Early-Age-at-Onset Colorectal Cancer and Microsatellite Instability as Markers of Hereditary Nonpolyposis Colorectal Cancer

Pucciarelli, Salvatore; Agostini, Marco; Viel, Alessandra; Bertorelle, Roberta; Russo, Valentina; Toppan, Paola; Lise, Mario

doi:10.1007/s10350-004-6546-9

Cited by 21 publications

(17 citation statements)

References 25 publications

(46 reference statements)

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“…The MSI status was determined by analysing five microsatellites of the Bethesda recommended panel (BAT-25, BAT-26, D2S123, D5S346, and D17S250) (Pucciarelli et al, 2003), and defining high MSI (MSI-H) tumours as those with two or more altered markers (Boland et al, 1998).…”

Section: P53 and Msi Analysesmentioning

confidence: 99%

Relationship between telomere shortening, genetic instability, and site of tumour origin in colorectal cancers

et al. 2010

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BACKGROUND: Telomeres, located at chromosome ends, are progressively shortened during each cell cycle by replication-dependent loss of DNA termini. Although maintenance of telomere length is critical for cell-replicative potential and tumourigenesis, the erosion of telomeres can lead to genetic instability, a pivotal mechanism in the neoplastic process. PATIENTS AND METHODS: A total of 118 colorectal cancer (CRC) samples (53 right-colon, 30 left-colon, and 35 rectal tumours) and corresponding adjacent non-cancerous tissues were evaluated for telomere length, p53 mutation, and microsatellite instability (MSI). Telomere length was estimated by real-time PCR. RESULTS: Telomeres were significantly shorter in CRCs than in adjacent tissues, regardless of tumour stage and grade, site, or genetic alterations (Po0.0001). Moreover, in normal tissues, but not in tumours, telomere length inversely correlated with age (r ¼ À0.24, P ¼ 0.017). Telomere length in CRCs did not differ with tumour progression or p53 status; however, in CRCs carrying the wild-type p53, telomeres were significantly shorter in tumours with MSI than in those with stable microsatellites (P ¼ 0.027). Furthermore, telomere length differed according to tumour location, being longer in rectal cancers (P ¼ 0.03). CONCLUSIONS: These findings suggest that telomere shortening is a key initial event in colorectal carcinogenesis. The extent of telomere erosion is related to tumour origin site and may be influenced by the mismatch repair pathway.

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Section: P53 and Msi Analysesmentioning

confidence: 99%

Relationship between telomere shortening, genetic instability, and site of tumour origin in colorectal cancers

et al. 2010

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“…The characteristic presentation of HNPCC is frequently right-sided localization, the presence of synchronous and metachronous CRCs, and its association with other HNPCC-related extracolonic tumors, including gastric, endometrial, and urinary and biliary tract cancers in afflicted families [2,3] . Compared to sporadic colorectal carcinomas, HNPCC has an earlier age of onset, Crohn's disease-like lymphocytic infiltration in tumor tissues, increased mucin production, and a lower degree of histological differentiation [3][4][5] . The classic adenoma-carcinoma sequence can be observed in HNPCC patients as well, but the conversion of polyps to malignant proliferation is accelerated, taking only 1-3 years, as opposed to sporadic adenomas, where this can take as long as 10-15 years [1] .…”

Section: Introductionmentioning

confidence: 99%

Pedigree and genetic analysis of a novel mutation carrier patient suffering from hereditary nonpolyposis colorectal cancer

Tanyi¹

2006

WJG

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hMSH2 gene might be responsible for the development of colon cancers. In family members where the exon 7 mutation is not coupled with this missense mutation, colon cancer appears after the age of 40. The association of these two mutations seems to decrease the age of manifestation of the disease into the early thirties. INTRODUCTIONAccording to published data, about 15-20 % of colorectal carcinomas (CRC) follow a familial pattern. Familial adenomatous polyposis coli syndrome (FAP) and its subtypes are responsible for only about 1 % of all CRCs, while hereditary nonpolyposis colon cancer (HNPCC) accounts for approximately 3-8 % of cases [1][2][3] . The characteristic presentation of HNPCC is frequently right-sided localization, the presence of synchronous and metachronous CRCs, and its association with other HNPCC-related extracolonic tumors, including gastric, endometrial, and urinary and biliary tract cancers in afflicted families [2,3] . Compared to sporadic colorectal carcinomas, HNPCC has an earlier age of onset, Crohn's disease-like lymphocytic infiltration in tumor tissues, increased mucin production, and a lower degree of histological differentiation [3][4][5] . The classic adenoma-carcinoma sequence can be observed in HNPCC patients as well, but the conversion of polyps to malignant proliferation is accelerated, taking only 1-3 years, as opposed to sporadic adenomas, where this can take as long as 10-15 years [1] . The number of polyps in the colon is not so high as in cases of FAP. The genetic background of HNPCC has been identified in the germline defect of DNA mismatch repair genes (MMR Abstract AIM: To screen a suspected Hungarian HNPCC family to find specific mutations and to evaluate their effect on the presentation of the disease. METHODS:The family was identified by applying the Amsterdam and Bethesda Criteria. Immunohistochemistry was performed, and DNA samples isolated from tumor tissue were evaluated for microsatellite instability. The identification of possible mutations was carried out by sequencing the hMLH1 and hMSH2 genes. RESULTS:Two different mutations were observed in the index patient and in his family members. The first mutation was located in exon 7, codon 422 of hMSH2, and caused a change from Glu to STOP codon. No other report of such a mutation has been published, as far as we could find in the international databases. The second mutation was found in exon 3 codon 127 of the hMSH2 gene, resulting in Asp→Ser substitution. The second mutation was already published, as a non-pathogenic allelic variation. CONCLUSION:The pedigree analysis suggested that the newly detected nonsense mutation in exon 7 of the

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“…HNPCC patients, who often carry inactivating mutations in the MSH2 gene, have better survival rates than sporadic CRC patients [21]. Nijhuis et al [22] found that the absence of MSH2 expression is associated with a high-risk profile in early stage cervical cancer.…”

Section: Discussionmentioning

confidence: 99%

MSH2 is required for cell proliferation, cell cycle control and cell invasiveness in colorectal cancer cells

Shen

Jiang

et al. 2012

Chin. Sci. Bull.

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We have investigated the role of MSH2, a mismatch repair gene in cell proliferation, cell cycle control and cell invasiveness in the SW480 human colorectal cancer cell line. RNAi-mediated inhibition of MSH2 expression was achieved using MSH2 shRNA lentiviral expression vectors. Effective knockdown of endogenous MSH2 expression was determined by real-time PCR analysis. The most efficient MSH2 knockdown vector was selected for subsequent studies using SW480 cells. Endogenous MSH2 mRNA levels decreased after lentiviral delivery of the MSH2-RNAi, indicating efficient silencing of MSH2 expression in SW480 cells. Cell proliferation, cell cycle progression and cell invasiveness were quantified by MTT assays, flow cytometry and transwell assays, respectively. RNAi-mediated inhibition of MSH2 expression in SW480 cells resulted in decreased cell proliferation, cell cycle arrest at the G0/G1 phase and decreased cell invasiveness. Taken together, these results provide evidence that MSH2 stimulates cell proliferation, promotes cell cycle progression and positively regulates cell invasiveness.

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Early-Age-at-Onset Colorectal Cancer and Microsatellite Instability as Markers of Hereditary Nonpolyposis Colorectal Cancer

Cited by 21 publications

References 25 publications

Relationship between telomere shortening, genetic instability, and site of tumour origin in colorectal cancers

Relationship between telomere shortening, genetic instability, and site of tumour origin in colorectal cancers

Pedigree and genetic analysis of a novel mutation carrier patient suffering from hereditary nonpolyposis colorectal cancer

MSH2 is required for cell proliferation, cell cycle control and cell invasiveness in colorectal cancer cells

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