POLD1 and POLE Gene Mutations in Jewish Cohorts of Early-Onset Colorectal Cancer and of Multiple Colorectal Adenomas.

BACKGROUND: Germline mutations in the DNA polymerase genes POLD1 and POLE confer high risk for multiple colorectal adenomas and colorectal cancer. However, prevalence and the clinical phenotype of mutation carriers are still not fully characterized. OBJECTIVE: The purpose of this study was to assess the prevalence of germline mutations and to describe the genotype-phenotype correlation in POLD1 and POLE genes in Jewish subjects with multiple colorectal adenomas and/or early-onset mismatch repair proficient colorectal cancers. DESIGN: This study is a comparison of genetic and clinical data from affected and control groups. SETTINGS: The study was conducted at a high-volume tertiary referral center. PATIENTS: The study cohort included 132 subjects: 68 with multiple colorectal adenomas and 64 with early-onset mismatch repair proficient colorectal cancers. The control group included 5685 individuals having no colorectal cancer or colorectal adenomas. MAIN OUTCOME MEASURES: Study and control subjects were tested for POLD1 and POLE mutations and a clinical correlation was assessed. RESULTS: Eleven of the 132 study subjects (8.3%) carried either a POLD1 or a POLE mutation: 7 of 68 (10.3%) subjects with multiple colorectal adenomas and 4 of 64 (6.2%) subjects with early-onset mismatch repair proficient colorectal cancer. Three mutations were detected, showing statistical significance in frequency between study and control groups (p < 0.001). Eight of the 11 mutation carriers were Ashkenazi Jews carrying the same POLD1 mutation (V759I), implicating it as a possible low-to-moderate risk founder mutation. Phenotype of mutation carriers was notable for age under 50 at diagnosis, a propensity toward left-sided colorectal cancer, and extracolonic tumors (64%, 100%, and 27% of cases). LIMITATIONS: The study cohort was limited by its relatively small size. CONCLUSIONS: Germline mutations in POLD1 and POLE were found to be relatively frequent in our Jewish cohorts. Further studies are needed to clarify the importance of POLD1 and POLE mutations and to define the most suitable surveillance program for Jewish and other POLD1 and POLE mutation carriers. See Video Abstract at http://links.lww.com/DCR/A658.

Endoscopy and EUS are key for effective surveillance and management of duodenal adenomas in familial adenomatous polyposis.

BACKGROUND: Patients with familial adenomatous polyposis (FAP) are prone to developing duodenal adenoma and cancer. Optimal surveillance and management of these adenomas are not well established. OBJECTIVE: We assessed the outcome of FAP patients undergoing intense multimodal surveillance and subsequent endoscopic resection of advanced lesions. PATIENTS: Eighty consecutive FAP patients enrolled during 2001 to 2011 from the Familial Cancer Clinic of a tertiary hospital as part of routine surveillance. DESIGN: Case series, prospective in years 2006 to 2011 and retrospective in years 2001 to 2006. SETTING AND INTERVENTION: Patients were followed by annual forward-view and/or side-view upper endoscopy. A biopsy sample was obtained from visible lesions and normal papillae. Ampullary adenomas were further assessed by EUS to determine dimensions and resectability. Advanced adenomas (size ≥ 10 mm, villous type, high-grade dysplasia) underwent endoscopic ampullectomy or polypectomy and continued surveillance. MAIN OUTCOME MEASUREMENTS: Detection of advanced adenomas by endoscopy and EUS, endoscopic maintenance of duodenum free of advanced adenoma and cancer. RESULTS: Patients (38 men and 42 women, mean age 32.68 ± 13.60) were followed 7.2 years and underwent 5.36 diagnostic studies on average. Thirty-eight patients had ampullary adenomas. Advanced adenoma was diagnosed by endoscopy in 10 patients. Importantly, EUS upstaged 9 additional patients to advanced adenoma and downstaged 1, thus altering the treatment course in 36% of patients performing EUS. Endoscopic ampullectomy was performed in 15 patients. Adenoma recurred in 10. Five remained nonadvanced and 5 in advanced stages: 3 were successfully retreated endoscopically and 2 ultimately required surgery for residual adenoma. Advanced nonampullary adenomas were successfully resected endoscopically in 23 patients. No patient had duodenal cancer during the study period. LIMITATIONS: Limited follow-up period, young age group, uncontrolled study. CONCLUSIONS: In an intense surveillance program for FAP patients, both endoscopy and EUS were key in accurate selection of advanced adenomas for endoscopic resection. During a 10-year period, only 2 patients required elective surgery and no cancer was observed.

Adenomatous Polyposis Phenotype in BMPR1A and SMAD4 Variant Carriers.

INTRODUCTION: Variants in SMAD4 or BMPR1A cause juvenile polyposis syndrome, a rare autosomal dominant condition characterized by multiple gastrointestinal hamartomatous polyps. A phenotype of attenuated adenomatous polyposis without hamartomatous polyps is rare. METHODS: We describe a retrospective cohort of individuals with SMAD4 or BMPR1A heterozygous germline variants, having ≥10 cumulative colorectal adenomas and/or colorectal cancer without hamartomatous polyps. All individuals had multigene panel and duplication/deletion analysis to exclude other genetic syndromes. RESULTS: The study cohort included 8 individuals. The pathogenic potential of the variants was analyzed. Variants detected included 4 missense variants, 1 nonsense variant, 1 splice site variant, and 2 genomic deletions. Features of pathogenicity were present in most variants, and cosegregation of the variant with polyposis or colorectal cancer was obtained in 7 of the 8 families. Three of 8 individuals had colorectal cancer (age less than 50 years) in addition to the polyposis phenotype. Two individuals had extraintestinal neoplasms (pancreas and ampulla of Vater). DISCUSSION: The clinical phenotype of SMAD4 and BMPR1A variants may infrequently extend beyond the classical juvenile polyposis syndrome phenotype. Applying multigene panel analysis of hereditary cancer-related genes in individuals with unexplained polyposis can provide syndrome-based clinical surveillance for carriers and their family members.

Efficacy of Wholistic Turmeric Supplement on Adenomatous Polyps in Patients with Familial Adenomatous Polyposis-A Randomized, Double-Blinded, Placebo-Controlled Study.

Several studies have demonstrated that curcumin can cause the regression of polyps in familial adenomatous polyposis (FAP), while others have shown negative results. Wholistic turmeric (WT) containing curcumin and additional bioactive compounds may contribute to this effect. We performed a double-blinded, randomized, controlled trial to assess the efficacy of WT in FAP patients. Ten FAP patients were randomly assigned to receive either WT or placebo for 6 months. Colonoscopies were performed at baseline and after 6 months. The polyp number and size, as well as the cumulative polyp burden, were assessed. No differences were noted between the groups in terms of changes from the baseline's polyp number, size, or burden. However, stratifying the data according to the right vs. left colon indicated a decrease in the median polyp number (from 5.5 to 1.5, p = 0.06) and polyp burden (from 24.25 mm to 11.5 mm, p = 0.028) in the left colon of the patients in the WT group. The adjusted left polyp number and burden in the WT arm were lower by 5.39 (p = 0.034) and 14.68 mm (p = 0.059), respectively. Whether WT can be used to reduce the polyp burden of patients with predominantly left-sided polyps remains to be seen; thus, further larger prospective trials are required.

Management of pouch related symptoms in patients who underwent ileal pouch anal anastomosis surgery for adenomatous polyposis.

BACKGROUND: Adenomatous polyposis syndromes (APS) patients with ileal pouch anal anastomosis (IPAA) suffer frequent symptoms with scarce signs of inflammation, distinct from ulcerative colitis patients. While the management of pouchitis in ulcerative colitis patients is well established, data regarding response to treatment modalities targeting pouch-related disorders in APS patient population is scarce. AIM: To assess clinical, endoscopic and histologic response to various treatment modalities employed in the therapy of pouch related disorders. METHODS: APS patients who underwent IPAA between 1987-2019 were followed every 6-12 mo and pouch-related symptoms were recorded at every visit. Lower endoscopy was performed annually, recording features of the pouch, cuff and terminal ileum. A dedicated gastrointestinal pathologist reviewed biopsies for signs and severity of inflammation. At current study, files were retrospectively reviewed for initiation and response to various treatment modalities between 2015-2019. Therapies included dietary modifications, probiotics, loperamide, antibiotics, bismuth subsalicylate, mebeverine hydrochloride, 5-aminosalicylic acid compounds and topical rectal steroids. Symptoms and endoscopic and histologic signs of inflammation before and after treatment were assessed. Pouchitis disease activity index (PDAI) and its subscores was calculated. Change of variables before and after therapy was assessed using Wilcoxon signed rank test for continuous variables and using McNemar's test for categorical variables. RESULTS: Thirty-three APS patients after IPAA were identified. Before treatment, 16 patients (48.4%) suffered from abdominal pain and 3 (9.1%) from bloody stools. Mean number of daily bowel movement was 10.3. Only 4 patients (12.1%) had a PDAI ≥ 7. Mean baseline PDAI was 2.5 ± 2.3. Overall, intervention was associated with symptomatic relief, mainly decreasing abdominal pain (from 48.4% to 27.2% of patients, P = 0.016). Daily bowel movements decreased from a mean of 10.3 to 9.3 (P = 0.003). Mean overall and clinical PDAI scores decreased from 2.58 to 1.94 (P = 0.016) and from 1.3 to 0.87 (P = 0.004), respectively. Analyzing each treatment modality separately, we observed that dietary modifications decreased abdominal pain (from 41.9% of patients to 19.35%, P = 0.016), daily bowel movements (from 10.5 to 9.3, P = 0.003), overall PDAI (from 2.46 to 2.03, P = 0.04) and clinical PDAI (1.33 to 0.86, P = 0.004). Probiotics effectively decreased daily bowel movements (from 10.2 to 8.8, P = 0.007), overall and clinical PDAI (from 2.9 to 2.1 and from 1.38 to 0.8, P = 0.032 and 0.01, respectively). While other therapies had minimal or no effects. No significant changes in endoscopic or histologic scores were seen with any therapy. CONCLUSION: APS patients benefit from dietary modifications and probiotics that improve their pouch-related symptoms but respond minimally to anti-inflammatory and antibiotic treatments. These results suggest a functional rather than inflammatory disorder.

A protocol for genetic evaluation of patients with multiple colorectal adenomas and without evidence of APC gene mutation.

BACKGROUND: Patients with multiple (< 100) colorectal adenomatous polyps are at increased risk for colorectal cancer. Genetic evaluation of those patients who test negative forAPCgene mutation is both a clinical and economic burden but is critical for counseling and surveillance. In Israel, this is confounded by the fact that national health insurance does not fully cover genetic evaluation of APC gene exon 16. OBJECTIVES: To perform a comprehensive genetic evaluation of APC gene mutation-negative polyposis patients with the aim of developing a future evaluation protocol. METHODS: Genetic analyses were performed in 29 APC gene mutation-negative Jewish individuals with 5 to > or = 40 colonic adenomas who did not fulfill Amsterdam (clinical) criteria for Lynch syndrome. Analyses included completion of APC gene exon 16 sequencing, analysis for APC gene copy number variations (deletions or duplications), MUTYH gene sequencing, and microsatellite instability in CRC patients fulfilling "Bethesda" (laboratory investigation) criteria for Lynch syndrome. RESULTS: Completion of APC gene exon 16 sequencing revealed one patient with the E1317Q polymorphism. All were normal by APC multiplex ligation-dependent probe amplification analysis. Pathogenic MUTYH mutations were found in three patients, all of North African origin; two additional patients had variants of unknown significance. One of six patients with Bethesda-positive criteria was MSI-High with immunohistology consistent with MLH1 mutation. CONCLUSIONS: Based on this small but well-characterized cohort with multiple colorectal adenomas, Lynch syndrome needs to be excluded if there are compatible criteria; otherwise MUTYH sequencing is probably the first step in evaluating APC-negative patients, especially for Jews of North African descent. Completing APC exon 16 sequencing and copy number variations analysis should probably be the last evaluations.

Clinical and Histologic Overlap and Distinction Among Various Hamartomatous Polyposis Syndromes.

INTRODUCTION: Hamartomatous polyposis syndromes (HPS) are rare autosomal-dominant inherited disorders associated with gastrointestinal (GI) tract and other cancers. HPS include Peutz-Jeghers syndrome (PJS), juvenile polyposis syndrome (JPS), and phosphatase and tensin homolog hamartomatous tumor syndromes (PHTS). Diagnosis, management, and outcome prediction of HPS pose a clinical challenge. To characterize genotype, phenotype, histology and outcomes of individuals with HPS. METHODS: A retrospective cohort study (2004-2017) of consecutive patients that were clinically diagnosed with HPS that visited a specialized GI oncology clinic. Demographic, clinicopathological, and genetic data were obtained from medical records. RESULTS: Fifty-two individuals from 34 families were included. Common clinical manifestations were GI bleeding (40% JPS, 23% PJS, and 25% PHTS) and bowel obstruction (46.15% PJS and 11.4% JPS). Twenty patients (38.4%) underwent surgery, 5 of whom required multiple procedures. Higher polyp burden was associated with the need for surgery (P = 0.007). Polyp histology varied widely with 69.2% of patients exhibiting histology different from the syndrome hallmark. GI cancer history was positive in 65%, 40%, and 50% of JPS, PJS, and PHTS families, respectively. Five (9.6%) patients developed cancers (one patient each had small bowel-1, colon-1, and thyroid-1, one patient had both small bowel adenocarcinoma and breast cancer, and one had both breast cancer and liposarcoma). Twenty (38.4%) patients tested positive for STK11, PTEN, SMAD4, BMPR1A, or AKT1 mutations: Sanger sequencing and multi-gene next generation sequencing panels detected mutations in 40.9% and 100% of tested cases, respectively. DISCUSSION: HPS patients present versatile phenotypes with overlapping clinical and histological characteristics. Polyp burden is associated with the need for surgery. Next-generation sequencing increases mutation detection.

Extracolonic manifestations of familial adenomatous polyposis after proctocolectomy.

HYPOTHESIS: Extracolonic manifestations have a major effect on the morbidity and mortality of patients with familial adenomatous polyposis following proctocolectomy. DESIGN: Case review study. SETTING: Colorectal unit, university-affiliated hospital. PATIENTS: Fifty patients (25 males and 25 females) with familial adenomatous polyposis WHO underwent proctocolectomy between January 1988 and October 2003. INTERVENTIONS: Ileal pouch-anal anastomosis (n = 41), Kock pouch (n = 1), end ileostomy (n = 6). Two patients underwent total colectomy with an ileorectal anastomosis. MAIN OUTCOME MEASURES: Clinical follow-up and telephone interview; contact with clinicians following up patients elsewhere. RESULTS: The patients' median age at surgery was 33 years. The mean length of follow-up was 74 months. Four patients were lost to follow-up. Extracolonic manifestations were diagnosed in 38 patients (76%). Twelve patients had 14 desmoid tumors: 7 were treated surgically and 7 medically (these patients received celecoxib and tamoxifen citrate therapy). Of the 41 patients who underwent upper gastrointestinal tract endoscopy, 11 developed duodenal and/or ampullary adenomas. Three patients had endoscopic polypectomy and 1 underwent a Whipple operation. Among the 29 patients who underwent pouchoscopy, 5 had pouch adenomas and 3 had adenomas that were found in the rectal stump. Two patients died--one of a huge mesenteric desmoid tumor and the other of an aggressive mesenteric malignant fibrous histiocytoma. CONCLUSIONS: Long-term morbidity and mortality were strongly related to the development of mesenteric tumors and ampullary-duodenal polyps. Early detection of desmoid tumors, duodenal, pouch, and rectal cuff adenomas by periodic computed tomography, gastroduodenoscopy, and pouchoscopy, respectively, may allow control by medical therapy, endoscopy, or limited surgical procedures. In most patients control of desmoid tumors was achieved using a combination of celecoxib and tamoxifen citrate therapy.

Increased risk for colorectal adenomas and cancer in mono-allelic MUTYH mutation carriers: results from a cohort of North-African Jews.

Bi-allelic MUTYH gene mutations are associated with a clinical phenotype of multiple colorectal adenomas and an increased risk for colorectal cancer (CRC). It is unclear whether mono-allelic MUTYH gene carriers (heterozygotes) are also at increased risk for even few adenomas or cancer. In order to clarify an association between MUTYH heterozygotes and adenomas, we evaluated the frequency and types of MUTYH mutations and variants in 72 North-African Jews having few (≥3) colorectal adenomas with or without early onset (<50 years) CRC compared to 29 healthy controls. Germ-line DNA was analyzed for a panel of 6 MUTYH mutations and variants, and Sanger sequencing of the entire MUTYH gene was performed for mono-allelic MUTYH mutation carriers. APC gene mutations and Lynch syndrome were excluded in the relevant cases according to accepted clinical criteria. Twenty-two of the 72 adenoma subjects (30.5%) had MUTYH mutations or variants. Nine were homozygotes or compound heterozygotes: all had >10 adenomas and one had CRC. Thirteen others were mono-allelic carriers (heterozygotes) of a single MUTYH mutation: six had more than ten adenomas and seven had less than ten adenomas; of these 13 mono-allelic carriers, six had a neoplasm: three CRCs and three extra-intestinal tumors. Eleven of the thirteen mono-allelic carriers with adenomas had a family history of cancer in first or second degree relatives. A multivariable model showed positive correlation between G396D, Y179C and 1186 ins GG mutations and number of adenomas (OR 8.6, 10.2 and 14.4, respectively). The Q324H variant was negatively associated with the number of adenomatous polyps (OR -5.23). In conclusion, MUTYH mutations are prevalent among Jews of North-African origin with colorectal adenomas with or without early onset CRC. Mono-allelic MUTYH carriers with a family history of cancer had a clinical phenotype that varied from having only few adenomas to multiple (>10) adenomas. These findings support MUTYH testing in patients with even few adenomas and suggest the consideration of increased surveillance in mono-allelic carriers with a family history of cancer.

The I1307K adenomatous polyposis coli gene variant does not contribute in the assessment of the risk for colorectal cancer in Ashkenazi Jews.

Ashkenazi Jews with the I1307K adenomatous polyposis coli gene variant were suggested to confer a higher risk for colorectal cancer (CRC). We assessed the clinical importance of this polymorphism in Israeli Jews at average and elevated risk for CRC. Among 1,370 consecutive subjects that were examined, 975 Ashkenazi Jews were stratified into those at average risk (no personal or family history of colorectal neoplasia) and those at high risk. DNA was obtained from peripheral leukocytes and amplified by PCR, with primers designed to detect the I1307K variant. Overall, I1307K polymorphism was found in 7.1% (9.1% among Ashkenazi and 1.7% among non-Ashkenazi Jews). The carrier rate was 8.3 and 9.3% in average and high-risk Ashkenazim, respectively (P = 0.65). The overall odds ratio for neoplasia in carriers was 1.43 (95% confidence interval, 0.89-2.30). Age, gender, and the histopathological features of adenomas and cancers did not differ between carriers and noncarriers. No interaction on the CRC risk was found between I1307K variant and lifestyle modifiers (such as cigarette smoking, alcohol consumption, high body mass index, low physical activity, and vitamins/antioxidant intake). The I1307K adenomatous polyposis coli gene variant is not an important marker for increased risk for CRC. It confirms previous reports of a slight nonsignificant increase (OR, 1.4) in the risk of CRC in these carriers. There is no interaction effect on the risk of colorectal neoplasia between the I1307K variant and various lifestyle risk factors. The usual recommended screening and surveillance strategies should be used for carriers of this polymorphism.

[Prevention and early detection of colorectal cancer in average risk population--summary of a meeting and the Israeli gastroenterology policy].

BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer mortality, with a lifetime risk of 5-6% and mortality rate of nearly 50%. About 75% of the cases occur in average-risk individuals. CRC ideally fulfills the criteria for organizing a mass-screening program: It is common and lethal, cancer is preceded by a pre-malignant lesion (adenoma) and transition from precursor to malignancy develops over years, providing an opportunity for intervention. It is well established that removal of adenomas (polypectomy) prevents CRC and CRC-related death in up to 90% of the cases. In Israel, we lack a clear policy for CRC screening and prevention by the health authorities. A meeting on this subject was held at the Israel Cancer Association, attended by the Minister of Health and leading figures in gastroenterology, oncology and public health. AIMS: To summarize the meeting and the Israeli Gastroenterology Association policy. SUMMARY: Current data on fecal occult blood test, sigmoidoscopy, and colonoscopy was presented, including the reduction of cancer incidence and mortality, safety and cost-effectiveness of each modality. Worldwide and Israeli results on colonoscopy in average-risk persons age 50-75, demonstrated a considerable prevalence of neoplasia, a low morbidity rate, no mortality and a high cost-effectiveness. Based on these results and the literature evidence of up to 90% reduction of CRC mortality following colonoscopy, CRC justifies all the criteria for organizing a prevention program by the health authorities for average-risk population age 50-75. Screening colonoscopy for CRC prevention should be included in this program.

Lynch Syndrome in high risk Ashkenazi Jews in Israel.

Lynch Syndrome is caused by mutations in DNA mismatch repair genes. Diagnosis is not always trivial and may be costly. Information regarding incidence, genotype-phenotype correlation, spectrum of mutations and genes involved in specific populations facilitate the diagnostic process and contribute to clinical work-up. To report gene distribution, mutations detected and co-occurrence of related syndromes in a cohort of Ashkenazi Jews in Israel. Patients were identified in dedicated high risk clinics in 3 medical centers in Israel. Diagnostic process followed a multi-step scheme. It included testing for founder mutations, tumor testing, gene sequencing and MLPA. Lynch Syndrome was defined either by positive mutation testing, or by clinical criteria and positive tumor analysis. We report a cohort of 75 Ashkenazi families suspected of Lynch Syndrome. Mutations were identified in 51/75 (68%) families: 38 in MSH2, 9 in MSH6, and 4 in MLH1. 37/51 (73%) of these families carried one of the 3 'Ashkenazi' founder mutations in MSH2 or MSH6. Each of the other 14 families carried a private mutation. 3 (6%) were large deletions. Only 20/51 (39%) families were Amsterdam Criteria positive; 42 (82%) were positive for the Bethesda guidelines and 9 (18%) did not fulfill any Lynch Syndrome criteria. We report C-MMRD and co-occurrence of BRCA and Lynch Syndrome in our cohort. Mutation spectra and gene distribution among Ashkenazi Jews are unique. Three founder Lynch Syndrome mutations are found in 73% families with known mutations. Among the three, MSH2 and MSH6 are the most common. These features affect the phenotype, the diagnostic process, risk estimation, and genetic counseling.

Do individuals with a family history of colorectal cancer adhere to medical recommendations for the prevention of colorectal cancer?

Individuals with a family history of colorectal cancer (CRC), have a two-to-five-fold increased lifetime risk to develop CRC. Thus, they are particularly likely to benefit from adherence to medical recommendations for CRC prevention. Despite this increased risk, previous studies have shown an underutilization of colonoscopy for screening and a paucity of data on lifestyle habits that could enhance colonoscopy rates in this population. The primary aims were (a) to assess CRC screening patterns and lifestyle choices among siblings and children of CRC patients, (b) to ascertain discrepancies between actual behavior and medical recommendations, and (c) to identify family members with multiple unhealthy lifestyle habits. The secondary aim was to test for possible associations between utilization rates for CRC screening and other preventive health services. A cross-sectional study was conducted among 318 first-degree relatives (FDRs) of 164 CRC patients treated at the Tel Aviv Sourasky Medical Center. Interviews were conducted with a structured questionnaire. There was significant underutilization of colonoscopy for screening with only 73 FDRs (23.0%) adhering to the recommended screening schedule. This rate was slightly improved (N = 58, 31.9%) among subjects aged 40 years and above, although it was still far below the optimum. A similar result (N = 70, 21.7%) was observed for other cancer screening tests and routine medical check-ups. A significant association (P < 0.0001) was found for healthful lifestyles, overall use of preventive health services, and adherence to CRC screening recommendations. CRC screening is significantly underutilized among FDRs of CRC patients. FDRs who do not comply with CRC screening guidelines, lead unhealthy lifestyles, and avoid other cancer screening tests are at increased risk and should be addressed specifically in future interventions.

Determinants of adherence to screening by colonoscopy in individuals with a family history of colorectal cancer.

OBJECTIVE: Although first-degree relatives (FDRs) of colorectal cancer (CRC) patients, as a high-risk population, have the most to gain from colonoscopy screening, their adherence is suboptimal. Thus, an assessment of the determinants of adherence to screening is of potential importance. METHODS: A cross-sectional study was conducted among 318 FDRs of 164 CRC patients treated at Tel-Aviv Sourasky Medical Center. Interviews were conducted with a questionnaire using I-Change Model. RESULTS: Adherence to interval colonoscopy was low with only 73 FDRs (23.0%). Greater adherence was associated with socio-demographic variables (older age, siblings, having spouse, higher level of education and income) and behavioral variables (healthier lifestyle, utilization of preventive health services). Family physicians and kin were identified as the most influential figures on uptake. Intention, affective barriers, positive attitudes, social support, cues to action, age, and health maintenance were the strongest determinants of participation in CRC screening. CONCLUSION: Adherence to colonoscopy is determined by multiple variables. Medical staff can play a key role in increasing adherence to colonoscopy. PRACTICE IMPLICATIONS: Future interventions should focus on fostering positive attitudes, overcoming barriers, enhancing social support and providing a medical recommendation. Special efforts should be invested in young FDRs, those of low socio-economic status and those who underutilize preventive medicine.

An Ashkenazi founder mutation in the MSH6 gene leading to HNPCC.

Mutations in DNA mismatch repair genes underlie lynch syndrome (HNPCC). Lynch syndrome resulting from mutations in MSH6 is considered to be attenuated in comparison to that caused by mutations in MLH1 and MSH2, thus more likely to be under diagnosed. In this study we report of a common mutation in the MSH6 gene in Ashkenazi Jews. Genetic counseling and diagnostic work-up for HNPCC was conducted in families who attended the high risk clinic for inherited cancer. We identified the mutation c.3984_3987dup in the MSH6 gene in 19 members of four unrelated Ashkenazi families. This mutation results in truncation of the transcript and in loss of expression of the MSH6 protein in tumors. Tumor spectrum among carriers included colon, endometrial, gastric, ovarian, urinary, and breast cancer. All but one family qualified for the Bethesda guidelines and none fulfilled the Amsterdam Criteria. Members of one family also co-inherited the c.6174delT mutation in the BRCA2 gene. The c.3984_3987dup in the MSH6 gene is a mutation leading to HNPCC among Ashkenazi Jews. This is most probably a founder mutation. In contrast to the c.1906G>C founder mutation in the MSH2 gene, tumors tend to occur later in life, and none of the families qualified for the Amsterdam criteria. c.3984_3987dup is responsible for 1/6 of the mutations identified among Ashkenazi HNPCC families in our cohort. Both mutations: c.3984_3987dup and c.1906G>C account for 61% of HNPCC Ashkenazi families in this cohort. These findings are of great importance for counseling, diagnosis, management and surveillance for Ashkenazi families with Lynch syndrome.

Screening techniques for prevention and early detection of colorectal cancer in the average-risk population.

Colorectal cancer (CRC) is associated with considerable morbidity and mortality, with more than 1,000,000 new cases and 500,000 deaths occurring annually. CRC has a natural history of transition from normal mucosa through adenoma to malignant lesion that spans, on average, 15 to 20 years, providing a window of opportunity for effective prevention and intervention through routine screening. The optimal screening strategy for the average-risk population aged >/= 50 years remains the subject of debate, however. Endoscopic screening is undoubtedly the most effective screening method, and is also therapeutic since it permits polyp removal. The simplest and best-evaluated available screening method is the fecal occult blood test, which is relatively inexpensive and noninvasive, but less accurate than colonoscopy. This method detects cancer at an early stage but, since precancerous polyps rarely bleed, it is not suitable for disease prevention. Compliance with current screening methods is a major barrier to optimal prevention. Several new screening modalities, such as self-navigating colonoscopes, prepless virtual colonoscopy, and stool genetic testing, may improve compliance. Until these technologies are available or shown to be appropriate for routine screening, however, conventional colonoscopy remains the most efficient method for CRC screening and prevention.

Re-evaluation of serum alanine aminotransferase upper normal limit and its modulating factors in a large-scale population study.

BACKGROUND: The upper normal limit (ULN) of serum alanine-aminotrasferase (ALT) normal range was recently challenged, because patients diagnosed with liver diseases may have 'normal' or near-'normal' ALT levels, and because possible modulators are often ignored in determining normal range. AIM: To estimate the ULN for serum ALT and to identify factors modulating it. SUBJECTS AND METHODS: We reviewed medical records of subjects aged 15-90, who underwent standard panels of laboratory tests, including serum ALT, over 6 months at a central laboratory. Three groups were defined: Group 1, comprised total study population (N=272 273). Group 2 (N=87 020) comprised total study population, excluding those receiving potentially hepatotoxic drugs, or diagnosed with liver disease, or had any abnormal laboratory test results other than for triglycerides, cholesterol, glucose, or HbA1c. Group 3 (N=17 496) the 'healthy' population, from whose ALT values we established the new ULN, comprised Group 2 subjects with normal triglycerides, cholesterol, glucose, and HbA1c levels. RESULTS: The 95th percentile ALT values, corresponding to the ULN, in groups 1, 2, and 3 were 50.1, 40, and 37.5 U/l, respectively. 6.2% (16 943/273 273) of subjects whose ALT was below ULN listed by the test manufacturer (52 U/l), had ALT level above our new ULN. Linear and logistic-regression analyses showed that ALT levels were significantly modified by gender, age, glucose, cholesterol, triglycerides, and overweight/obesity diagnosis. Significant interaction was found between gender, glucose and cholesterol levels. CONCLUSIONS: In this first large-scale study of 'healthy' population, serum ALT ULN was far lower than currently accepted value. Age and gender may be considered when determining the ULN for ALT.

The prevalence rate and anatomic location of colorectal adenoma and cancer detected by colonoscopy in average-risk individuals aged 40-80 years.

BACKGROUND: The role of screening colonoscopy for colorectal (CR) neoplasia in average-risk population, remains to be determined. OBJECTIVES: To evaluate the prevalence and anatomic location of CR adenoma and carcinoma and the morbidity of colonoscopy in individuals at average risk for CR cancer (CRC). METHODS: A retrospective prevalence study of subjects aged 40-80 yr, with no cancer-related symptoms, personal or family history of CR neoplasia, who underwent a colonoscopy. RESULTS: Enrolled were 1,177 persons; 183 aged 40-49 yr (young), 917 aged 50-75 yr, and 77 aged 76-80 yr (elderly). The prevalence of overall CR neoplasia, advanced neoplasia, and cancer was 20.9%, 6.3%, and 1.1%, respectively. In the 50-75 age group, the prevalence of overall adenoma, advanced neoplasia, and cancer was 21.3%, 6.7%, and 1.2%, respectively. Of the 206 neoplasia cases, 21-43% harbored proximal neoplasia beyond the reach of sigmoidoscopy, without distal lesions. Among the elderly, the prevalence of overall adenoma, advanced neoplasia, and cancer reached 26.0%, 14.3%, and 2.6%, respectively. In the young group, 9.8% had overall neoplasia, 1.1% had advanced adenoma, and none had CRC. Procedure-related morbidity rate was 0.1%, with no perforations, bleedings, or mortality. CONCLUSIONS: Screening colonoscopy in average-risk subjects demonstrated a considerable prevalence of CR neoplasia and proximal lesions beyond the reach of sigmoidoscopy. The morbidity rate was negligible. Primary screening colonoscopy should be considered in health programs for the average-risk population, beginning at the age of 50 yr. The significantly high rate of advanced and proximal neoplasia in the elderly, encourages the inclusion of healthy subjects aged 76-80 yr in future prospective studies.

Clinical and screening implications of the I1307K adenomatous polyposis coli gene variant in Israeli Ashkenazi Jews with familial colorectal neoplasia. Evidence for a founder effect.

BACKGROUND: The authors previously found the I1307K adenomatous polyposis coli (APC) gene variant in 5% of Ashkenazi control participants, in 15.4% of those who had familial colorectal neoplasia, but also in 1.6% of non-Ashkenazi control participants. In this study, they evaluated its use in a screening program for familial colorectal neoplasia and examined for a founder effect. METHODS: Consecutive Ashkenazim with a personal and/or family history of colorectal neoplasia had the DNA test. Markers flanking the APC gene were examined in Ashkenazi and non-Ashkenazi I1307K carriers and noncarriers. RESULTS: Among 718 persons, I1307K occurred in 6.2% of Ashkenazi participants, in 1.5% of non-Ashkenazi control participants (P = 0.02), and in 10.7% of Ashkenazim with familial neoplasia (relative risk, 1.73 [not significant compared with controls]; 95% confidence interval, 0.7-3.2). Colorectal neoplasia was detected in carriers at a younger age (P < 0.05) without excess risk for multiple colorectal neoplasia or noncolorectal neoplasia. I1307K attributable risk for colorectal neoplasia was 0.5-0.6%. Compared with noncarriers, both Ashkenazi and non-Ashkenazi I1307K carriers had similar flanking polymorphic alleles (P < 0.01). CONCLUSIONS: I1307K is a low-penetrance genetic variant that indicates a 1.7 relative risk for neoplasia in carriers who have familial carcinoma, clinically equivalent to obtaining a family history of sporadic colorectal neoplasia and promoting early screening. I1307K is a founder genetic variant in Jews of different ethnic origin, mainly Ashkenazim, but it explains only partially their higher incidence of colorectal carcinoma.