microscopic view of pancreatic acini pancreatic duct duodenum.
Tu1895 Psychological Burden of Repeated Pancreatic Surveillance in High Risk Individuals for...
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AGA Abstracts Tu1893 MUTYH Mutations and Variants in Jews of North-African Origin With or Without Minimal Colorectal Adenomatous Polyposis Guy Rosner, Dani Bercovich, Hana Strul, Erwin Santo, Zamir Halpern, Revital Kariv Background: Israeli-Jews of North-African origin are ~ 1/6 of the Israeli population, and have been considered as a low-risk population for colorectal cancer (CRC). In recent years CRC risk has been increased in this population. However, the contributing genetic susceptibil- ity is currently unknown. Mutations in the MUTYH gene, which cause multiple colorectal adenomas and early onset colon cancer, might play a role in their increased CRC risk. Objectives: Evaluate frequency and types of MUTYH mutations and variants in a population of Jews from North-African origin having colorectal adenomas and early onset CRC. Methods: The study population included North-African Jews having colonoscopy between 2007-12, having ≥3 colorectal adenomas and/or CRC, and were matched to controls having normal colonoscopy. Germ-line DNA was tested for a panel of 6 MUTYH mutations or variants and Sanger sequencing of the entire MUTYH gene for heterozygotes. Familial Adenomatous Polyposis (FAP) and Lynch Syndrome were excluded in the relevant cases. Results: 99 subjects, 69 with adenomas had MUTYH analysis; 19 (27.5%) had mutations or variants identified. In adenoma patients there were eight homozygotes or compound heterozygotes to either Y179C or G396D mutations: all had >10 adenomas and 5 had familial neoplasia. Six others were heterozygotes to only one mutation: 4 with <10 and 2 with >10 adenomas; 5 had familial neoplasia and 3 a neoplasm. Four subjects found as S512F heterozygotes: two had <10 adenomas and familial neoplasms, one had dozens of adenomas and an extracolonic neoplasm, and one had CRC and few adenomas; another subject found as a 1186_1187ins GG mutation heterozygote having >10 adenomas. Two heterozygotes had the Q324H variant. In 23 non-adenoma controls: 1 had the S512F another the L417M variant, another the R509C variant and 16 the Q324H variant. Conclusions: MUTYH mutations are prevalent among Jews of North-African origin having colonic adenomas and/or early onset CRC. The clinical phenotype can be associated with only few adenoma and with family and personal history of cancer similar to sporadic CRC. The S512F mutation appears to be pathogenic, the Q324H a frequent variant that was not found to be associated with adenomas. The findings suggest MUTYH evaluation in these patients with even few adenomas, and need to follow-up heterozygotes carriers for CRC. Tu1894 Small Intestinal Polyp Development in 10q23 Deletion Syndrome Kate M. Ellery, Vinay Prasad, Harohalli Shashidhar, Steven H. Erdman 10q23 Deletion Syndrome (10q23 DS [OMIM 612242]) is a polygenic syndrome resulting from variable interstitial microdeletions in the short arm of chromosome 10 that can involve the tumor suppressor genes BMPR1A & PTEN. Depending on the deletion, the syndrome can have features of both Juvenile Polyposis Syndrome (JPS) and PTEN Hamartoma Tumor Syndrome (PHTS) (gastrointestinal polyps, macrocephaly, congenital heart defects, skin findings & developmental delay) but appears to have earlier and more robust polyp develop- ment. Synergism between the two genes has been suggested resulting in a more aggressive malignant phenotype with an increased risk for cancers of the digestive tract, thyroid and reproductive organs in comparison to JPS and PHTS as single gene syndromes. Small intestinal cancer is described in these patients with little knowledge of the precursor lesion. We describe two patients with 10q23 DS both diagnosed during childhood with variable gastrointestinal polyp phenotypes that include the small intestine. CASE 1 (17 years ♀) was found to have a chromosomal microdeletion of 10q23 involving BMPR1A & PTEN at 3 years of age during evaluation for dysmorphic features, developmental delay and macrocephaly. She has had recurrent gastric and colon (juvenile & hyperplastic) polyps. At age 12 years, sessile duodenal polyps were identified with features of dysplasia. Video capsule endoscopy (VCE) identified several suspicious lesions in the duodenum and jejunum leading to double balloon enteroscopy (DBE). Both sessile & pedunculated lesions of varying sizes and morphology were removed with histology again showing features of juvenile polyps with adenomatous change. Surveillance over 5 years has documented continued benign hamartoma development throughout the digestive tract. She recently underwent thyroidectomy due to adenoma concerns. CASE 2 (10 years ♀) was noted to have developmental delay, macrocephaly and hemangiomas and presented at 2 years with rectal bleeding due to colonic polyps. Genetic evaluation at age 4 years revealed a 4.8 Mb deletion of 10q23 including the BMPR1A and PTEN genes. She has required regular polypectomy for recurrent juvenile colonic polyps. At age 8, VCE suggested small bowel polyps however DBE to an approximate depth of 320 cm failed to identify significant polyps suggesting an ileal location. Due to her lack of symptoms and age, DBE of the distal small intestine was deferred pending repeat VCE. CONCLUSION: This recently appreciated rare syndrome with variable clinical phenotype likely carries increased cancer risk when compared to JPS or PHTS as has been seen with other polygenic hereditary colorectal cancer syndromes. Patients with 10q23 DS can have small intestinal polyp development and therefore should be considered for small intestinal surveillance in addition to the specified surveillance guidelines for JPS and PTHS. Tu1895 Psychological Burden of Repeated Pancreatic Surveillance in High Risk Individuals for Pancreatic Cancer Ingrid C. Konings, Grace N. Sidharta, Femme Harinck, Cora M. Aalfs, Ellen Smets, Jan- Werner Poley, Anja Wagner, Jeanin E. van Hooft, Anja van Rens, Paul Fockens, Marco J. Bruno, Eveline Bleiker Introduction Pancreatic cancer (PC) is one of the most fatal human malignancies with a median survival of <6 months. Survival rates strongly depend on stage of PC. Therefore, there is great interest in PC surveillance for high risk individuals to detect PC or precursor lesions in an earlier, potentially curable stage. Studies assessing the feasibility of such PC surveillance programs have, however, not addressed the psychological burden for partici- pants. The aim of this ongoing, prospective study is therefore to evaluate the psychological burden of repeated pancreatic surveillance of individuals at genetically high risk to develop S-866 AGA Abstracts PC. Methods Individuals with a lifetime risk of developing PC>10%, who are offered yearly pancreatic surveillance with MRI and endoscopic ultrasound (EUS) in a Dutch ongoing prospective multicenter cohort study (FPC-study), were invited to complete a questionnaire each year to assess their experience with MRI and EUS, and their psychological distress (assessed with the Cancer Worry Scale (CWS) and the Hospital Anxiety and Depression Scale (HADS)). The questionnaires were sent after intake for participation in the FPC-study but before the first MRI and EUS (T1), after the first MRI and EUS (T2), and after the MRI and EUS one (T3), two (T4) and three years (T5) after initial intake. Results A total of 134 out of 152 individuals (88%) returned one or more completed questionnaires (n= 69, 66, 108, 85 and 51 at T1, T2, T3, T4 and T5 respectively; response-rate varying between 79- 94% per assessment). An average of 90% experienced the MRI as ‘not' or ‘a little' burdensome (88%, 91%, 90% and 92% at T2, T3, T4 and T5 respectively) versus an average of 91% in case of an EUS (89%, 92%, 94% and 86% at T2, T3, T4 and T5 respectively). The percentage of individuals who dreaded a next MRI was low (5%, 5%, 2% and 0% at T2, T3, T4 and T5 respectively), as well as the percentage of individuals who dreaded a next EUS (3%, 7%, 4% and 6%). The mean CWS-score (12.8) remained stable and low as surveillance progressed. An average of 7% showed clinical relevant anxiety levels (HADS-A-score ≥11; 3%, 8%, 6%, 6% and 10% at T1, T2, T3, T4 and T5 respectively) and an average of 5% showed clinical relevant depression levels (HADS-D-score ≥11; 4%, 2%, 5%, 7% and 4% at T1, T2, T3, T4 and T5 respectively). Conclusion The psychological burden of repeated pancreatic surveil- lance seems tolerable with an average of >90% of high risk individuals experiencing no or little burden of the yearly MRI and EUS. Participants also have limited worries about cancer and the percentage of individuals with clinical relevant levels of anxiety and depression is comparable to that of the general population. Therefore, from a psychological point of view, repeated participation of high risk individuals in a yearly pancreatic surveillance program seems feasible. Tu1896 A Novel Method for Early Detection of Lynch Syndrome Ian C. Grimes, Richard B. Halberg, Jennifer M. Weiss, Dawn Albrecht, Jeffery Bacher Background: Lynch Syndrome is the most common inherited cancer syndrome and is characterized by a high risk of developing colorectal and other cancers. The syndrome is due to a germline defect in DNA mismatch repair genes, leading to a widespread increase in mutations and accelerated tumor development. Microsatellite instability (MSI), is a hall- mark of Lynch Syndrome. Current identification strategies using the Amsterdam and Bethesda criteria suffer from low specificity and patients are often diagnosed at time of malignancy. MSI testing of adenomas obtained during routine colonoscopy screenings has the potential to identify at risk individuals before cancer develops. However, it is less sensitive than in more advanced tumors using currently available markers. The goals of this study are to compare current methods of MSI detection to experimental markers in adenomatous polyps. Methods: Patients ≤55 years of age with one or more adenomas ≥5mm were selected for the adenoma study. MSI testing was performed using Promega's MSI Analysis System (For Research Use Only), the Bethesda marker panel, and a new panel of mononucleotide repeats with long polyA tracts. MSI positive samples were screened for MLH1, MSH2, MSH6 and PMS2 expression by immunohistochemistry. Results: Over 700 colon adenomas from 259 patients were tested for MSI. Overall, 7.7% of patients had one or more MSI positive adenomas. 2.3% of the tumors were MSI-High with conventional marker panels and 5.6% were MSI positive using the long mononucleotides. A significant portion (4 out of 7) of the false negative results using conventiional methods were confirmed by immunohistochemistry to be Lynch Syndrome. Conclusion: Current methods of screening for Lynch Syndrome are inadequate. Evaluation of adenomas in at risk individuals may allow Lynch Syndrome to be identified prior to the development of malignancy. MSI sensitivity for adenomas can be increased by at least 2-fold over current marker panels using a panel of long mononucleotide repeats. The improved MSI sensitivity has the potential to increase early detection of Lynch Syndrome prior to the development of cancer. Tu1897 Lynch Syndrome Screening Strategies: A Six Year Clinical Experience Trilokesh Kidambi, Amie Blanco, Megan Myers, Peggy Conrad, Kate Loranger, Jonathan P. Terdiman Background: Lynch syndrome (LS), an autosomal dominant disorder of defective mismatch repair (MMR), is the most common cause of hereditary colorectal cancer (CRC) and confers increased risk of other cancers. Identifying LS patients and counseling families allows for primary screening which can reduce morbidity and mortality. Because clinical criteria alone lack sensitivity for LS, screening CRC and endometrial tumors for absent MMR expression is recommended. Furthermore, universal screening of colon cancers may be cost-effective, but significant variations in screening protocols remain in clinical practice. Methods: A retrospective study of three different LS screening protocols at an urban, university hospital was performed. Outcomes from a "reflex" screening strategy utilized from August 2007-July 2010 on CRC tumors from patients under the age of 50, between the age of 50-60 with histology suggestive of microsatellite instability, or of any age with prior history of LS related cancer were compared with a "universal" strategy of screening all CRC tumors from July 2010-August 2013. CRC patients "referred" for LS screening from other institutions from 2007-2013 were analyzed as a separate strategy. Positive screening was defined by absent MMR protein expression (MLH1, MSH2, MSH6, PMS2) on immunohistochemistry stains with negative BRAF V600E mutation when absent MLH1 and PMS2 expression was found. Patients with a positive screen were referred for genetic counseling and offered germline mutation testing. Results: A total of 577 CRC tumors were screened: 107 reflexively, 285 universally and 185 by referral. There was no difference in the rate of positive tumors screened by each strategy. Only 58% of the positive tumors in the universal group (p<0.01) would have been identified by the reflex strategy. There was a trend (p=0.06) towards fewer universally screened patients agreeing to genetic counseling (58%) compared to reflexive screening (87%). There were no differences in mutation testing rate once a subject was counseled between groups. The overall prevalence of LS was 3.6% with no difference in prevalence by screening strategy. Reflex criteria would have failed to identify only one of
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MUTYH Mutations and Variants in Jews of North-African Origin With orWithout Minimal Colorectal Adenomatous PolyposisGuy Rosner, Dani Bercovich, Hana Strul, Erwin Santo, Zamir Halpern, Revital Kariv
Background: Israeli-Jews of North-African origin are ~ 1/6 of the Israeli population, andhave been considered as a low-risk population for colorectal cancer (CRC). In recent yearsCRC risk has been increased in this population. However, the contributing genetic susceptibil-ity is currently unknown. Mutations in the MUTYH gene, which cause multiple colorectaladenomas and early onset colon cancer, might play a role in their increased CRC risk.Objectives: Evaluate frequency and types of MUTYH mutations and variants in a populationof Jews from North-African origin having colorectal adenomas and early onset CRC. Methods:The study population included North-African Jews having colonoscopy between 2007-12,having ≥3 colorectal adenomas and/or CRC, and were matched to controls having normalcolonoscopy. Germ-line DNA was tested for a panel of 6 MUTYH mutations or variants andSanger sequencing of the entire MUTYH gene for heterozygotes. Familial AdenomatousPolyposis (FAP) and Lynch Syndrome were excluded in the relevant cases. Results: 99subjects, 69 with adenomas had MUTYH analysis; 19 (27.5%) had mutations or variantsidentified. In adenoma patients there were eight homozygotes or compound heterozygotesto either Y179C or G396D mutations: all had >10 adenomas and 5 had familial neoplasia.Six others were heterozygotes to only one mutation: 4 with <10 and 2 with >10 adenomas;5 had familial neoplasia and 3 a neoplasm. Four subjects found as S512F heterozygotes:two had <10 adenomas and familial neoplasms, one had dozens of adenomas and anextracolonic neoplasm, and one had CRC and few adenomas; another subject found as a1186_1187ins GG mutation heterozygote having >10 adenomas. Two heterozygotes hadthe Q324H variant. In 23 non-adenoma controls: 1 had the S512F another the L417M variant,another the R509C variant and 16 the Q324H variant. Conclusions: MUTYH mutations areprevalent among Jews of North-African origin having colonic adenomas and/or early onsetCRC. The clinical phenotype can be associated with only few adenoma and with family andpersonal history of cancer similar to sporadic CRC. The S512F mutation appears to bepathogenic, the Q324H a frequent variant that was not found to be associated with adenomas.The findings suggest MUTYH evaluation in these patients with even few adenomas, andneed to follow-up heterozygotes carriers for CRC.
Tu1894
Small Intestinal Polyp Development in 10q23 Deletion SyndromeKate M. Ellery, Vinay Prasad, Harohalli Shashidhar, Steven H. Erdman
10q23 Deletion Syndrome (10q23 DS [OMIM 612242]) is a polygenic syndrome resultingfrom variable interstitial microdeletions in the short arm of chromosome 10 that can involvethe tumor suppressor genes BMPR1A & PTEN. Depending on the deletion, the syndromecan have features of both Juvenile Polyposis Syndrome (JPS) and PTEN Hamartoma TumorSyndrome (PHTS) (gastrointestinal polyps, macrocephaly, congenital heart defects, skinfindings & developmental delay) but appears to have earlier and more robust polyp develop-ment. Synergism between the two genes has been suggested resulting in a more aggressivemalignant phenotype with an increased risk for cancers of the digestive tract, thyroid andreproductive organs in comparison to JPS and PHTS as single gene syndromes. Smallintestinal cancer is described in these patients with little knowledge of the precursor lesion.We describe two patients with 10q23 DS both diagnosed during childhood with variablegastrointestinal polyp phenotypes that include the small intestine. CASE 1 (17 years ♀) wasfound to have a chromosomal microdeletion of 10q23 involving BMPR1A & PTEN at 3 yearsof age during evaluation for dysmorphic features, developmental delay and macrocephaly. Shehas had recurrent gastric and colon (juvenile & hyperplastic) polyps. At age 12 years, sessileduodenal polyps were identified with features of dysplasia. Video capsule endoscopy (VCE)identified several suspicious lesions in the duodenum and jejunum leading to double balloonenteroscopy (DBE). Both sessile & pedunculated lesions of varying sizes and morphologywere removed with histology again showing features of juvenile polyps with adenomatouschange. Surveillance over 5 years has documented continued benign hamartoma developmentthroughout the digestive tract. She recently underwent thyroidectomy due to adenomaconcerns. CASE 2 (10 years ♀) was noted to have developmental delay, macrocephaly andhemangiomas and presented at 2 years with rectal bleeding due to colonic polyps. Geneticevaluation at age 4 years revealed a 4.8 Mb deletion of 10q23 including the BMPR1A andPTEN genes. She has required regular polypectomy for recurrent juvenile colonic polyps.At age 8, VCE suggested small bowel polyps however DBE to an approximate depth of 320cm failed to identify significant polyps suggesting an ileal location. Due to her lack ofsymptoms and age, DBE of the distal small intestine was deferred pending repeat VCE.CONCLUSION: This recently appreciated rare syndrome with variable clinical phenotypelikely carries increased cancer risk when compared to JPS or PHTS as has been seen withother polygenic hereditary colorectal cancer syndromes. Patients with 10q23 DS can havesmall intestinal polyp development and therefore should be considered for small intestinalsurveillance in addition to the specified surveillance guidelines for JPS and PTHS.
Tu1895
Psychological Burden of Repeated Pancreatic Surveillance in High RiskIndividuals for Pancreatic CancerIngrid C. Konings, Grace N. Sidharta, Femme Harinck, Cora M. Aalfs, Ellen Smets, Jan-Werner Poley, Anja Wagner, Jeanin E. van Hooft, Anja van Rens, Paul Fockens, Marco J.Bruno, Eveline Bleiker
Introduction Pancreatic cancer (PC) is one of the most fatal human malignancies with amedian survival of <6 months. Survival rates strongly depend on stage of PC. Therefore,there is great interest in PC surveillance for high risk individuals to detect PC or precursorlesions in an earlier, potentially curable stage. Studies assessing the feasibility of such PCsurveillance programs have, however, not addressed the psychological burden for partici-pants. The aim of this ongoing, prospective study is therefore to evaluate the psychologicalburden of repeated pancreatic surveillance of individuals at genetically high risk to develop
S-866AGA Abstracts
PC. Methods Individuals with a lifetime risk of developing PC>10%, who are offered yearlypancreatic surveillance with MRI and endoscopic ultrasound (EUS) in a Dutch ongoingprospective multicenter cohort study (FPC-study), were invited to complete a questionnaireeach year to assess their experience with MRI and EUS, and their psychological distress(assessed with the Cancer Worry Scale (CWS) and the Hospital Anxiety and DepressionScale (HADS)). The questionnaires were sent after intake for participation in the FPC-studybut before the first MRI and EUS (T1), after the first MRI and EUS (T2), and after the MRIand EUS one (T3), two (T4) and three years (T5) after initial intake. Results A total of 134out of 152 individuals (88%) returned one or more completed questionnaires (n= 69, 66,108, 85 and 51 at T1, T2, T3, T4 and T5 respectively; response-rate varying between 79-94% per assessment). An average of 90% experienced the MRI as ‘not' or ‘a little' burdensome(88%, 91%, 90% and 92% at T2, T3, T4 and T5 respectively) versus an average of 91% incase of an EUS (89%, 92%, 94% and 86% at T2, T3, T4 and T5 respectively). The percentageof individuals who dreaded a next MRI was low (5%, 5%, 2% and 0% at T2, T3, T4 andT5 respectively), as well as the percentage of individuals who dreaded a next EUS (3%, 7%,4% and 6%). The mean CWS-score (12.8) remained stable and low as surveillance progressed.An average of 7% showed clinical relevant anxiety levels (HADS-A-score ≥11; 3%, 8%, 6%,6% and 10% at T1, T2, T3, T4 and T5 respectively) and an average of 5% showed clinicalrelevant depression levels (HADS-D-score ≥11; 4%, 2%, 5%, 7% and 4% at T1, T2, T3, T4and T5 respectively). Conclusion The psychological burden of repeated pancreatic surveil-lance seems tolerable with an average of >90% of high risk individuals experiencing no orlittle burden of the yearly MRI and EUS. Participants also have limited worries about cancerand the percentage of individuals with clinical relevant levels of anxiety and depression iscomparable to that of the general population. Therefore, from a psychological point of view,repeated participation of high risk individuals in a yearly pancreatic surveillance programseems feasible.
Tu1896
A Novel Method for Early Detection of Lynch SyndromeIan C. Grimes, Richard B. Halberg, Jennifer M. Weiss, Dawn Albrecht, Jeffery Bacher
Background: Lynch Syndrome is the most common inherited cancer syndrome and ischaracterized by a high risk of developing colorectal and other cancers. The syndrome isdue to a germline defect in DNA mismatch repair genes, leading to a widespread increasein mutations and accelerated tumor development. Microsatellite instability (MSI), is a hall-mark of Lynch Syndrome. Current identification strategies using the Amsterdam and Bethesdacriteria suffer from low specificity and patients are often diagnosed at time of malignancy.MSI testing of adenomas obtained during routine colonoscopy screenings has the potentialto identify at risk individuals before cancer develops. However, it is less sensitive than inmore advanced tumors using currently available markers. The goals of this study are tocompare current methods of MSI detection to experimental markers in adenomatous polyps.Methods: Patients ≤55 years of age with one or more adenomas ≥5mm were selected forthe adenoma study. MSI testing was performed using Promega's MSI Analysis System (ForResearch Use Only), the Bethesda marker panel, and a new panel of mononucleotide repeatswith long polyA tracts. MSI positive samples were screened for MLH1, MSH2, MSH6 andPMS2 expression by immunohistochemistry. Results: Over 700 colon adenomas from 259patients were tested for MSI. Overall, 7.7% of patients had one or more MSI positiveadenomas. 2.3% of the tumors were MSI-High with conventional marker panels and 5.6%were MSI positive using the long mononucleotides. A significant portion (4 out of 7) of thefalse negative results using conventiional methods were confirmed by immunohistochemistryto be Lynch Syndrome. Conclusion: Current methods of screening for Lynch Syndrome areinadequate. Evaluation of adenomas in at risk individuals may allow Lynch Syndrome tobe identified prior to the development of malignancy. MSI sensitivity for adenomas can beincreased by at least 2-fold over current marker panels using a panel of long mononucleotiderepeats. The improved MSI sensitivity has the potential to increase early detection of LynchSyndrome prior to the development of cancer.
Tu1897
Lynch Syndrome Screening Strategies: A Six Year Clinical ExperienceTrilokesh Kidambi, Amie Blanco, Megan Myers, Peggy Conrad, Kate Loranger, Jonathan P.Terdiman
Background: Lynch syndrome (LS), an autosomal dominant disorder of defective mismatchrepair (MMR), is the most common cause of hereditary colorectal cancer (CRC) and confersincreased risk of other cancers. Identifying LS patients and counseling families allows forprimary screening which can reduce morbidity and mortality. Because clinical criteria alonelack sensitivity for LS, screening CRC and endometrial tumors for absent MMR expressionis recommended. Furthermore, universal screening of colon cancers may be cost-effective,but significant variations in screening protocols remain in clinical practice. Methods: Aretrospective study of three different LS screening protocols at an urban, university hospitalwas performed. Outcomes from a "reflex" screening strategy utilized from August 2007-July2010 on CRC tumors from patients under the age of 50, between the age of 50-60 withhistology suggestive of microsatellite instability, or of any age with prior history of LS relatedcancer were compared with a "universal" strategy of screening all CRC tumors from July2010-August 2013. CRC patients "referred" for LS screening from other institutions from2007-2013 were analyzed as a separate strategy. Positive screening was defined by absentMMR protein expression (MLH1, MSH2, MSH6, PMS2) on immunohistochemistry stainswith negative BRAF V600E mutation when absent MLH1 and PMS2 expression was found.Patients with a positive screen were referred for genetic counseling and offered germlinemutation testing. Results: A total of 577 CRC tumors were screened: 107 reflexively, 285universally and 185 by referral. There was no difference in the rate of positive tumorsscreened by each strategy. Only 58% of the positive tumors in the universal group (p<0.01)would have been identified by the reflex strategy. There was a trend (p=0.06) towards feweruniversally screened patients agreeing to genetic counseling (58%) compared to reflexivescreening (87%). There were no differences in mutation testing rate once a subject wascounseled between groups. The overall prevalence of LS was 3.6% with no difference inprevalence by screening strategy. Reflex criteria would have failed to identify only one of
