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sS1979

Low Educational Level is Associated With an Increased Risk of ColorectalCancer in the European Prospective Investigation Into Cancer and NutritionAnke M. Leufkens, Fränzel J. van Duijnhoven, Hendriek C. Boshuizen, Anton Kunst,Traci Mouw, Hendrik B. Bueno-de-Mesquita, Peter D. Siersema

Background: Evidence on the relationship between educational level and colorectal cancer(CRC) risk is inconsistent, with both low and high educational levels having been associatedwith a risk of developing CRC. Aim: To investigate the relationship between educationallevel and risk of CRC. Methods: We studied data from 465,785 participants included inthe EPIC (European Prospective Investigation into Cancer and Nutrition) study, of whom2,784 developed CRC during a mean follow-up of 8.7 years. All analyses were adjusted forBMI (Body Mass Index), physical activity, smoking status and duration, dietary intake ofenergy from fat, energy from non-fat, fibre, fruit, vegetables, red meat, processed meat,alcohol, and of fish. Relative indices of inequality (RIIs) with 95% confidence intervals (95%CIs) for education were estimated using Cox regression models. A RII that is lower than 1means that CRC risk decreases with decreasing education. We conducted separate analysesfor gender, age and geographical region. Results: Relative indices of inequality for educationshowed that a lower educational level was associated with a lower risk of CRC overall (RII0.84, 95%CI 0.71-0.99), CRC confined to the colon (RII 0.79, 95%CI 0.64-0.97) and CRClocated in the proximal colon (RII 0.66, 95%CI 0.48-0.91). These associations were foundin women and subjects younger than 60 years. A clear north-south gradient in risks, withno effect in northern Europe, a statistically not significantly reduced risk in middle Europeancountries and a statistically significant reduced risk in southern Europe was observed forparticipants with a lower education (RII 0.60, 95%CI 0.42-0.86 for colorectal cancer, RII0.50, 95%CI 0.33-0.77 for colon cancer and RII 0.26, 95%CI 0.13-0.52 for rectal cancer).Despite extensive correction for potential confounders, these estimates remained statisticallysignificant for CRC overall, CRC confined to the colon and proximally located CRC. Conclu-sions: These findings indicate that persons with a lower educational level have a decreasedrisk of CRC, This was particularly true for women, subjects younger than 60 years of ageand subjects from southern Europe. Further studies in genetic and environmental factorsare needed to elucidate the mechanism of this observation.

S1980

Dietary Factors and Risk for Esophageal Squamous Cell Carcinoma in Shanxi,ChinaYing Gao, Philip Taylor

Smoking and alcohol consumption are important risk factors for esophageal squamous cellcarcinomas (ESCC) in the West, but they explain little of the risk in North China, whereover half of all cases in the world occur. Some specific dietary elements, like pickled vegetablejuice and moldy food, as well as micronutrient deficiencies have been associated with ESCCrisk in North China. We evaluated questionnaire-based dietary factors for ESCC risk in acase-control study from Shanxi, including 600 ESCC cases and 1514 controls frequency-matched on age, gender, and neighborhood. Odds ratios (OR) and 95% confidence intervals(CI) were calculated using logistic regression models adjusted for the matching factors andpotential confounders. The primary staple cereal foods in controls shifted from corn (86%reported corn as a primary staple food) and sorghum (44%) before 1984, to wheat (98%)and rice (37%) after 1984. Intake of protein-providing food items dramatically increasedafter 1984, and daily fish intake was associated with a 50% lower ESCC risk. Comparedwith the lowest intake quartiles, higher intakes of fresh vegetables and fruits were associatedwith monotonically decreased ESCC risk (Ptrend<0.0001 for both vegetables and fruits). Incontrast, persons who reported ever using milk or dairy products had a 56% higher ESCCrisk than never users. Intake of scalding hot food was associated with a monotonicallyincreased ESCC risk (Ptrend<0.0001). Daily consumption of scalding hot food was reportedby 25% of controls and was a particularly strong risk factor for ESCC (OR 2.74, 95% CI2.06-3.65) compared to never users. Daily vinegar and seasoning users had 29% and 25%lowered ESCC risk compared to never users. This study highlights thermal damage as aleading etiologic factor in this region. Future epidemiological studies may benefit from theassessment of specific dietary elements to obtain a more comprehensive view of the etiologyof ESCC.

S1981

Routine MSI-Analysis in Advanced Adenomas in Patients Younger Than 45Years Leads to the Identification of More Patients at High Risk for LynchSyndromeCeline H. Leenen, Margot G. van Lier, Anja Wagner, W. Dinjens, Erik-Jan Dubbink,Monique E. van Leerdam, Ernst J. Kuipers, Ewout W Steyerberg

Background: Lynch Syndrome (LS) is caused by germline mutations in mismatch repair(MMR) genes and is responsible for at least 3% of all colorectal carcinomas (CRC). Colorectaladenomas are thought to occur at a relatively young age in LS patients. Diagnostic strategiesfor LS include assessment for microsatellite instability (MSI) and immunohistochemicalanalysis (IHC) of tumor tissue. Although identification of LS is important, the detection isfar from optimal. The aim of this study was to evaluate a new diagnostic strategy for LS byperforming routine molecular analysis of advanced adenomas (AA) in patients ≤45 years.Methods: In 9 hospitals all consecutive patients ≤45 yrs with AA were included (May 2007-Nov 2009) as part of a population based study. AA were defined as ≥10 mm and/or avillous component and/or high grade dysplasia. Additionally, patients with≥3 synchronousadenomas were included. All AA were analyzed for MSI and IHC of MMR proteins MLH1,MSH2, MSH6, and PMS2. AA were classified as 1)suspect for LS if MSI-high (MSI-H) andsimultaneously showing absent MMR protein expression with exclusion of MLH1 promoterhypermethylation in case of absent MLH1 expression, 2)sporadic if microsatellite stable(MSS/MSI-L) or MSI-H and absent MLH1 expression with MLH1 promoter methylation.Results: A total AA of 69 patients were analyzed (57% males), median age 40 yrs (range22-45). AA were located left-sided in 51 patients (73%), right-sided in 30 patients (17%),

S-294AGA Abstracts

in 9% the location in the colon was not further specified. In 45% the adenoma size was≥10mm (range 10-27mm). A villous component was observed in 58%. 15% of AA showedhigh grade dysplasia. In 7 patients (10%) ≥3 adenomas were removed during colonoscopy.Molecular analyses revealed 3/69 AA (4.3%;95%CI 3.5-5.1) suspect for LS (all other AAwere MSS). Mean age of these 3 male patients was 40 yrs (range 34-44). All MSI-H adenomaswere located in the left hemicolon (2/3 in the rectum). The MSI-H adenomas showed villoushistology in 2/3 and a size ≥10 mm in 2/3 cases. IHC was compatible with lack of MLH1expression in 2/3 patients, and lack of MSH6 in 1 patient. In 2 cases MMR gene germlinemutations were confirmed by DNA analysis (MLH1 and MSH6). DNA analysis in the thirdpatient is pending. 2/3 families did not fulfill the Amsterdam II criteria. Conclusion: Molecularscreening for LS in young patients presenting with AA leads to early identification of aprofile pathognomic for LS in 4.3% of patients. The routine use of molecular screening ofAA thus may contribute to detect more LS patients, which is of major relevance in orderto decrease CRC-related mortality by surveillance colonoscopy.

S1982

Biallelic Pms2 Germline Mutations in a Family With a Microsatellite-StableBrain Tumor and Early Onset Colorectal CancerCeline H. Leenen, Ina R. Geurts-Giele, W. Dinjens, Erik Jan Dubbink, Ernst J. Kuipers,Monique E. van Leerdam, Anja Wagner

Background: Heterozygous germline mutations in the mismatch repair (MMR) genes MLH1,MSH2, MSH6 and PMS2 cause Lynch syndrome (LS). Biallelic mutations in the MMR geneslead to a childhood cancer syndrome. This is predominantly characterized by hematologicalmalignancies, tumors of bowel and brain, often associated with signs of neurofibromatosistype 1 (NF1). Diagnostic strategies for selection of patients for MMR gene analysis includemicrosatellite instability (MSI) and immunohistochemical analysis (IHC) of tumor tissue.However, the sensitivity of molecular tests in tumor tissue of patients with biallelic MMRgene mutations is unclear. The aim of this study is to describe the molecular analysis oftumor specimens from a family with biallelic PMS2 germline mutations and pitfalls of presentmolecular screening strategies. Methods: Molecular analyses of tissue and blood samples offamily members from a non-consanguineous family with biallelic PMS2 germline mutationswere performed. A review of literature regarding children with biallelic MMR gene mutationswas conducted. Results: Tissue of 4 family members including colorectal carcinoma fromfather (age 43), colonic adenoma from mother (age 45) and brain tumor specimens fromtheir son and daughter (age 4 and 8 respectively) were analyzed for MSI and IHC. Braintissue of the daughter was found to be MSI-high. IHC staining showed unclear changes.Specimens from family members were microsatellite stable. IHC showed no absence of MMRproteins, except for the analyzed brain tissue of the son (unclear changes). However, mutationanalyses in the blood samples of both children showed compound heterozygosity for thePMS2 mutations p.Pro246fs and p.Ser46IIe. The heterozygous mutations p.Ser46IIe andp.Pro246fs were confirmed in respectively father and mother. In literature 36 patients withbiallelic MMR gene mutations and brain cancer were identified. In 8/36 cases (mean 8 yrs,range 4-17, 88% male) brain tumor specimens were analyzed for MSI and IHC. GermlineMMR gene mutation analysis included MLH1(N=1), MSH2(N=1), MSH6(N=4), PMS2(N=2).In 6/8 cases no MSI was found in brain tumor tissue. However, IHC showed absent immunestaining in 5/8 cases. Conclusions: Biallelic MMR gene mutations are a rare cause of earlyonset cancer. IHC seems to be more sensitive than MSI. However, molecular analysis ofvarious tumor specimens is not in all cases conclusive. In patients with early onset cancerand signs of NF1, without a NF1 gene mutation, DNA analysis of the MMR genes shouldbe considered, regardless of the results of tissue analysis, and combined with assessment ofDNA from both parents if applicable and consented.

S1983

Phenotypic Differences Between APC and Biallelic MUTYH Mutation Carriersin 1193 Individuals With Attenuated PolyposisShilpa Grover, Akriti Dewanwala, Sapna Syngal

Background and Aims: Familial adenomatous polyposis and MUTYH associated polyposiscan both present with an attenuated colorectal polyposis phenotype. We aimed to evaluatephenotypic differences between individuals with APC and biallelic MUTYH mutations.Methods: The study cohort comprised 3471 unrelated probands who provided a personal andfamily history and submitted blood samples for full gene sequencing and large rearrangementanalysis of the APC gene and DNA analysis to detect the two most common MUTYH genemutations Y179C and G396D. Of these, 1193 individuals reported an attenuated polyposisphenotype (20-99 polyps). Phenotypic differences by mutation status were compared usingunivariate and multinomial logistic regression analysis. Results: Of the 1193 individualswith 20-99 polyps, 12% (141/1193) had a pathogenic APC mutation, 8% (95/1193) hadpathogenic biallelic MUTYH mutations, 2% (29/1193) had a monoallelic MUTYH mutationand 78% (928/1193) had no pathogenic mutation (non-pathogenic APC or MUTYH alterationor no alteration). Individuals with an APC mutation were younger at first polyp diagnosis(mean age 37.3 years) as compared to those with a biallelic MUTYH mutation (46.7 years),and those with no mutation (51.0 years) (p <0.001). Individuals with an APC mutationwere also younger at colorectal cancer (CRC) diagnosis (42.2 years) as compared to thosewith a biallelic MUTYH mutation (46.9 years) and no mutation (53.1 years) (p 0.002). Inlogistic regression analysis, compared to individuals with no mutation, APC mutation carrierswere more likely to be diagnosed with polyps before the age of 40 years (OR 2.8, 95% CI1.5-5.0) and individuals with a MUTYH mutation were more likely to be 40-49 years at thetime of first polyp diagnosis (OR 2.1, 95% CI 1.2-3.6) and at CRC diagnosis (OR 5.1, 95%CI 2.7-9.5). Although individuals with no mutations had fewer first-degree relatives withCRC than those with an APC mutation (OR 0.6, 95% CI 0.5-0.8), they were likely to havemore first-degree relatives with CRC than individuals with a MUTYH mutation (OR 1.9,95% CI 1.1-3.2). Conclusions: Among individuals with attenuated polyposis, prevalencerates of APC and MUTYH mutations were similar. APC mutation carriers presented withpolyps at a younger age than biallelic MUTYH mutation carriers and those with no mutation.MUTYH carriers had the fewest affected first-degree relatives with CRC compared to APCmutation carriers and those with no mutation.