Association between family history and mismatch repair in colorectal cancer

Coggins, R.; Cawkwell, Lynn; Bell, Sandra; Crockford, Gillian P.; Quirke, Philip; Finan, P. J.; Bishop, D. Timothy

doi:10.1136/gut.2003.017517

Cited by 12 publications

(12 citation statements)

References 36 publications

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“…As seen in other studies [4, 15, 37, 56, 67, 93, 94, 100–102], colorectal tumors with lack of MMR protein expression, suggesting MMR deficiency, were associated with a proximal location in the colon and poor histological differentiation. However, opposing previous publications [4, 17, 19, 37, 55, 72, 79, 101–104], we did not observe associations of MMR protein-negative tumors with gender, earlier age at diagnosis of cancer, positive personal and family history of cancer, or earlier tumor stage, when compared to tumors with MMR protein-positive expression.…”

Section: Discussionsupporting

confidence: 69%

Mismatch repair protein expression and colorectal cancer in Hispanics from Puerto Rico

et al. 2009

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Colorectal cancer (CRC) is a leading cause of morbidity and mortality and alterations in mismatch repair (MMR) genes, leading to absent protein (negative) expression, are responsible for approximately 20% of CRC cases. Immunohistochemistry is a tool for prescreening of MMR protein expression in CRC but the literature on its use on Hispanics is scarce. However, Hispanics represent the second leading ethnicity in the United States (US) and CRC is a public health burden in this group. Our objectives were to determine the frequency of MMR protein-negative CRC and to evaluate its association with clinical and pathological characteristics among Hispanics from Puerto Rico, for the first time to our knowledge. A retrospective observational study of unselected CRC patients from the Puerto Rico Medical Center from 2001 to 2005 was done. MLH1 and MSH2, the most commonly altered MMR genes, protein expression was evaluated using immunohistochemistry, with microsatellite instability (MSI) and BRAF gene analyses in the absence of MLH1 protein expression. One-hundred sixty-four CRC patients were evaluated: the overall MMR protein-negative NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript frequency was 4.3%, with 0.6% frequency of co-occurrence of MLH1-protein negative expression, MSI-high, and normal BRAF gene. MMR protein-negative expression was associated with proximal colon location (p = 0.02) and poor histological tumor differentiation (p = 0.001), but not with other characteristics. The frequency of MMR protein-negative CRC in Hispanics from Puerto Rico was lower than reported in other populations. This finding may explain the lower CRC incidence rate among US Hispanics as compared to US non-Hispanic whites and blacks.

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Section: Discussionsupporting

confidence: 69%

Mismatch repair protein expression and colorectal cancer in Hispanics from Puerto Rico

et al. 2009

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“…In a case-control analysis using only cases and matched controls recruited via the Northern UK case:control study 12,13 (detailed in Materials and Methods), the MLH1 293A allele was not associated with an elevated risk of CRC independent of tumour site (GA 1 AA vs GG, OR 5 1.13, 95% C.I. 0.84-1.53, p 5 0.43, n 5 366 cases and 589 controls (GG homozygotes (n 5 369), GA heterozygotes (n 5 196), AA homozygotes (n 5 24)).…”

Section: Resultsmentioning

confidence: 99%

“…These included 776 Caucasian individuals with CRC diagnosed in the north of the United Kingdom, which comprised 366 incident cases who participated in a case:control study 12,13 (DNA from 589 age-and sex-matched Caucasian controls were also available from this study); 233 patients who underwent surgery for CRC in South Yorkshire, UK; 31 patients with MMR deficient CRC from St. James's University Hospital (Leeds, UK); and 146 cases with CRC identified retrospectively from the pathology database at Sheffield Hallamshire Hospital (Sheffield, UK). For simplicity, in the present study, these 776 CRC cases are collectively referred to as the ''Northern UK'' cases (Table I).…”

Section: Patientsmentioning

confidence: 99%

MLH1 −93G>A promoter polymorphism and risk of mismatch repair deficient colorectal cancer

Allan

Shorto

Adlard

et al. 2008

Intl Journal of Cancer

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Rare inherited mutations in the mutL homolog 1 (MLH1) DNA mismatch repair gene can confer an increased susceptibility to colorectal cancer (CRC) with high penetrance where disease frequently develops in the proximal colon. The core promoter of MLH1 contains a common single nucleotide polymorphism (SNP) (293G>A, dbSNP ID:rs1800734) located in a region essential for maximum transcriptional activity. We used logistic regression analysis to examine the association between this variant and risk of CRC in patients in the United Kingdom. All statistical tests were 2 sided. In an analysis of 1,518 patients with CRC, homozygosity for the MLH1 293A variant was associated with a significantly increased 3-fold risk of CRC negative for MLH1 protein by immunohistochemistry (odds ratio (OR): AA vs GG 5 3.30, 95% CI 1.46-7.47, n 5 1392, p 5 0.004, MLH1 negative vs MLH1 positive CRC) and with a 68% excess of proximal CRC (OR: AA vs GG51.68, 95% confidence interval (CI) 1.00-2.83, n 5 1,518, p 5 0.05, proximal vs distal CRC). These findings suggest that the MLH1 293G>A polymorphism defines a low penetrance risk allele for CRC. ' 2008 Wiley-Liss, Inc.Key words: MLH1; mismatch repair; colorectal; polymorphism; proximal; promoter; dna repair; cancer MLH1 and MSH2 are components of the DNA mismatch repair (MMR) system, which recognises and repairs mismatches in DNA that occur during replication. 1 Rare constitutional mutations in MLH1, MSH2 and other genes are responsible for the autosomal dominant disorder hereditary nonpolyposis colorectal cancer (HNPCC), 2,3 where loss of MMR predisposes to colorectal cancer (CRC) with high penetrance. Loss of MMR can also develop somatically and occurs in 15-20% of all CRC. 4 Loss of MMR frequently involves MLH1 gene promoter silencing and concomitant loss of protein expression, which gives rise to CRC predominantly in the proximal colon. In addition to rare constitutional mutations, MMR genes also contain common single nucleotide polymorphisms (SNP) which can predispose to nonfamilial CRC with low to moderate penetrance, 5-7 suggesting an important contribution of common genetic variants to the burden of CRC in the general population.In view of the importance of MLH1 in colorectal carcinogenesis, we examined the association between a potentially functional SNP in MLH1 (dbSNP ID:rs1800734) and risk of CRC. The MLH1 293G>A polymorphism is located in the core promoter of MLH1, 93 bases upstream of the transcription start site in a region that is required for maximal transcriptional activity. 8,9 Polymorphic variation in this region is predicted to affect MLH1 protein expression. Indeed, site-directed mutagenesis of the adenine residue 2 bases downstream of the 293G>A polmorphism (position-91) reduces promoter activity by 75%. 9 These observations suggest that the MLH1 293G>A polymorphism might affect risk of CRC. Consistent with this hypothesis, the MLH1 293A variant has been associated with an increased risk of developing hyperplastic colonic polyps in smokers, 10

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“…34 Furthermore, IHC triage of women with endometrial cancer having at least one affected first-degree relative was reported to be the most cost-effective strategy to identify mutation carriers and to prevent colorectal cancer. 35 Because some highly penetrant MMR missense mutations are reported to present with immunonormal tumor profiles, [36][37][38][39][40][41] we believe that IHC testing should support but not supplant the role of family history records in the detection of Lynch syndrome patients.…”

Section: Early Detection and Diagnosismentioning

confidence: 99%

Improving identification of lynch syndrome patients: A comparison of research data with clinical records

Tan

McGaughran

Ferguson

et al. 2013

Intl Journal of Cancer

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Current evidence suggests poor identification and referral of Lynch syndrome patients. This study evaluated the strategies by which patients with endometrial cancer were referred to genetics services. Data from clinic-based patients with endometrial cancer enrolled through the Australian National Endometrial Cancer population-based research study with detailed family history information were analyzed. The Amsterdam II criteria, the revised Bethesda guidelines, and criteria adapted for this study was assessed using personal/family history information. The percentages of patients referred and who could have been referred to genetics services, and the performance of each criterion for identifying possible mismatch-repair (MMR) gene mutation carriers, based on tumor MMR immunohistochemistry (IHC), were determined. Research data indicated that 236/397(59%) of patients with endometrial cancer had family/personal history of cancer, including 14 (4%) who fulfilled Amsterdam II criteria. Family history information was noted in the hospital records for only 61(15%) patients, including 7/14 (50%) of patients meeting Amsterdam criteria, and always less extensively than that recorded in the research setting. Only 13 patients (two meeting Amsterdam criteria) were referred for genetic assessment. Of 58 patients with tumor MMR protein-IHC loss, the Amsterdam criteria and Bethesda guidelines identified only three and 34% of these possible germline mutation carriers, respectively. Greater sensitivity (60%) was obtained using a single criterion proposed by our study, 2 first-degree or second-degree relatives reporting Lynch cancers. Hospital records indicate poor recognition of family history. Application of research methods show improved identification and may facilitate appropriate referrals of endometrial cancer patients with possible Lynch syndrome.

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Association between family history and mismatch repair in colorectal cancer

Cited by 12 publications

References 36 publications

Mismatch repair protein expression and colorectal cancer in Hispanics from Puerto Rico

Mismatch repair protein expression and colorectal cancer in Hispanics from Puerto Rico

MLH1 −93G>A promoter polymorphism and risk of mismatch repair deficient colorectal cancer

Improving identification of lynch syndrome patients: A comparison of research data with clinical records

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