Crohn's Disease and Ulcerative Colitis Are Associated With the DNA Repair Gene MLH1

Pokorný, Richard; Hofmeister, Arnd; Galandiuk, Susan; Dietz, Allan B.; Cohen, Noah D.; Neibergs, Holly L.

doi:10.1097/00000658-199706000-00009

Cited by 46 publications

(29 citation statements)

References 13 publications

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“…17 Satsangi et al observed the strongest evidence of linkage in CD families, 2 while in our material the greatest evidence of linkage seems to be from the mixed families, which may reflect greater average size of the families in this group. The chromosome 3 region has also raised attention in an association study by Pokorny et al 30 who reported an increase of a specific haplotype, constructed from the alleles of the marker D3S1611 and the HNPCC (hereditary non-polyposis colon cancer) gene MLH1, in IBD patients. The chromosome 3p21 region seems intriguing as it harbours, in addition to MLH1, other interesting candidates genes including those encoding a cluster of chemokine receptors, and a G protein subunit a i2 (GNAI2) the deficiency of which causes an UC-like phenotype in knockout mice.…”

Section: Discussionmentioning

confidence: 99%

Genetic analysis in Finnish families with inflammatory bowel disease supports linkage to chromosome 3p21

et al. 2001

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In inflammatory bowel diseases (IBD), certain chromosomal candidate loci have been repeatedly identified by independent studies in different populations. To investigate the contribution of the loci on chromosomes 1, 3, 7, 12, 14, and 16 to the susceptibility of IBD in Finnish population, where the predominant feature is the excess of ulcerative colitis (UC) families compared to Crohn's disease (CD) families, we carried out linkage analyses using 93 Finnish, multiply-affected IBD families. We observed nominal evidence for linkage to chromosome 3p21, consistent with earlier reports. The lod scores peaked at D3S2432, with a maximum two-point lod score of 1.68 (P=0.0027). In addition, we studied whether risk of IBD is associated with functional variants of two positional candidate genes; the chemokine receptor CCR5 gene on chromosome 3p21 and the interleukin-4 receptor a-subunit gene (IL4RA) on chromosome 16. We did not find any significant correlation between a 32-bp deletion variant of CCR5 or a single nucleotide change A1902G (Gln576Arg) of IL4RA, and IBD phenotypes, with the exception that in the UC group homozygosity for the G1902 allele of IL4RA was less frequent (0.019 vs 0.049, P=0.038). In conclusion, our study, carried out in a genetically homogenous population, suggests that chromosome 3 may contain a susceptibility gene for IBD.

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Section: Discussionmentioning

confidence: 99%

Genetic analysis in Finnish families with inflammatory bowel disease supports linkage to chromosome 3p21

et al. 2001

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“…(20)(21)(22)(23) Recentemente, novas pesquisas tentam atribuir como causas a mutação da integrina beta-2, (24) de populações de monócitos CD14+ (25) e do gene de reparo do DNA MLH-1. (26) Histologicamente, a DCM se caracteriza por granulomas cutâneos não-caseosos, com células gigantes multinucleadas de Langhans e do tipo corpo estranho, os quais se distribuem na derme superficial, derme profunda e no tecido adiposo, similares aos granulomas do trato gastrointestinal. (1,2,4-7,9,12,16) Outras caracterís-ticas descritas são o infiltrado rico em eosinófilos e degeneração cística do colágeno (necrobiose).…”

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Uso de terapia biológica na doença de Crohn metastática: relato de caso e revisão da literatura

Batista

Pozzobon

Lopes³

et al. 2009

Rev bras. colo-proctol.

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RESUMO: A doença de Crohn metastática envolve a infiltração cutânea granulomatosa em locais anatomicamente separados do trato gastrointestinal, com tendência à cronicidade. É relatado caso de paciente masculino, 20 anos, há seis meses com dor e eliminação de secreção purulenta de úlceras em região perianal, inguinal direita e genital, sem melhora com o uso metronidazol e ciprofloxacina. Antecedente de proctocolectomia em 2002. Ao exame, à inspeção, evidenciava-se orifício fistuloso posterior a 2,0 cm da borda anal, úlcera de 5,0 cm na base do escroto e outra úlcera circundando a base do pênis; ao toque, ânus fibrótico e encarcerado. Realizada fistulotomia, biópsia e curetagem das úlceras genital e inguinal. O resultado histopatológico evidenciou processo inflamatório granuloso não caseoso. Em virtude da falha terapêutica dos antimicrobianos, foi optado pelo tratamento com infliximabe na dose 5 mg/kg nas semanas 0, 2 e 6, e azatioprina 2 mg/kg/dia. Ao término da fase de indução, o paciente apresentava cicatrização parcial das lesões ulceradas, ausência de secreção e alívio da dor. Atualmente em acompanhamento ambulatorial com infusões de infliximabe a cada oito semanas. Descritores INTRODUÇÃOA doença de Crohn (DC) é uma doença inflamatória intestinal de evolução crônica e recidivante, caracterizada por inflamação transmural segmentar e alterações granulomatosas, que pode envolver qualquer segmento do trato gastrointestinal. (1-9) Foi descrita em 1932 por Crohn, Ginzberg e Oppenheimer, e originalmente chamada de ileíte regional. (10) Os pacientes podem desenvolver manifestações extra-intestinais em 25 a 30% dos casos, principalmente cutâneas, as quais ocorrem em 14-44% dos casos, dependendo se a doença perineal é ou não considerada uma manifestação cutânea. (1,3,8,11) A doença de Crohn metastática (DCM) envolve a infiltração cutânea granulomatosa em locais anatomicamente separados do trato gastrointestinal, com tendência à cronicidade. (1)(2)(3)(4)(5)(6)9,(11)(12)(13)(14) Foi primeiramente descrita por Parks AG et al. em 1965. (17) Em 1970, o termo ulceração metastática foi adotado por Mountain JC para descrever as úlceras cutâneas que surgiam distantes da região perianal ou periostomal. (18) As terapias convencionais têm resultado pouco satisfatório na DCM. (2,15) A terapia biológica com

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“…[16][17][18][19][20][21][22][23] However, the reported frequency of MSI-H, a consequence of a defective mismatch repair (MMR) system (notably MLH1 or MSH2), and MSI-L, a consequence in part of O 6 -methylguanine-DNA methyltransferase (MGMT) deficiency, 24 has varied considerably from 9 to 50%, and 11 to 85%, respectively. 22,[25][26][27] In situation of considerable genetic heterogeneity within a sample, collection of samples without microdissection could possibly obscure the findings of MSI. 28,29 In fact, analysis of mixed MSI-L components could result in a false diagnosis as MSI-H. To verify true MSI status and to clarify the significance of MSI in colitic carcinogenesis, precise analysis of individual microfoci from various pathological lesions (including stroma) is required.…”

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confidence: 99%

Heterogeneous microsatellite instability observed within epithelium of ulcerative colitis

Ozaki

Nagasaka

Notohara

et al. 2006

Intl Journal of Cancer

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Microsatellite instability (MSI) has been associated with colitic cancer. However, reported frequency of MSI was varied and the association of MSI with mismatch repair (MMR) deficiency was unclear. In addition, the occurrence of genetic alterations in stromal cells within ulcerative colitis (UC) is still controversial. We therefore sampled 164 microareas in various pathological lesions of UC with or without colitic cancer and studied the MSI status in relation to the DNA repair protein expressions. A total of 129 microfoci from colorectal tissue of 5 colitic cancer patients and 35 microfoci of 7 UC patients (without neoplasm) were carefully sampled by laser-capture microdissection. MSI was analyzed in each microsamples. The protein expression of MMR genes (MLH1, MSH2, MSH6), O 6 -methylguanine-DNA methyltransferase and p53 were assessed by immunohistochemical analysis. Variety of di-nulcleotide microsatellite markers was altered in individual microfoci from different morphological epithelial lesions, in full range of nonneoplastic epithelium to colitic cancer. Interestingly, MSI was not observed in stromal cells at any sites, including those within colitic cancer/dysplasia lesions. Expression of the MMR proteins was not lost in any of the lesions examined. Microsatellite alterations rather seem to be related to the initiation than to the progression of colitic cancer. ' 2006 Wiley-Liss, Inc.Key words: colitic cancer; ulcerative colitis; microsatellite instability; stroma; mismatch repair Colorectal epithelium with a long-standing ulcerative colitis (UC) has an increased risk of developing cancer. 1-6 An invasive colitic cancer often arises from a preceding flat dysplastic epithelium and tend to develop multifocally over the background inflamed epithelium, whilst sporadic colorectal cancer (CRC) develops from a preexisting adenoma, suggesting a dissimilar carcinogenic pathway in colitic cancer. [7][8][9][10][11][12][13][14][15] In lesions undergoing chronic inflammation, microsatellite instability (MSI) is a possible genetic alteration, and high-and low-level of MSI (MSI-H and MSI-L) has been described in UC associated neoplasm (UCAN). [16][17][18][19][20][21][22][23] However, the reported frequency of MSI-H, a consequence of a defective mismatch repair (MMR) system (notably MLH1 or MSH2), and MSI-L, a consequence in part of O 6 -methylguanine-DNA methyltransferase (MGMT) deficiency, 24 has varied considerably from 9 to 50%, and 11 to 85%, respectively. 22,[25][26][27] In situation of considerable genetic heterogeneity within a sample, collection of samples without microdissection could possibly obscure the findings of MSI. 28,29 In fact, analysis of mixed MSI-L components could result in a false diagnosis as MSI-H. To verify true MSI status and to clarify the significance of MSI in colitic carcinogenesis, precise analysis of individual microfoci from various pathological lesions (including stroma) is required. 16,18,19 Accordingly, we sampled 164 microfoci, including nondysplastic epithelium, dysplastic epithel...

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Crohn's Disease and Ulcerative Colitis Are Associated With the DNA Repair Gene MLH1

Abstract: This study identifies a novel genetic and clinical association between MLH1 and inflammatory bowel disease.

Cited by 46 publications

References 13 publications

Genetic analysis in Finnish families with inflammatory bowel disease supports linkage to chromosome 3p21

Genetic analysis in Finnish families with inflammatory bowel disease supports linkage to chromosome 3p21

Uso de terapia biológica na doença de Crohn metastática: relato de caso e revisão da literatura

Heterogeneous microsatellite instability observed within epithelium of ulcerative colitis

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