Phenotypic characteristics of colo-rectal cancer in I1307K APC germline mutation carriers compared with sporadic cases

The I1307K APC germline mutation is associated with an increased risk to colo-rectal cancer (CRC). Whether and to what extent the phenotype of CRC in mutation carriers differs from sporadic cases, remains unknown. To gain insight into this issue, we analysed 307 unselected Israeli patients with CRC, who were treated in a single medical centre, for harbouring the I1307K mutation. Twenty-eight mutation carriers (9.1%) were detected. Two of 28 mutation carriers (7.1%) and 93/277 (33.6%) of non-carriers, were of non-Ashkenazi origin (P< 0.01). In 74/278 (26.6%) of the sporadic cases, and only 1/28 (3.6%) of mutation carriers (3.6%) the tumour was located in the right colon (P< 0.01). Mutation carriers had a more advanced disease stage (14/28 – 50% Dukes C), as compared with 60 (19.5%) of non-carriers (P= 0.02). The mean age at diagnosis was similar: 65 (+/– 9.7) years and 66.3 (+/– 11.6) years, for mutation carriers and non-carriers, respectively. No statistical differences were noted between the two groups in sex distribution, tumour grade, and family history of cancer. We conclude that early age at diagnosis and family history of cancer cannot be used to predict who is likely to harbour the I1307K APC germline mutation carriers. However, the tumours in patients with this mutation appear different than those without, are less likely to be proximal and more likely to be advanced than tumours in non-carriers.   http://www.bjcancer.com © 2001 Cancer Research Campaig

COL11A1 in FAP polyps and in sporadic colorectal tumors

BACKGROUND: We previously reported that the α-1 chain of type 11 collagen (COL11A1), not normally expressed in the colon, was up-regulated in stromal fibroblasts in most sporadic colorectal carcinomas. Patients with germline mutations in the APC gene show, besides colonic polyposis, symptoms of stromal fibroblast involvement, which could be related to COL11A1 expression. Most colorectal carcinomas are suggested to be a result of an activated Wnt- pathway, most often involving an inactivation of the APC gene or activation of β-catenin. METHODS: We used normal and polyp tissue samples from one FAP patient and a set of 37 sporadic colorectal carcinomas to find out if the up-regulation of COL11A1 was associated with an active APC/β-catenin pathway. RESULTS: In this study we found a statistically significant difference in COL11A1 expression between normal tissue and adenomas from one FAP patient, and all adenomas gave evidence for an active APC/β-catenin pathway. An active Wnt pathway has been suggested to involve stromal expression of WISP-1. We found a strong correlation between WISP-1 and COL11A1 expression in sporadic carcinomas. CONCLUSIONS: Our results suggest that expression of COL11A1 in colorectal tumors could be associated with the APC/β-catenin pathway in FAP and sporadic colorectal cancer

Novel APC mutations in Czech and Slovak FAP families: clinical and genetic aspects

BACKGROUND: Germline mutations in the adenomatous polyposis gene (APC) result in familial adenomatous polyposis (FAP). FAP is an autosomal dominantly inherited disorder predisposing to colorectal cancer. Typical FAP is characterized by hundreds to thousands of colorectal adenomatous polyps and by several extracolonic manifestations. An attenuated form of polyposis (AFAP) is characterized by less than 100 adenomas and later onset of the disease. METHODS: Here, we analyzed the APC gene for germline mutations in 59 Czech and 15 Slovak FAP patients. In addition, 50 apparently APC mutation negative Czech probands and 3 probands of Slovak origin were screened for large deletions encompassing the APC gene. Mutation screening was performed using denaturing gradient gel electrophoresis and/or protein truncation test. DNA fragments showing an aberrant electrophoretic banding pattern were sequenced. Screening for large deletions was performed by multiplex ligation dependent probe amplification. The extent of deletions was analyzed using following microsatellite markers: D5S299, D5S82, D5S134 and D5S346. RESULTS: In the set of Czech and Slovak patients, we identified 46 germline mutations among 74 unrelated probands. Total mutation capture is 62,2% including large deletions. Thirty seven mutations were detected in 49 patients presenting a classical FAP phenotype (75,5%) and 9 mutations in 25 patients with attenuated FAP (36%). We report 20 novel germline APC mutations and 3 large deletions (6%) encompassing the whole-gene deletions and/or exon 14 deletion. In the patients with novel mutations, correlations of the mutation localization are discussed in context of the classical and/or attenuated phenotype of the disease. CONCLUSION: The results of the molecular genetic testing are used both in the establishment of the predictive diagnosis and in the clinical management of patients. In some cases this study has also shown the difficulty to classify clinically between the classical and the attenuated form of FAP according to the established criteria. Interfamilial and/or intrafamilial phenotype variability was also confirmed in some cases which did not fit well with predicted genotype-phenotype correlation. All these findings have to be taken into consideration both in the genetic counselling and in the patient care

Design and methods for a randomized clinical trial comparing three outreach efforts to improve screening mammography adherence

<p>Abstract</p> <p>Background</p> <p>Despite the demonstrated need to increase screening mammography utilization and strong evidence that mail and telephone outreach to women can increase screening, most managed care organizations have not adopted comprehensive outreach programs. The uncertainty about optimum strategies and cost effectiveness have retarded widespread acceptance. While 70% of women report getting a mammogram within the prior 2 years, repeat mammography rates are less than 50%. This 5-year study is conducted though a Central Massachusetts healthcare plan and affiliated clinic. All womenhave adequate health insurance to cover the test.</p> <p>Methods/Design</p> <p>This randomized study compares 3 arms: reminder letter alone; reminder letter plus reminder call; reminder letter plus a second reminder and booklet plus a counselor call. All calls provide women with the opportunity to schedule a mammogram in a reasonable time. The invention period will span 4 years and include repeat attempts. The counselor arm is designed to educate, motivate and counsel women in an effort to alleviate PCP burden.</p> <p>All women who have been in the healthcare plan for 24 months and who have a current primary care provider (PCP) and who are aged 51-84 are randomized to 1 of 3 arms. Interventions are limited to women who become ≥18 months from a prior mammogram. Women and their physicians may opt out of the intervention study.</p> <p>Measurement of completed mammograms will use plan billing records and clinic electronic records. The primary outcome is the proportion of women continuously enrolled for ≥24 months who have had ≥1 mammogram in the last 24 months. Secondary outcomes include the number of women who need repeat interventions. The cost effectiveness analysis will measure all costs from the provider perspective.</p> <p>Discussion</p> <p>So far, 18,509 women aged 51-84 have been enrolled into our tracking database and were randomized into one of three arms. At baseline, 5,223 women were eligible for an intervention. We anticipate that the outcome will provide firm data about the maximal effectiveness as well as the cost effectiveness of the interventions both for increasing the mammography rate and the repeat mammography rate.</p> <p>Trial registration</p> <p><url>http://clinicaltrials.gov/</url><a href="http://www.clinicaltrials.gov/ct2/show/NCT01332032">NCT01332032</a></p

Association of RET codon 691 polymorphism in radiation-induced human thyroid tumours with C-cell hyperplasia in peritumoural tissue

The RET proto-oncogene encodes a protein structurally related to transmembrane receptors with an intracellular tyrosine kinase domain. In human thyroid gland, the RET proto-oncogene is normally expressed in parafollicular C-cells. Thyroid C-cell hyperplasia is associated with inherited medullary thyroid carcinomas and is considered as a pre-neoplastic stage of C-cells disease. It has also been observed in thyroid tissues adjacent to follicular and papillary carcinomas. In order to study the relationship between a misfunctioning of the RET proto-oncogene and the presence of C-cell hyperplasia, we compared a series of thyroid glands presenting sporadic or radiation-associated tumours, as well as samples of unrelated normal thyroid tissues, for alteration in exons 10 and 11 of the gene and for the presence or absence of C-cell hyperplasia. Here we report a significantly higher frequency of C-cell hyperplasia present in peritumoural thyroid tissues of radiation-induced epithelial thyroid tumours, than in peritumoural of sporadic thyroid tumours or in control normal thyroid tissues (P=0.001). A G691S RET polymorphism was present with a higher frequency in radiation-induced epithelial thyroid tumours (55%) than in sporadic tumours (20%) and in control normal thyroid tissues (15%). Interestingly, this polymorphism was associated in the majority (88%) of radiation-induced tumours with a C-cell hyperplasia in the peritumoural tissues. Several explanations for this association are discussed