein (BMP) pathway play important roles in the pathogenesis of colorectal cancer (CRC) and other intestinal tumors: Inactivating TGFBR2 mutations occur in CRCs with microsatellite instability (MSI) (1), germline mutations in SMAD4 and BMPR1A predispose to juvenile polyposis (2, 3), and SMAD4 is mutated in some MSInegative CRCs (4). In addition, common germline variants in the BMP pathway are associated with increased risk for CRC (5). It is therefore highly plausible that germline variation at TGFBR1 itself has effects on the risk for CRC in the general population.Considerable attention has been focused on a common TGFBR1 polymorphism (TGFBR1*6A/9A, rs11466445) in exon 1 that results in the deletion of three alanines from a stretch of nine alanines. This 9-bp deletion is located within the predicted signal sequence cleavage region. Functional studies have suggested that TGFBR1*6A responds less well than the TGFBR1*9A allele to growth inhibitory signals of TGFB1. Some studies have suggested that individuals who carry a TGFBR1*6A allele are at increased risk for cancers of several types, including CRC (6). Overall, however, evidence for the association with CRC is mixed and relatively small cohorts have been analyzed.The effects on cancer risk of other common polymorphisms and rare variants at TGFBR1 have not specifically been assessed.A second line of evidence for the importance of TGFB...

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