Chromosomal Instability (CIN) Phenotype, CIN High or CIN Low, Predicts Survival for Colorectal Cancer

Watanabe, Toshiaki; Kobunai, Takashi; Yamamoto, Yasutake; Matsuda, Keiji; Ishihara, Soichiro; Nozawa, Keijiro; Yamada, Hideki; Hayama, Tamuro; Inoue, Eisuke; Tamura, Junko; Iinuma, Hisae; Akiyoshi, Takashi; Muto, Tetsuichiro

doi:10.1200/jco.2011.38.6490

Cited by 95 publications

(74 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The recent findings showing that the CIN phenotype is a predictive marker for survival and may be used to select high-risk patients with stages II and III CRC (Watanabe et al 2012), combined with the specific involvement of CCAT2 in MSS CRCs indicate that CCAT2 has the potential to become Figure 7. A model of CCAT2 locus involvement in CRC.…”

Section: Discussionmentioning

confidence: 99%

CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer

et al. 2013

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 99%

CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer

et al. 2013

View full text Add to dashboard Cite

show abstract

“…We acknowledge the Victorian Cancer Biobank for the provision of ( 39 ). Th ere was a strong association between LOH ratio and DI ( P < 0.001, trend test).…”

Section: Acknowledgmentsmentioning

confidence: 97%

“…Recently, Watanabe et al ( 39 ) studied survival in 1,103 patients, using LOH at chromosomes 2p, 5q, 17p, and 18q as a surrogate for CIN. Th ey reported poor prognosis for MSI-tumors with high-frequency LOH, whereas MSI + tumors and MSI − tumors with low-frequency LOH showed similarly favorable outcomes.…”

Section: Loh Is a Good Surrogate For Cin But An Inferior Indicator Omentioning

confidence: 99%

Survival in stage II/III colorectal cancer is independently predicted by chromosomal and microsatellite instability, but not by specific driver mutations

Mouradov

Domingo

Gibbs

et al. 2013

American Journal of Gastroenterology

128

View full text Add to dashboard Cite

Microsatellite instability (MSI) is an established marker of good prognosis in colorectal cancer (CRC).Chromosomal instability (CIN) is strongly negatively associated with MSI and has been shown to be a marker of poor prognosis in a small number of studies. However, a substantial group of " doublenegative " (MSI − / CIN − ) CRCs exists. The prognosis of these patients is unclear. Furthermore, MSI and CIN are each associated with specifi c molecular changes, such as mutations in KRAS and BRAF , that have been associated with prognosis. It is not known which of MSI, CIN, and the specifi c gene mutations are primary predictors of survival. METHODS:We evaluated the prognostic value (disease-free survival, DFS) of CIN, MSI, mutations in KRAS , NRAS , BRAF , PIK3CA , FBXW7 , and TP53 , and chromosome 18q loss-of-heterozygosity (LOH) in 822 patients from the VICTOR trial of stage II / III CRC. We followed up promising associations in an Australian community-based cohort ( N = 375). RESULTS:In the VICTOR patients, no specifi c mutation was associated with DFS, but individually MSI and CIN showed signifi cant associations after adjusting for stage, age, gender, tumor location, and therapy. A combined analysis of the VICTOR and community-based cohorts showed that MSI and CIN were independent predictors of DFS (for MSI, hazard ratio (HR) = 0.58, 95 % confi dence interval (CI) 0.36 -0.93, and P = 0.021; for CIN, HR = 1.54, 95 % CI 1.14 -2.08, and P = 0.005), and joint CIN / MSI testing signifi cantly improved the prognostic prediction of MSI alone ( P = 0.028). Higher levels of CIN were monotonically associated with progressively poorer DFS, and a semi-quantitative measure of CIN was a better predictor of outcome than a simple CIN + / − variable . All measures of CIN predicted DFS better than the recently described Watanabe LOH ratio. SUPPLEMENTARY MATERIAL is linked to the online version of the paper at

show abstract

“…Una de las formas de evaluarla es mediante la pérdida de heterocigosidad (LOH). La vía CIN ha sido propuesta como marcador predictivo en pacientes con etapas II y III 9,10 . La MSI es causada por la incapacidad de la cé-lula cancerosa en corregir deleciones o inserciones en regiones repetitivas del ADN por el complejo de reparación "mismatch repair" (MMR).…”

unclassified

Caracterización de pacientes con cáncer colorrectal esporádico basado en la nueva subclasificación molecular de consenso

et al. 2017

View full text Add to dashboard Cite

show abstract

Chromosomal Instability (CIN) Phenotype, CIN High or CIN Low, Predicts Survival for Colorectal Cancer

Abstract: The CIN phenotype is a predictive marker for survival and may be used to select high-risk patients with stages II and III CRC.

Cited by 95 publications

References 26 publications

CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer

CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer

Survival in stage II/III colorectal cancer is independently predicted by chromosomal and microsatellite instability, but not by specific driver mutations

Caracterización de pacientes con cáncer colorrectal esporádico basado en la nueva subclasificación molecular de consenso

Contact Info

Product

Resources

About