Article

Loss of mismatch repair protein immunostaining in colorectal adenomas from patients with hereditary nonpolyposis colorectal cancer

Lund University, Lund, Skåne, Sweden
Modern Pathology (Impact Factor: 6.19). 09/2005; 18(8):1095-101. DOI: 10.1038/modpathol.3800392
Source: PubMed

ABSTRACT

Colorectal adenomas occur at younger age, at increased frequency and have a greater tendency for malignant transformation in patients with hereditary nonpolyposis colorectal cancer (HNPCC). We performed immunostaining for the mismatch repair proteins MLH1, PMS2, MSH2 and MSH6 in 35 colorectal adenomas from 26 patients with HNPCC and identified loss of immunostaining in 23/35 (0.66) adenomas. Loss of mismatch repair protein immunostaining was particularly frequent in large (>5 mm) (14/16) and proximally located (13/15) adenomas, whereas the gene mutated--MLH1 or MSH2--and the type of mutation did not seem to affect the results. We conclude that loss of mismatch repair protein immunostaining is detected at a lower rate in adenomas than in carcinomas associated with HNPCC. Adenomatous tissue can thus be used for immunostaining of mismatch repair proteins in clinical investigations of HNPCC, but whereas loss of immunostaining may pinpoint the gene affected and thereby guide mutation analysis, retained staining cannot exclude that the adenoma developed as part of the syndrome due to reduced sensitivity. However, the analysis has a greater chance of being informative if large and proximally located adenomas are selected.

Download full-text

Full-text

Available from: Kristina Lagerstedt, Apr 06, 2015
  • Source
    • "There is theoretical evidence that the adenomas of Lynch syndrome can progress to carcinoma more rapidly than sporadic adenomas. Immunohistochemistry generally shows loss of staining for mismatch repair proteins in adenomas from Lynch syndrome patients [20,21], meaning that they have already lost the ability to repair DNA mismatches. The very rapid rate at which mutations accumulate in this setting provides a molecular mechanism for the “aggressive adenoma” concept proposed many years ago [22-24]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Lynch syndrome confers increased risk for various malignancies, including colorectal cancer. Colonoscopic surveillance programs have led to reduced incidence of colorectal cancer and reduced mortality from colorectal cancer. Colonoscopy every 1–2 years beginning at age 20–25, or 10 years earlier than the first diagnosis of colorectal cancer in a family, with annual colonoscopy after age 40, is the recommended management for mutation carriers. Screening programs have reduced colon cancer mortality, but interval cancers may occur. Case presentation We describe a 48-year-old woman with Lynch syndrome who was found to have an adenoma with invasive colorectal cancer within one year after a normal colonoscopy. Conclusion Our patient illustrates two current concepts about Lynch syndrome: 1) adenomas are the cancer precursor and 2) such adenomas may be “aggressive,” in the sense that the adenoma progresses more readily and more rapidly to carcinoma in this setting compared to usual colorectal adenomas. Our patient’s resected tumor invaded only into submucosa and all lymph nodes were negative; in that sense, she represents a success for annual colonoscopic surveillance. Still, this case does raise the question of whether advanced imaging techniques are advisable for surveillance colonoscopy in these high-risk patients.
    Full-text · Article · May 2012 · BMC Gastroenterology
  • Source

    Preview · Article ·
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hereditary nonpolyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP) are characterized by a high risk and early onset of colorectal cancer (CRC). HNPCC is due to a germline mutation in one of the following MMR genes: MLH1, MSH2, MSH6 and PMS2. A majority of FAP and attenuated FAP (AFAP) cases are due to germline mutations of APC, causing the development of multiple colorectal polyps. To date, over 450 MMR gene mutations and over 800 APC mutations have been identified. Most of these mutations lead to a truncated protein, easily detected by conventional mutation detection methods. However, in about 30% of HNPCC and FAP, and about 90% of AFAP families, mutations remain unknown. We aimed to clarify the genetic basis and genotype-phenotype correlation of mutation negative HNPCC and FAP/AFAP families by advanced mutation detection methods designed to detect large genomic rearrangements, mRNA and protein expression alterations, promoter mutations, phenotype linked haplotypes, and tumoral loss of heterozygosity. We also aimed to estimate the frequency of HNPCC in Uruguayan CRC patients. Our expression based analysis of mutation negative HNPCC divided these families into two categories: 1) 42% of families linked to the MMR genes with a phenotype resembling that of mutation positive, and 2) 58% of families likely to be associated with other susceptibility genes. Unbalanced mRNA expression of MLH1 was observed in two families. Further studies revealed that a MLH1 nonsense mutation, R100X was associated with aberrant splicing of exons not related to the mutation and an MLH1 deletion (AGAA) at nucleotide 210 was associated with multiple exon skipping, without an overall increase in the frequency of splice events. APC mutation negative FAP/AFAP families were divided into four groups according to the genetic basis of their predisposition. Four (14%) families displayed a constitutional deletion of APC with profuse polyposis, early age of onset and frequent extracolonic manifestations. Aberrant mRNA expression of one allele was observed in seven (24%) families with later onset and less frequent extracolonic manifestations. In 15 (52%) families the involvement of APC could neither be confirmed nor excluded. In three (10%) of the families a germline mutation was detected in genes other than APC: AXIN2 in one family, and MYH in two families. The families with undefined genetic basis and especially those with AXIN2 or MYH mutations frequently displayed AFAP or atypical polyposis. Of the Uruguayan CRC patients, 2.6% (12/461) fulfilled the diagnostic criteria for HNPCC and 5.6% (26/461) were associated with increased risk of cancer. Unexpectedly low frequency of molecularly defined HNPCC cases may suggest a different genetic profile in the Uruguayan population and the involvement of novel susceptibility genes. Accurate genetic and clinical characterization of families with hereditary colorectal cancers, and the definition of the genetic basis of "mutation negative" families in particular, facilitate proper clinical management of such families. Periytyvä ei-polypoottinen paksusuolisyöpä (HNPCC) ja periytyvä adenomatoottinen polypoosi (FAP) altistavat paksusuolisyövälle nuorella iällä. HNPCC on seurausta ituratamutaatiosta yhdessä DNA:n kahdentumisvirheiden korjaamiseen osallistuvista MMR-geeneistä: MLH1, MSH2, MSH6 tai PMS2. Valtaosassa polypoosisuvuista on APC-geenin ituratamutaatio. Vaikka tällä hetkellä on tunnistettu jo yli 450 MMR-geenien ja yli 800 APC-geenin mutaatiota, vähintään kolmanneksessa suvuista alttiusmutaatio jää tunnistamatta käytettäessä perinteisiä mutaationtunnistusmenetelmiä. Tavoitteenamme oli selvittää mutaationegatiivisten sukujen geneettinen tausta sekä HNPCC:n yleisyys uruguaylaisten paksusuolisyöpäpotilaiden joukossa. Perinteisten mutaationtunnistusmenetelmien lisäksi käytimme spesifisempiä menetelmiä mm. mRNA:n ja proteiinien ilmentymistason analysoimiseksi sekä genomisten DNA:n uudelleenjärjestelyjen tunnistamiseksi. Mutaationegatiiviset HNPCC-suvut jakautuivat sukuihin, joissa alttius oli kytkeytynyt MMR-geenien piilomutaatioihin (42 %) ja sukuihin, joissa alttiuden taustalla on jokin muu kuin MMR-geeni (58 %). Havaitsimme, että MMR-geenien mutaatiot usein johtavat vastaavan mRNA:n epävakauteen ja joskus epänormaaliin silmikointiin. Ilmiöitä voidaan hyödyntää mutaatiodiagnostiikassa. Mutaationegatiivisista FAP-suvuista 14 %:ssa altistuksen aiheutti APC-geenin toisen alleelin kokonainen tai osittainen häviäminen ja 24 %:ssa alttius kytkeytyi mRNA:n epätasaiseen ilmentymiseen. APC-geenin osuutta syöpäalttiuden synnyssä ei voitu poissulkea 52 %:ssa suvuista. MYH-geenin mutaatio tunnistettiin 7 %:ssa ja AXIN2-geenin mutaatio 3 %:ssa suvuista. Vaikea polypoosi, syövän varhainen kehittyminen ja suolen ulkopuoliset ilmentymät olivat yleisempiä suvuissa, joissa todettiin APC-geenin häviämä verrattuna epätasaisen mRNA:n ilmentymisen sukuihin. Geneettiseltä etiologialtaan tuntematomaksi jääneissä sekä erityisesti MYH- ja AXIN2-kytketyissä suvuissa tavattiin muita useammin epätyypillistä/lievempää polypoosia. Uruguaylaisista paksusuolisyöpätapauksista 2,6 % täytti HNPCC:n diagnostiset kriteerit ja 5,6 %:ssa oli kohonnut syöpäriski. Odotettua matalampi mutaatiofrekvenssi (25 %) uruguaylaisissa HNPCC-suvuissa viitannee muihin kuin MMR-geeneihin paksusuolisyöpäalttiuden taustalla ja väestön erilaiseen geneettiseen profiiliin paksusuolisyövälle altistumisessa. Lukuisten erilaisten geenivirheiden esiintyminen selittää syndroomien ilmentymisen vaihtelun ja vaikeuttaa geenidiagnostiikkaa. Perinnöllisten paksusuolisyöpäsukujen geneettisen taustan huolellinen selvittäminen mahdollistaa syöpäsukujen oireettomien/uusien jäsenien geneettisen testauksen periytyvän alttiuden varmentamiseksi tai poissulkemiseksi. Geneettisen alttiuden tunnistaminen mahdollistaa ennaltaehkäisevät kliiniset seulontatutkimukset, joiden avulla paksusuolisyöpään sairastuvuutta ja kuolleisuutta voidaan merkittävästi vähentää.
    Preview · Article ·
Show more