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sgroups. MSH6 carriers were unlikely to have other nonendometrial LS related cancers withthe exception of ovarian cancer (N=8). Conclusions: In this large cohort of MMR genemutation carriers, MLH1 carriers had more CRC than MSH2 and MSH6 carriers. Endometrialcancer was most prevalent among MSH6 carriers who had a later age of onset compared toMLH1 and MSH2 probands and their first-degree relatives. Evaluation for an MSH6 genemutation may be indicated in individuals with a family history of multiple, late-onsetendometrial cancer diagnoses.

M1934

High Sensitivity of Microsatellite Instability (MSI) and Immunohistochemistry(IHC) Testing in Benign Colorectal Adenomas from Patients with LynchSyndromeMaria S. Pino, Mari Mino-Kenudson, Bernadette M. Wildemore, Aniruddha Ganguly, JulieM. Batten, Anthony J. Iafrate, Daniel Chung

BACKGROUND: Lynch syndrome is an autosomal dominant disorder caused by germlinemutations in DNA mismatch repair (MMR) genes. Microsatellite instability (MSI) and immu-nohistochemical (IHC) testing of colon cancers is a valuable diagnostic strategy for Lynchsyndrome. We sought to determine whether these markers of mismatch repair deficiencywere also detectable in pre-cancerous colorectal adenomas. METHODS: Thirteen patients(8 males and 5 females) with a germline mutation in the MLH1 (6 patients) or MSH2 (7patients) gene and at least one adenoma removed during a surveillance colonoscopy wereidentified. Forty-one adenomas were detected during 28 colonoscopies over a 10 yearperiod from 1997 to 2007. MSI and IHC analysis were performed in 37 and 41 adenomas,respectively. RESULTS: Thirty-nine adenomas were tubular and 2 had villous features; severedysplasia was present in eight (19%) adenomas. Twenty-eight (68%) adenomas were locatedin the right colon and 13 (32%) were on the left. The adenomas showed a wide range ofsize with a mean of 7.3 mm (range, 2-22 mm). MSI was detected in 23 (62%) adenomas,and 91% of these exhibited high levels of instability (MSI-H). A significant association wasfound between MSI and high-grade dysplasia (P=0.01) and also distal location (P=0.002).Loss of MMR protein staining by IHC was detected in 31 (76%) adenomas and was morefrequent in adenomas ≥ 5 mm (22/27; 81%), located distally (11/13; 85%) and with high-grade dysplasia (8/8;100%). Among the 37 adenomas in which both MSI and IHC testswere performed, the presence of a germline mutation correlated with an abnormal MSIresult in 62% of cases (23/37), an abnormal IHC result in 76% (28/37) of cases, or eitheran abnormal MSI or IHC result in 78% (29/37) of cases. Hyperplastic polyps identified inour cohort of Lynch syndrome patients did not exhibit abnormal MSI or IHC. CONCLU-SIONS: The combination of MSI and IHC testing in colorectal adenomas is a sensitive screenfor the detection of Lynch syndrome, particularly among polyps located distally or withhigh-grade dysplasia. These tests may be valuable when Lynch syndrome is suspected andadenomatous polyps are the only tissue available for analysis.

M1935

Premm1,2 and Barnetson-MMRpredict Risk Models Have High Sensitivity forIdentifying Individuals with Lynch SyndromeAkriti Dewanwala, Prathap Bandipalliam, Shilpa Grover, Sapna Syngal, Elena M. Stoffel

Background: Lynch Syndrome is the most common hereditary colorectal cancer (CRC)syndrome and is caused by mutations in the mismatch repair (MMR) genes MLH1, MSH2,MSH6, and PMS2. The PREMM1,2 and Barnetson-MMRpredict risk assessment models useindividuals' personal and family history to estimate the probability of a MMR gene mutation.Aim: To evaluate the performance of the PREMM1,2 and Barnetson-MMRpredict modelsfor identifying individuals with Lynch Syndrome. Methods: Medical records of subjects withMMR gene mutations who underwent clinical genetic testing through the Cancer Risk andPrevention Clinic at the Dana-Farber Cancer Institute were reviewed. Scores for probabilityof MMR mutation were computed using the PREMM1,2 (www.dana-farber.org/pat/cancer/gastrointestinal/crc-calculator) and Barnetson-MMRpredict (stage 1) (https://hnpccpredic-t.hgu.mrc.ac.uk) web-based models. Results: 91 individuals with mutations in MMR genes(44 MSH2, 41 MLH1, 6 MSH6) from 91 different families were identified. 69 (76%) hada personal history of cancer. PREMM1,2 scores could be calculated for all subjects. 90/91(99%) subjects had PREMM1,2 scores higher than the 5% cutoff for recommending geneticevaluation. For the PREMM1,2 scores, distribution of mutation carriers was <5%: 1 (1%);5-9%: 4 (4%); 10-19%: 17 (19%); 20-39%: 15 (16%); 40-59%: 16 (18%); 60-79%: 13(14%); >80%: 25 (27%). Barnetson-MMRpredict scores could be calculated for only 53/91subjects (38 could not be scored because they lacked a personal history of CRC). Withimputation of scores calculated for subjects' closest relative with CRC, 85/91 (93%) hadBarnetson-MMRpredict model scores higher than the 0.5% cutoff for recommending geneticevaluation. For the MMRpredict scores, distribution of mutation carriers was <0.5%: 6 (7%);0.5-9%: 4 (4%); 10-19%: 7 (8%); 20-39%: 7 (8%); 40-59%: 11 (12%); 60-79%: 11 (12%);>80%: 45 (49%). Mean mutation probability scores from both models were significantlylower for individuals with mutations in the MSH6 gene compared with MLH1 or MSH2.While PREMM1,2 identified all subjects with MSH6 gene mutations, Barnetson-MMRpredictdid not score 2 of 6 MSH6 carriers as they had no personal or family history of CRC.Conclusion: PREMM1,2 and Barnetson-MMRpredict models have high sensitivity (99% and93%, respectively) for identifying MMR mutation carriers; however utility of the Barnetson-MMRpredict model is limited in the absence of CRC. Use of these web-based models forclinical CRC risk-assessment can facilitate identification of patients who may require special-ized cancer surveillance and referral for genetic evaluation for Lynch Syndrome.

A-450AGA Abstracts

M1936

Clinical Genetic Testing in Prospective Risk Assessment of Pancreatic CancerKindreds: the Experience At One Academic CenterCaroline Hwang, Sheila Kumar, Aimee L. Lucas, Elizabeth C. Verna, Lauren G. Khanna,Joanna Martinez-Gomez, John A. Chabot, Harold Frucht

About 10% of pancreatic cancer (PC) is hereditary, including those associated with syndromessuch as hereditary breast syndrome (BRCA), HNPCC (MLH1/MSH2) and FAMMM (p16).Genetic testing is being increasingly performed in PC kindreds to identify high-risk patientsappropriate for initial screening trials. The clinical utility of genetic testing for prospectivePC risk assessment is not known. AIM: To report the genetic testing experience of anacademic center for PC prevention. METHODS: We performed a chart review of patientsreferred for suspected genetic predisposition to PC. Pedigrees were prospectively obtained.Genetic testing was performed in those with personal or family history suggestive of a cancersyndrome. Multisite BRCA testing was utilized in Ashkenazi Jews while comprehensivesequencing was done in all others. RESULTS: 124 patients (105 families) were evaluatedfrom 2005-2008. 36% had personal history of PC and 64% were asymptomatic kindreds.Mean age was 54, 50% were male, and 52% were Ashkenazi. Mean number of PC casesper family was 1.6, and of any cancer was 5. A total of 67 patients in 44 families (42%)underwent genetic testing. BRCA was most often tested (72%), followed by p16 (21%),MLH1/MSH2 (5%) and STK11 (3%). 13 families were found to have BRCA mutation, 2 withp16, and 1 with MLH1. To assess the yield of our genetic testing efforts, we excluded patientswith prior positive testing in a proband or at another testing site. Of the remaining families,we tested 32 for BRCA, 12 for p16, and 5 for MLH1/MSH2. Diagnostic yield of our programwas 28% (29% for BRCA). Of the 5 BRCA+ patients with personal history of PC, 80% wereAshkenazi males. 2 had mutations in BRCA1 and 3 in BRCA2. Only 2 had >1 first-degreerelative with breast or ovarian cancer. Compared to PC patients who were BRCA-, BRCA+patients had more breast and ovarian cancers in their families (mean 2.3 vs 0.8, p<0.01).In contrast, BRCA+ patients were less likely (20% vs 47%, p<0.01) to have family historyof PC. In fact, 4 of our 5 BRCA+ were the index case of PC in their family. Mean age of PCwas similar between BRCA+ and BRCA- patients (57 vs 60, p=0.88). CONCLUSION: Whenperformed at an experienced center, genetic testing of PC kindreds has high diagnostic yield(28%). In our referral population, BRCA was most often tested, with 13% of families BRCA+.BRCA+ status was associated with significant heterogeneity in familial penetrance of breast,ovarian, and especially pancreatic cancer. This suggests limitations of genetic testing inassessing PC risk and the need to consider overall personal and familial cancer history indeveloping preventive strategies for PC.

M1937

Risk of Development of Gastric Cancer in Relatives of Patients with Non-Hereditary Gastric Cancer: A Meta-AnalysisMohammad Yaghoobi, Raheleh Bijarchi, Richard H. Hunt

Background: Gastric cancer is the second most frequent cause of death from cancer. Inmost case-control studies, first-degree relatives of patients with gastric cancer have beenfound to be at higher risk compared to general population; however a quantitative analysisof the risk has not been done. Methods: A comprehensive literature search was performedusing PubMed and other sources up to June 2008. Case-control trials comparing the frequencyof a positive first or second-degree family history of non-hereditary gastric cancer in patientswith gastric cancer, versus non-gastric cancer controls were retrieved. Search was not limitedby language, quality or geographical location. A funnel plot was applied to explore likelihoodof publication bias. The Newcastle-Ottawa Scale was applied to evaluate the quality ofstudies. A meta-analysis of pooled relative risk (random-model effect) was performed usingReview Manager 4.2. The Cochran's Q test and I2 were applied to detect heterogeneity.Results: Fourteen out of 113 potential studies were included with a total of 8,506 patientswith gastric cancer and 53,782 controls. Funnel plot did not reveal major asymmetry. 23.5%of the patients and 11.5% of the controls had at least one relative with gastric cancer (p <0.00001). The pooled relative risk (RR) for the development of gastric cancer in associationwith a positive family history was 2.9 (95% CI: 2.2 - 3.7). In the subgroup analysis of 11studies, exclusively done among first-degree relatives, RR remained 2.9 (95% CI: 2.1-3.9;p <0.00001). Subgroup analysis in Asian patients also revealed a RR of 2.6 (95% CI: 1.8-3.7, p < 0.0001). Significant heterogeneity existed along the main and subgroup analysesbut disappeared after excluding studies of lower quality (P = 0.02, I2 = 69.5%). In the onlystudy adjusting the results for simultaneous Helicobacter pylori (HP) status the RR for thedevelopment of gastric cancer with positive family history decreased from 3.2 to 2.8 afteradjustment for HP status. In this study individuals with both HP infection and a positivefamily history of gastric cancer had eight-fold increased risk of development of gastric cancerthan people without these. Conclusion: Individuals with a first or second-degree relativeaffected with gastric cancer have an approximately three-fold increased risk of the develop-ment of gastric cancer compared to general population. This could be due to shared environ-mental, genetic and epigenetic risk factors which need to be further investigated. HP infectioncan increase this risk even more. Screening and preventive strategies should be developedspecifically for these high-risk individuals.

M1938

Does Expression of the Gastric Mucin MUC6 Help Identify Advanced SerratedColorectal Polyps?Susan Parry, Michael D. Walsh, Sally- Ann Pearson, Daniel Buchanan, Rhiannon Walters,Kevin Sweet, Albert de la Chapelle, Neal I. Walker, Joanne Young

Recently, an alternative developmental pathway for colorectal cancers involving serratedpolyps has been recognised. The need to identify serrated lesions with malignant potential hasbeen hampered by a lack of consensus terminology and significant inter-observer variation.Recently, expression of MUC6, was found to correlate with 100% specificity with sessileserrated adenomas (SSA) a lesion thought to be an important precursor of colorectal cancer(Owens et al 2008; Mod Pathol 21:660-9). Our aim was to explore this finding in a series