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P Rozen

Publications and source records attributed to P Rozen.

At least 37 records · Page 2Linked to original sources
PubMed2000

Analysis of genetic and phenotypic heterogeneity in juvenile polyposis.

BACKGROUND: Juvenile polyposis syndrome (JPS) is characterised by gastrointestinal (GI) hamartomatous polyposis and an increased risk of GI malignancy. Juvenile polyps also occur in the Cowden (CS), Bannayan-Ruvalcaba-Riley (BRRS) and Gorlin (GS) syndromes. Diagnosing JPS can be problematic because it relies on exclusion of CS, BRRS, and GS. Germline mutations in the PTCH, PTEN and DPC4 (SMAD4) genes can cause GS, CS/BRRS, and JPS, respectively. AIMS: To examine the contribution of mutations in PTCH, PTEN, and DPC4 (SMAD4) to JPS. METHODS: Forty seven individuals from 15 families and nine apparently sporadic cases with JPS were screened for germline mutations in DPC4, PTEN, and PTCH. RESULTS: No patient had a mutation in PTEN or PTCH. Five different germline mutations were detected in DPC4; three of these were deletions, one a single base substitution creating a stop codon, and one a missense change. None of these patients had distinguishing clinical features. CONCLUSIONS: Mutations in PTEN and PTCH are unlikely to cause juvenile polyposis in the absence of clinical features indicative of CS, BRRS, or GS. A proportion of JPS patients harbour DPC4 mutations (21% in this study) but there remains uncharacterized genetic heterogeneity in JPS.

Adenomatous Polyposis Coli↗
PubMed1999

[Muir-Torre syndrome and HNPCC: importance of clinical diagnosis and genetic investigation in family members].

Muir-Torre syndrome is a relatively rare cutaneous manifestation of hereditary nonpolypous colorectal cancer (HNPCC). This autosomal dominant syndrome is characterized by a combination of sebaceous gland and malignant visceral tumors. The common sites of internal malignancies are the gastrointestinal tract and urinary system. It appears in early adult life and its clinical course is relatively slow. In some families genetic diagnosis can identify asymptomatic carriers of the mutation. All first-degree relatives, especially mutation carriers, should be referred from the age of 20 years for routine follow-up and early treatment, as it has been proven to decrease morbidity and mortality. We present a 51-year-old man with Muir-Torre syndrome diagnosed by the presence of multiple adenomas of sebaceous glands, colonic adenoma and adenocarcinoma of the duodenum. The family history was typical for HNPCC. A mutation in the hMSH2 gene on chromosome 2p was found in the patient and in several asymptomatic family members. The aim of this report is to increase awareness of this syndrome and emphasize the importance of referring patients and their families for clinical and genetic counseling and diagnosis.

Adult↗
PubMed1999

Prevalence of the I1307K APC gene variant in Israeli Jews of differing ethnic origin and risk for colorectal cancer.

BACKGROUND & AIMS: Israeli Jews of European birth, i.e., Ashkenazim, have the highest colorectal cancer incidence of any Israeli ethnic group. The I1307K APC gene variant was found in 6.1% of American Jews, 28% of their familial colorectal cancer cases, but not in non-Jews. We assessed the I1307K prevalence in Israeli Jews of differing ethnic origin and risk for colorectal cancer. METHODS: DNA samples from 500 unrelated Jews of European or non-European origin, with or without a personal and/or family history of neoplasia, were examined for the I1307K variant by the allele-specific oligonucleotide (ASO) method. RESULTS: In persons at average risk for colorectal cancer, I1307K was found in 5.0% of 120 European and 1.6% of 188 non-European Jews (P = 0.08). It occurred in 15.4% of 52 Ashkenazi Israelis with familial cancer (P = 0.02) and was not detected in 51 non-European Jews at increased cancer risk. Colorectal neoplasia occurred personally or in the families of 13 of 20 Ashkenazi I1307K carriers, 8 of whom also had a personal or family history of noncolonic neoplasia. CONCLUSIONS: The I1307K APC variant may represent a susceptibility gene for colorectal, or other, cancers in Ashkenazi Jews, and partially explains the higher incidence of colorectal cancer in European Israelis.

Adenomatous Polyposis Coli Protein↗
PubMed1999

Eliminating the need for dietary restrictions when using a sensitive guaiac fecal occult blood test.

When using the peroxidase-sensitive guaiac fecal occult blood test, Hemoccult Sensa (HOS), dietary restrictions are recommended so as to reduce its false positivity from ingested peroxidases. As dietary restrictions could reduce compliance for annual retesting, we reexamined their need. HOS was given to 944 persons in an endoscopic screening/follow-up program. Only the first 403 received instructions regarding a low peroxidase-containing diet for three days before and during HOS collection. Development was delayed 3-14 days after HOS preparation, and there were no significant differences in duration before HOS development in examinees with or without colorectal neoplasia and having or not having a positive test. Of the 901 persons without endoscopic evidence of neoplasia, 377 had received and 524 had not received instructions on dietary restrictions. Their HOS positivity was 7.2% and 5.5%, respectively (P = 0.26). When using HOS, delaying development by 3-14 days allows breakdown of ingested peroxidases, so dietary restrictions are not needed in our population, which has a low red meat intake.

Aged↗
PubMed1999

Screening SMAD1, SMAD2, SMAD3, and SMAD5 for germline mutations in juvenile polyposis syndrome.

BACKGROUND AND AIMS: Juvenile polyps occur in several Mendelian disorders, whether in association with gastrointestinal cancer alone (juvenile polyposis syndrome, JPS) or as part of known syndromes (Cowden, Gorlin, and Bannayan-Zonana) in association with developmental abnormalities, dysmorphic features, or extraintestinal tumours. Recently, some JPS families were shown to harbour germline mutations in the SMAD4 (DPC4) gene, providing further evidence for the importance of the TGFbeta signalling pathway in colorectal cancer. There remains, however, considerable, unexplained genetic heterogeneity in JPS. Other members of the SMAD family are excellent candidates for JPS, especially SMAD2 (which, like SMAD4, is mutated somatically in colorectal cancers), SMAD3 (which causes colorectal cancer when "knocked out" in mice), SMAD5, and SMAD1. METHODS: SMAD1, SMAD2, SMAD3, and SMAD5 were screened for germline mutations in 30 patients with JPS and without SMAD4 mutations. RESULTS: No mutations were found in any of these genes. A G-A C89Y polymorphism with possible effects on protein function was found in SMAD3, but the frequencies of the G and A alleles did not differ between patients with JPS and controls. CONCLUSIONS: It remains to be determined whether or not this polymorphism is involved in a minor predisposition to colorectal or other carcinomas. SMAD4 may be the only member of the SMAD family which causes JPS when mutant in the germline. The other genes underlying JPS remain to be identified.

Adenomatous Polyposis Coli↗
PubMed1999

Notable intrafamilial phenotypic variability in a kindred with familial adenomatous polyposis and an APC mutation in exon 9.

BACKGROUND: The phenotypic spectrum of familial adenomatous polyposis (FAP) varies from the classic appearance of hundreds of adenomatous colonic polyps in the young adult and early onset colorectal cancer, to the occurrence of sparse adenomas in the older adult, "attenuated" FAP, due to mutations at the 5' or 3' ends of the APC gene. AIMS: To investigate marked intrafamilial phenotypic variation occurring in a family with an APC gene mutation in exon 9. PATIENTS: An extended kindred of 22 people of whom 16 had colorectal neoplasia and/or were APC mutation carriers. RESULTS: Phenotypic manifestation varied from classic FAP to a complete lack of clinical or endoscopic, or bioptic disease in five people in three different generations. This occurred in four of them over two generations, in spite of having a confirmed 11 bp insertion causing a frame shift and stop codon (363) in exon 9 of the APC gene. CONCLUSIONS: At present, it is assumed that in this family there is alternative splicing of the APC gene, and/or unidentified modifying genetic factors. The family illustrates the importance of genetic testing in evaluating carrier status and not just clinical examination. This clinical observation also high- lights the dilemma in recognising the possible contribution of low penetrance germline APC mutations to what has been considered "sporadic" colorectal neoplasia.

Adenomatous Polyposis Coli↗
PubMed1998

Rectal epithelial proliferation in persons with or without a history of adenoma and its association with diet and lifestyle habits.

BACKGROUND: Rectal epithelial proliferation (REP) measurements are used as a biomarker of risk for colorectal neoplasia and response to chemoprevention. The authors evaluated REP in screenees with and without a history of adenoma and its association with demographic and adenoma characteristics, diet, and other lifestyle habits. METHODS: Long term lifestyle habits were evaluated and proliferation assessed by in vitro bromodeoxyuridine labeling of rectal biopsies in 223 screenees, 132 of whom had adenomas removed > 3 years previously. Analyses included the total population, screenees with a previous history of adenomas and adenoma free screenees separately, and a subgroup of 55 matched adenoma cases and controls. RESULTS: Crypt proliferation measurements were not elevated in screenees with a history of adenomas compared with adenoma free screenees (mean total labeling index [LI] of 4.8% and 4.9%, respectively). This was confirmed by the case-control analysis, in which the LI of the most superficial crypt compartment was lower in the adenoma cases (P=0.05). Moreover, their total LI correlated negatively with the number of adenomas removed previously (P < 0.01). Proliferation was more frequent in the most superficial crypt compartments of female adenoma free screenees than in female screenees with a history of adenomas (P=0.02), and in men age > 65 years compared with younger men (P=0.06). In the total population, negative Spearman rank correlations were found between total LI and long term dietary intake of calcium (correlation coefficient [r]=-0.15; P=0.02), LI of the two most superficial crypt compartments and intake of fiber (r=-0.18; P=0.01), water (r=-0.12; P=0.08), and carbohydrates (not significant). A positive correlation was found between LI of the most superficial crypt compartment and cigarette smoking (r=0.4; P=0.02). CONCLUSIONS: REP measurements did not discriminate between screenees with a history of adenomas and adenoma free screenees. Long-term lifestyle habits, gender, and age were associated with REP levels and need to be considered when evaluating human intervention studies.

Adenoma↗
PubMed1998

Characteristics of small bowel carcinoma in hereditary nonpolyposis colorectal carcinoma. International Collaborative Group on HNPCC.

BACKGROUND: Small bowel carcinoma is uncommon. However, hereditary nonpolyposis colorectal carcinoma (HNPCC) patients are at increased risk of small bowel carcinoma. The purpose of this study was to characterize small bowel tumors in HNPCC patients. METHODS: A questionnaire was mailed to the members of International Collaborative Group on HNPCC (ICG-HNPCC) requesting clinicopathologic data in their registries on HNPCC patients with small bowel carcinoma. Survival was estimated utilizing the Kaplan-Meier method. RESULTS: Forty-two individuals from 40 HNPCC families developed 42 primary and 7 metachronous small bowel tumors. There were 46 adenocarcinomas and 3 carcinoid tumors. The median age at diagnosis of the index small bowel tumor was 49 years. Mismatch repair gene mutations were present in 15 of 42 patients (36%). There were nine hMLH1 and six hMSH2 mutations. The small bowel was the first site of carcinoma in 24 patients (57%). The median survival for the 42 patients was 47 months (range, 0-447 months). The overall 5- and 10-year survival rates were 44% and 33%, respectively. CONCLUSIONS: Small bowel tumors can be the presenting neoplasms in HNPCC patients. Similar to colorectal carcinoma in HNPCC, small bowel adenocarcinomas in HNPCC patients occur at an earlier age and appear to have a better prognosis than those occurring in the general population.

Adenocarcinoma↗
PubMed1998

Shared tumor antigens in colorectal carcinoma and neuroendocrine tumors.

ND4 monoclonal antibody recognizes a tumor marker found on poorly differentiated colorectal cancer. We demonstrate its expression in 25% of gastrointestinal neuroendocrine tumors, which also express CEA in 37% of cases. As in colorectal cancer the ND4 marker is predominantly membrane bound in a colonic neuroendocrine tumor cell line, LCC-18 (p < 0.05). The ND4 marker is absent in a poorly differentiated colorectal cancer cell line that does not express CEA or other tumor antigens. Shed antigen in the serum of patients with neuroendocrine tumors is detected in only five of seven patients with the carcinoid syndrome and two of four of those without evidence of the syndrome. However, the reactivity was less in the patients with localized disease, and this test is unlikely to be of diagnostic utility in this group of patients. The sharing of this antigen in colorectal cancer and neuroendocrine tumors is not universal, but does support the common-cell progenitor theory for the origin of these tumors.

Animals↗
PubMed1998

Mutations in DPC4 (SMAD4) cause juvenile polyposis syndrome, but only account for a minority of cases.

Juvenile polyps are present in a number of Mendelian disorders, sometimes in association only with gastrointestinal cancer [juvenile polyposis syndrome (JPS)] and sometimes as part of known syndromes (Cowden, Gorlin and Banayan-Zonana) in association with developmental abnormalities, dysmorphic features or extra-intestinal tumours. Recently, a gene for JPS was mapped to 18q21.1 and the candidate gene DPC4 (SMAD4) was shown to carry frameshift mutations in some JPS families. We have analysed eight JPS families for linkage to DPC4. Overall, there was no evidence for linkage to DPC4; linkage could be excluded in two of the eight pedigrees and was unlikely in two others. We then tested these eight families and a further 13 familial and sporadic JPS cases for germline mutations in DPC4. Just one germline DPC4 mutation was found (in a familial JPS patient from a pedigree unsuitable for linkage analysis). Like all three previously reported germline mutations, this variant occurred towards the C-terminus of the DPC4 protein. However, our patient's mutation is a missense change (R361C); somatic missense mutations in DPC4 have been reported previously in tumours. We therefore confirm DPC4 as a cause of JPS, but show that there is considerable remaining, uncharacterized genetic heterogeneity in this disease.

DNA-Binding Proteins↗
PubMed1997

Exclusion of PTEN and 10q22-24 as the susceptibility locus for juvenile polyposis syndrome.

Juvenile polyposis syndrome (JPS; MIM 174900) is an autosomal dominant condition with incomplete penetrance characterized by hamartomatous polyps of the gastrointestinal tract and a risk of gastrointestinal cancer. Gastrointestinal hamartomatous polyps are also present in Cowden syndrome (CS; MIM 158350) and Bannayan-Zonana syndrome (BZS; also called Ruvalcaba-Myhre-Smith syndrome; MIM 153480). The susceptibility locus for both CS and BZS has recently been identified as the novel tumor suppressor gene PTEN, encoding a dual specificity phosphatase, located at 10q23.3. A putative JPS locus, JP1, which most likely functions as a tumor suppressor, had previously been mapped to 10q22-24 in both familial and sporadic juvenile polyps. Given the shared clinical features of gastrointestinal hamartomatous polyps among the three syndromes and the coincident mapping of JP1 to the region of PTEN, we sought to determine whether JPS was allelic to CS and BZS by mutation analysis of PTEN and linkage approaches. Microsatellite markers spanning the CS/BZS locus (D10S219, D10S551, D10S579, and D10S541) were used to compute multipoint lod scores in eight informative families with JPS. Lod scores of < -2.0 were generated for the entire region, thus excluding PTEN and any genes within the flanking 20-cM interval as candidate loci for familial JPS under our statistical models. In addition, analysis of PTEN using a combination of denaturing gradient gel electrophoresis and direct sequencing was unable to identify a germline mutation in 14 families with JPS and 11 sporadic cases. Therefore, at least a proportion of JPS cases are not caused by germline PTEN alteration or by an alternative locus at 10q22-24.

Chromosomes, Human, Pair 10↗
PubMed1997

[Familial adenomatous polyposis: establishing a registry and genetic and molecular analysis].

Familial adenomatous polyposis (FAP), a dominantly inherited disease, is caused by a mutation in the adenomatous polyposis coli gene in chromosome 5q21. The gene has 15 exons, a physical length of 10 Kb and an open reading frame of 8.5 Kb. Exon 15 codes 66% of the mRNA and has a mutation cluster region which accounts for over 50% of mutations. The disease usually leads to the appearance of hundreds of adenomatous polyps in the transverse and descending colon between puberty and age 20 years and to colon cancer before the age of 40. Early detection is essential to prevent the development of metastasizing cancer. Since 1994 we have recruited 23 families for genetic counseling. DNA was obtained from 19 unrelated FAP patients and 219 high risk relatives in 19 unrelated families following confirmation of the diagnosis. In addition to linkage studies, direct mutational analysis was performed using the protein truncation test for most of exon 15 and single strand conformation polymorphism analysis for the other exons. These exons account for most of the mutations identified to date. Of 19 unrelated probands, 14 had detectable mutations. Exon 15 accounted for 6 families, exons 5, 7 and 14 for 1 each, exon 9 for 3, and exon 8 for 2. Combined mutational and linkage analysis identified 18 presymptomatic carriers who received genetic and clinical counseling. Our FAP patients did not differ significantly from those of larger studies in other countries with regard to the distribution of the mutations, gender and genotype-phenotype correlation, or ethnic distribution.

Adenomatous Polyposis Coli↗
PubMed1997

Performance characteristics and comparison of two immunochemical and two guaiac fecal occult blood screening tests for colorectal neoplasia.

A new immunochemical test for stool Hb, FlexSure OBT, was compared with the immunochemical HemeSelect and guaiac Hemoccult II and Hemoccult SENSA tests. Blinded development of test cards smeared with stools having added human blood showed better analytical sensitivity of FlexSure OBT (0.2 ml blood/100 g feces), than Hemoccult SENSA (> or =0.5 ml) or Hemoccult II (> or =1.0 ml). All four stool tests were prepared by 403 subjects having endoscopic examinations. The guaiac tests and FlexSure OBT were easy to prepare and develop. The positivity rate of Hemoccult SENSA was 8.7%, Hemoccult II 6%, FlexSure OBT 4.2%, and HemeSelect 3.4%. In this mainly asymptomatic (97%) population, 98% were free of clinically significant neoplasia (five had cancers, three had adenomas > or =1.0 cm). Sensitivity for cancers or adenomas > or =1.0 cm was similar for all tests (62.5-86%, NS) and Hemoccult SENSA had the lowest specificity (92% vs 95-98%, P < 0.05); but both Hemoccult II and Hemoccult SENSA had significantly lower predictive positive values (21% and 14%) than either FlexSure OBT (29%) or HemeSelect (50%) (P < 0.05). If both Hemoccult SENSA and FlexSure OBT were positive in the same subjects (1.7%), sensitivity for cancer or adenomas > or =1.0 cm (50%) was not significantly better than guaiac tests, but specificity (99.2%) and predictive positive (57%) values were improved (P < 0.05). In this population, guaiac tests were as sensitive as immunochemical tests for clinically significant colorectal neoplasia, but with significantly lower predictive positive values. A combination of a sensitive guaiac test (Hemoccult SENSA) and a specific confirmatory test for human Hb (FlexSure OBT) provided high specificity, comparable to HemeSelect.

Adenoma↗
PubMed1997

Rectal cancer risk in hereditary nonpolyposis colorectal cancer after abdominal colectomy. International Collaborative Group on HNPCC.

OBJECTIVE: The authors analyzed the incidence of rectal cancer in patients with hereditary nonpolyposis colorectal cancer (HNPCC) after an abdominal colectomy. SUMMARY BACKGROUND DATA: The treatment of choice for a newly diagnosed patient with HNPCC with colon cancer is an abdominal colectomy. The incidence of rectal cancer after abdominal colectomy in HNPCC is not known. MATERIALS AND METHODS: A questionnaire was mailed to all International Collaborative Group on HNPCC members to identify patients in whom rectal cancer developed after total, subtotal or completion colectomy. Statistics were performed using the log-rank test, Kaplan-Meier method, and Cox's proportional hazards model. RESULTS: Rectal cancer developed in 8 (11%) of 71 patients a median of 158 months (range, 38-282 months) from their primary procedure. Of these eight patients, adenomas in the rectal mucosa developed in five at risk either before (4) or synchronous (1) with the diagnosis of rectal cancer. At the time of diagnosis of rectal cancer, six of eight patients were being observed. Age at first procedure and whether the patient was under surveillance were the only significant variables (p < 0.05) in the multivariate analysis in terms of rectal cancer risk. The risk of developing rectal cancer was estimated to be 3% every 3 years after abdominal colectomy for the first 12 years. CONCLUSIONS: The risk of rectal cancer in patients with HNPCC after an abdominal colectomy is approximately 12% at 12 years. Age at first surgical procedure and surveillance correlated with rectal cancer risk. Aggressive endoscopic surveillance of the rectum should be performed after abdominal colectomy.

Abdomen↗
PubMed1997

Nutritional and lifestyle habits and water-fiber interaction in colorectal adenoma etiology.

Adenomatous polyps are neoplasms that may progress to colorectal cancer. The role of diet and other lifestyle habits in their etiology is now being elucidated. The aim of this study was to evaluate effects of nutritional habits, weight and weight gain, tobacco smoking, and physical activity in adenoma etiology. A quantified dietary history questionnaire was designed to evaluate long-term dietary habits in addition to more recent ones. The study population comprised 196 adenoma patients and matched asymptomatic, screened controls. Statistical analysis used multivariate conditional logistic models, adjusting for total energy intake and physical activity. Odds ratios (ORs) and 95% confidence intervals (CIs) for adenoma associated with highest versus lowest tertiles of mean daily intake were as follows: for energy, OR 3.7 and CI 2.1-6.7; for animal fat, OR 2.4 and CI 1.2-4.7; for tobacco smoking, OR 3.1 and CI 1.1-2.8; and for weight gain, OR 2.2 and CI 1.2-4.1 (P for linear trend for all, < or = 0.01). Significant negative associations were found with intake of total carbohydrates (OR, 0.3; CI, 0.1-0.7) and fluids (OR, 0.4; CI, 0.2-0.8) (P for both < 0.01) as well as for physical activity (OR, 0.6; CI, 0.3-0.9; P = 0.03). Increased risk for adenoma was observed with decreased intake of carotene (OR, 0.6; CI, 0.3-1.0; P = 0.06), vitamin E (OR, 0.6; CI, 0.3-1.0; P = 0.07), and dietary fiber (OR, 0.6; CI, 0.3-1.3; not significant). The OR of interaction between water and dietary fiber was significant (OR, 0.7; CI, 0.6-0.9; P = 0.01), suggesting a synergistic protective effect. Specific dietary and lifestyle habits were identified as independent factors associated with colorectal adenomas; of special interest is the interaction between water and fiber intake. Avoiding these factors might delay or prevent neoplasia.

Adenoma↗
PubMed1996

Differing proliferative responses in proximal and distal colons of growing rats fed food eaten by adenoma patients.

Animal dietary studies related to human colorectal carcinogenesis are usually based on AIN-76A diet, which is dissimilar to human food in source, preparation, and content. Our aim was to examine colonic epithelial proliferation in rats fed a diet based on the mean daily food intake of adenoma patients. Foods were prepared as reported by the adenoma patients and dehydrated; 64 Sprague-Dawley rats were fed either "human adenoma" or AIN-76A diet and every eight weeks, eight from each group were sacrificed. Both groups gained weight equally, had no colonic histological changes, but during the study showed progressive lengthening of colonic crypts (P < 0.01) and decreased proliferation (P < 0.05) in distal colons. Compared to controls, rats fed human adenoma diet had significantly longer crypts (P < 0.01) and more labeled cells (P < 0.05) at 32 weeks; overall they had increased proliferation (P < 0.01), most significantly in the distal colon. Thus, food eaten by adenoma patients induced hyperproliferative changes in the rat colon during growth and maturity, especially the distal colon, as found in humans at risk for neoplasia.

Adenoma↗