Early-onset colorectal cancer with stable microsatellite DNA and near-diploid chromosomes

Chan, Tsun Leung; Curtis, Lucy C.; Leung, Suet Yi; Farrington, Susan M.; Ho, Judy W. C.; Chan, Alan K. L.; Lam, Polly W.Y.; Tse, Chun Wah; Dunlop, Malcolm G.; Wyllie, Andrew H.; Yuen, Siu Tsan

doi:10.1038/sj.onc.1204653

Cited by 66 publications

(58 citation statements)

References 28 publications

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“…This finding is similar to the situation in colorectal cancer, where MACS is identified in 15-30% of tumors. 17,[41][42][43] The pathogenesis of MACS tumors is not understood. It is noteworthy, however, that we have previously identified 44 largescale N-terminal deletion mutations of b-catenin in three small bowel adenocarcinomas characterized as MACS in the present study, indicating that inactivation of DNA repair mechanisms other than those implicated in mismatch or chromosomal repair could be involved in MACS tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Genetics and epigenetics of small bowel adenocarcinoma: the interactions of CIN, MSI, and CIMP

et al. 2011

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Characterization of tumor genetics and epigenetics allows to stratify a tumor entity according to molecular pathways and may shed light on the interactions of different types of DNA alterations during tumorigenesis. Small intestinal adenocarcinoma is rare, and to date the interrelation of genomic instability and epigenetics has not been investigated in this tumor type. We therefore analyzed 37 primary small bowel carcinomas with known microsatellite instability and KRAS status for chromosomal instability using comparative genomic hybridization, for the presence of aberrant methylation (CpG island methylation phenotype) by methylation-specific polymerase chain reaction, and for BRAF mutations. Chromosomal instability was detected in 22 of 37 (59%) tumors (3 of 9 microsatellite instable, and 19 of 28 microsatellite stable carcinomas). Nine carcinomas (24%) were microsatellite and chromosomally stable. High-level DNA methylation was found in 16% of chromosomal instable tumors and in 44% of both microsatellite instable and microsatellite and chromosomally stable carcinomas. KRAS was mutated in 55, 0, and 10% of chromosomal instable, microsatellite instable, and microsatellite and chromosomally stable tumors, respectively whereas the frequencies of BRAF mutations were 6% for chromosomal instable and 22% for both microsatellite instable and microsatellite and chromosomally stable carcinomas. In conclusion, in this study we show that chromosomal instable carcinomas of the small intestine are distinguished from microsatellite instable and microsatellite and chromosomally stable tumors by a high frequency of KRAS mutations, low frequencies of CpG island methylation phenotype, and BRAF mutations. In microsatellite instable and microsatellite and chromosomally stable cancers, CpG island methylation phenotype and BRAF/KRAS mutations are similarly distributed, indicating common mechanisms of tumor initiation or progression in their molecular pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Genetics and epigenetics of small bowel adenocarcinoma: the interactions of CIN, MSI, and CIMP

et al. 2011

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“…Previous CGH studies have shown the virtual absence of gross chromosomal gains and losses in MSI þ colon carcinomas (Schlegel et al, 1995;Chan et al, 2001); we therefore focused on the MMR gene mutation negative group. High quality DNA suitable for performing CGH was available from 16 MMR gene mutation negative tumors.…”

Section: Cghmentioning

confidence: 99%

“…CDX2 expression changes did not correlate with b-catenin activation status. CDX2 exon 3, which contains most of the reported pathogenic Total number of CGH changes was counted for chromosome arms so that a gain or loss of a whole chromosome is considered as two events for this purpose (Chan et al, 2001). According to this number, cases were divided into CINÀ and CIN+ subgroups (above and below the middle line respectively, see Results) (Wicking et al, 1998;Yagi et al, 1999), was sequenced for possible mutations, without finding any.…”

Section: Cdx2mentioning

confidence: 99%

“…Table 3 shows detailed description of the CGH results. We used a cutoff level of 5 or more events of chromosome arm gain or loss to classify a case as CIN þ (Chan et al, 2001). This level clearly separated the cases into two groups: a stable (CINÀ) group (9/16, 56%) with the number of chromosome arm gains or losses ranging from 0 to 4 with a mean of 1; and an unstable (CIN þ ) group (7/16, 44%) with the number of chromosome arm gains or losses ranging from 7 to 18 with a mean of 10.6.…”

Section: Cghmentioning

confidence: 99%

“…For example, a report suggested the existence of an additional group of microsatellite stable and chromosomally stable colorectal cancers with a tendency to young age or familial clustering (Chan et al, 2001). We performed a comprehensive molecular and DNA copy number analysis on colorectal carcinomas arising in cohorts of families with clinical features of HNPCC.…”

Section: Introductionmentioning

confidence: 99%

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Comprehensive characterization of HNPCC-related colorectal cancers reveals striking molecular features in families with no germline mismatch repair gene mutations

et al. 2005

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A considerable fraction of families with HNPCC shows no germline mismatch repair (MMR) gene mutations. We previously detected 'hidden' MMR gene defects in 42% of such families, leaving the remaining 58% 'truly' mutation negative. Here, we characterized 50 colorectal carcinomas and five adenomas arising in HNPCC families; 24 truly MMR gene mutation negative and 31 MMR gene mutation positive. Among 31 tumors from MMR gene mutation positive families, 25 (81%) had active Wnt signaling as indicated by aberrant b-catenin localization with or without CTNNB1 mutations, compared to only 7/ 18 tumors from MMR gene mutation negative families (39%; P ¼ 0.005). CGH studies revealed stable profiles in 9/16 (56%) of MMR gene mutation negative tumors, which was significantly associated with membranous b-catenin (P ¼ 0.005). Tumors with membranous b-catenin from the MMR gene mutation negative group also showed low frequency of TP53 mutations compared to those with nuclear b-catenin. Thus, a majority of the MMR gene mutation negative cases exhibited a novel molecular pattern characterized by the paucity of changes in common pathways to colorectal carcinogenesis. This feature distinguishes the MMR gene mutation negative families from both HNPCC families linked to MMR defects and sporadic cases, suggesting the involvement of novel predisposition genes and pathways in such families.

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Early‐onset colorectal cancer in young individuals

et al. 2018

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Treatment of young adults with colorectal cancer (CRC) represents an unmet clinical need, especially as diagnosis in this population might lead to the greatest loss of years of life. Since 1994, CRC incidence in individuals younger than 50 years has been increasing by 2% per year. The surge in CRC incidence in young adults is particularly alarming as the overall CRC frequency has been decreasing. Early‐onset CRC are characterized by a more advanced stage at diagnosis, poorer cell differentiation, higher prevalence of signet ring cell histology, and left colon‐sided location of the primary tumor. Among EO‐CRC, approximately 30% of patients are affected by tumors harboring mutations causing hereditary cancer predisposing syndromes, and 20% have familial CRC. Most notably, the remaining 50% of EO‐CRC patients have neither hereditary syndromes nor familial CRC, thus representing a formidable challenge for research. In this review article we summarize epidemiology, clinical and molecular features, heredity and outcome of treatments of EO‐CRC, and provide considerations for future perspectives.

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Early-onset colorectal cancer with stable microsatellite DNA and near-diploid chromosomes

Cited by 66 publications

References 28 publications

Genetics and epigenetics of small bowel adenocarcinoma: the interactions of CIN, MSI, and CIMP

Genetics and epigenetics of small bowel adenocarcinoma: the interactions of CIN, MSI, and CIMP

Comprehensive characterization of HNPCC-related colorectal cancers reveals striking molecular features in families with no germline mismatch repair gene mutations

Early‐onset colorectal cancer in young individuals

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