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- Renkonen, E, et al.
(author)
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Altered expression of MLH1, MSH2, and MSH6 in predisposition to hereditary nonpolyposis colorectal cancer
- 2003
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In: Journal of Clinical Oncology. - 1527-7755. ; 21:19, s. 3629-3637
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Journal article (peer-reviewed)abstract
- Purpose: A considerable fraction (30% to 70%) of families with verified or putative hereditary nonpolyposis colorectal cancer fails to show mutations in DNA mismatch repair (MMR) genes. Our purpose was to address the genetic etiology of such families. Materials and Methods: We scrutinized a population-based cohort of 26 families from Finland that had screened mutation-negative by previous techniques. Blood was tested for allelic messenger RNA (mRNA) expression of MLH1, MSH2, and MSH6 by single nucleotide primer extension (SNuPE), and tumor tissue for MMR protein expression by immunohistochemistry (IHC) as well as for microsatellite instability (MSI). Full-length cDNAs of genes implicated by SNuPE or IHC were cloned and sequenced. Results: Unbalanced mRNA expression of MLH1 alleles was evident in two families. An inherited nonsense mutation was subsequently identified in one family, and complete silencing of the mutated allele was identified in the other family. Extinct protein expression by IHC implicated MLH1 in these two and in four other families, MSH2 in four families, and MSH6 in one family. Although no unequivocal genomic mutations were detected in the latter families, haplotype and other findings provided support for heritable defects. With one exception, all tumors with IHC alterations showed MSI, in contrast to the remaining families, which showed neither IHC changes nor MSI. Conclusion: Our expression-based strategy stratified the present "mutation-negative" cohort into two discrete categories: families linked to the major MMR genes MLH1, MSH2, and MSH6 (11 [42%] of 26) and those likely to be associated with other, as yet unknown susceptibility genes (15 [58%] of 26). (C) 2003 by American Society of Clinical Oncology.
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| 3. |
- Vasen, HFA, et al.
(author)
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Decision analysis in the surgical treatment of patients with familial adenomatous polyposis: a Dutch-Scandinavian collaborative study including 659 patients
- 2001
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In: Gut. - : BMJ. - 0017-5749 .- 1468-3288. ; 49:2, s. 231-235
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Journal article (peer-reviewed)abstract
- The choice of colorectal surgery in patients with familial adenomatous polyposis lies between the morbidity of proctocolectomy and ileum-pouch-anal anastomosis (IPAA) and the mortality from rectal cancer after total colectomy and ileorectal anastomosis (IRA). The aims of the present study were: (1) to assess the risk of dying from rectal cancer after IRA, (2) to compare the life expectancy between patients with an IRA and those with an IPAA, and (3) to investigate whether regular endoscopic examination of the rectum leads to detection of cancer at an earlier stage.METHODSClinical and pathological data on 659 patients who underwent colectomy and ileorectal anastomosis were collected from four national polyposis registries—that is, in Denmark, Finland, Sweden, and the Netherlands. Data were analysed using survival analysis methods. Decision analysis was used to compare the life expectancy between patients with an IRA and those with an IPAA.RESULTSA total of 47 patients developed rectal cancer after IRA. The risk of dying from rectal cancer was 12.5% (95% confidence interval 7.1–17.9%) by age 65. Compared with IRA, IPAA would lead to an increase in life expectancy of 1.8 years. Seventy five per cent of patients with rectal cancer had a negative rectoscopy within 12 months before the diagnosis.CONCLUSIONIRA is associated with substantial mortality due to rectal cancer. Follow up examinations of the rectum does not have sufficient preventive effect on morbidity and mortality of rectal cancer.
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