Molecular Screening for Hereditary Nonpolyposis Colorectal Cancer: A Prospective, Population-Based Study

Percesepe, Antonio; Borghi, Francesca; Menigatti, Mirco; Losi, Lorena; Foroni, Moira; Gregorio, Carmela Di; Rossi, Giuseppina; Pedroni, Monica; Sala, Elisa; Vaccina, F.; Roncucci, Luca; Benatti, Piero; Viel, Alessandra; Genuardi, Maurizio; Marra, Giancarlo; Kristo, Paula; Peltomäki, Païvi; Leòn, Maurizio Ponz de

doi:10.1200/jco.2001.19.19.3944

Cited by 94 publications

(52 citation statements)

References 28 publications

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“…The frequency of defective protein expression of hMSH2 and/or hMLH1 in cases with CRC alone was 7.2% in our study and this finding closely correlated to the reported frequency of MSI or RER in sporadic CRC. MSI-H has been reported to be observed from 5-20% of sporadic CRC cases (27,28). A high frequency loss of the two MMR gene proteins was observed in patients with GC and CRC.…”

Section: Discussionmentioning

confidence: 99%

Loss of protein expression of hMLH1 and hMSH2 with double primary carcinomas of the stomach and colorectum

Yamamoto¹,

Taguchi²,

Baba³

et al. 2006

Oncol Rep

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Abstract. The frequency of synchronous or metachronous multiple primary carcinomas in patients with gastrointestinal carcinoma or colorectal carcinoma (CRC) has been reported to be ~10%. We determined the role of hMSH2 and hMLH1 in double carcinomas with both GC and CRC. Fifty-six patients with synchronous or metachronous colorectal carcinoma with gastric carcinoma (CRC with GC), and 69 patients with CRC alone was included in our study. We investigated their clinicopathological characteristics, family history and immunohistochemical stains of hMSH2 and hMLH1 were compared between the patients with CRC alone and those with both CRC with GC. The defective protein expression of hMSH1 and/or hMLH1 in colorectal carcinomas was significantly higher in patients with both CRC with GC than in those with CRC alone (p<0.0001). The survival rate in patients with both CRC with GC was significantly lower than that in those with CRC alone (p<0.01), in addition, the survival rate in patients with defective protein expression of hMSH2 and/or hMLH1 was higher than in those with a positive protein expression of hMSH2 and/or hMLH1 in CRC with GC (p<0.05). The incidence of defective protein expression of hMSH2 and/or hMLH1 in CRC with GC patients suggests that abnormalities in the function of hMSH2 and hMLH1 may play an important role in carcinogenesis. Our findings indicate that the CRC patients who demonstrate a defective protein expression of hMSH2 and/or hMLH1 have a higher risk of developing secondary carcinoma in the gastrointestinal tract.

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Section: Discussionmentioning

confidence: 99%

Loss of protein expression of hMLH1 and hMSH2 with double primary carcinomas of the stomach and colorectum

Yamamoto¹,

Taguchi²,

Baba³

et al. 2006

Oncol Rep

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“…Approximately 15% of all colorectal cancers show high-level microsatellite instability (MSI) (Aaltonen et al, 1993;Ionov et al, 1993;Thibodeau et al, 1993) reflecting dysfunction of the postreplicative DNA mismatch repair system, and in most of these tumors (roughly 10% of all colon cancers), the instability stems from CpG methylation-mediated silencing of the mismatch repair gene hMLH1 (Kane et al, 1997). Indeed, hMLH1 promoter methylation is a defining feature of CIMP-positive colorectal cancers, which are preferentially located in the right colon and usually affect older women (Malkhosyan et al, 2000;Percesepe et al, 2001;Slattery et al, 2001). An even larger percentage of colorectal cancers (20-40%) are characterized by promoter methylation-mediated silencing of MGMT (Esteller et al, 2000;Whitehall et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Normal colorectal mucosa exhibits sex- and segment-specific susceptibility to DNA methylation at the hMLH1 and MGMT promoters

et al. 2008

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Silencing of gene expression by aberrant cytosine methylation is a prominent feature of human tumors, including colorectal cancers. Epigenetic changes of this type play undisputed roles in cell transformation when they involve genes that safeguard genome stability, and they can also be detected in precancerous lesions and seemingly normal peritumoral tissues. We explored physiological conditions associated with aberrant promoter methylation involving two DNA-repair genes in normal colorectal mucosa. Samples of cecal, transverse colon, sigmoid and rectal mucosa collected from 100 healthy individuals undergoing screening colonoscopy were analysed for hMLH1 and MGMT promoter methylation with a quantitative PCR assay. Positivity in at least one colon segment was common in both sexes, with methylation involving 0.1-18.8% of the alleles (median ¼ 0.49%). Samples from males showed no consistent patterns for either promoter, but there were striking age-and colon segmentspecific differences in the female subgroup. Here, the prevalence of hMLH1 and MGMT methylation increased significantly with age, particularly in the right colon, where there was also an age-related increase in the percentage of alleles showing hMLH1 methylation. Concomitant methylation of both promoters was also significantly more common in the right colon of women. These findings paralleled immunohistochemical patterns of hMLH1 and MGMT protein loss in an independent series of 231 colorectal cancers and were consistent with current epigenetic profiles of colorectal cancer subsets. They suggest the intriguing possibility that the epigenetic signatures of cancers may have early-stage, normal-tissue counterparts that reflect potentially important aspects of the initial carcinogenetic process.

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“…The most common inherited condition that gives rise to MSI positive cancers is Lynch syndrome, an autosomal dominant disease, also referred to as Hereditary Non-polyposis Colorectal Cancer (HNPCC), where gastric cancer is a common neoplasia, occurring in 6% of Lynch syndrome cases (Percesepe et al, 2001;Samowitz et al, 2001). Predisposed individuals carry a recessive, first-hit germline mutation in the MMR genes, including large genomic rearrangement, which account for 5-20% of all mutations.…”

Section: Mutational Impairment Of Mmr Activity and Pathogenic Signifimentioning

confidence: 99%

Genetic Instability in Gastric Cancer

Hudler¹,

Vogelsang²,

Komel³

2011

Gastric Carcinoma - Molecular Aspects and Current Advances

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Molecular Screening for Hereditary Nonpolyposis Colorectal Cancer: A Prospective, Population-Based Study

Abstract: We conclude that the incidence of molecularly confirmed HNPCC (one [0.3%] of 336) in a high-incidence area for CRC is lower than in previous biomolecular and clinical estimates.

Cited by 94 publications

References 28 publications

Loss of protein expression of hMLH1 and hMSH2 with double primary carcinomas of the stomach and colorectum

Loss of protein expression of hMLH1 and hMSH2 with double primary carcinomas of the stomach and colorectum

Normal colorectal mucosa exhibits sex- and segment-specific susceptibility to DNA methylation at the hMLH1 and MGMT promoters

Genetic Instability in Gastric Cancer

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