412 research outputs found
Reply: Evaluation of management of desmoid tumours associated with familial adenomatous polyposis in Dutch patients
Cellular mechanisms in basic and clinical gastroenterology and hepatolog
Family history is neglected in the work-up of patients with colorectal cancer: a quality assessment using cancer registry data
In the diagnostic work-up of hereditary non-polyposis colorectal cancer (HNPCC, Lynch syndrome), high-risk patients can be identified using information from the family history on cancer (‘Amsterdam criteria’ and ‘Bethesda guidelines’). To investigate to what extent the medical specialists apply these criteria to patients with colorectal carcinoma and a suspicion of HNPCC, we collected information on diagnostic work-up of 224 patients of seven hospitals in the region of the Comprehensive Cancer Centre West in Leiden, The Netherlands. These patients were diagnosed with colorectal cancer between 1999 and 2001 and satisfied at least one of the Bethesda guidelines. A complete family history was recorded for 38 of the 244 patients (16%). Patients with a complete family history were more likely to be referred to the Clinical Genetic Centre than those with an incomplete or absent family history (53% vs. 13% and 4%, respectively; P < 0.0001), and more likely to be analyzed for microsatellite instability (MSI), which is a characteristic of HNPCC (34% vs. 6% and 1%, respectively; P < 0.0001). We conclude that the family history is neglected in the majority of patients with colorectal cancer and MSI-analysis is only performed in a small proportion of the patients that meet the guidelines for this analysis
MEN-2 Syndrome: The Value of Screening and Central Registration; A Study of Six Kindreds in The Netherlands
Since 1975, six families with the MEN-2A syndrome including 66 patients have been identified in The Netherlands. All these patients underwent thyroidectomy for C-cell hyperplasia and/or medullary thyroid carcinoma (MTC); eight were symptomatic (Group A), 51 were relatives of patients found to be affected (Group B), and seven had had a negative screening test that became positive (Group C). To assess the effect of screening, we compared these groups with respect to the occurrence of metastatic MTC at thyroidectomy and the results of the postoperative calcitonin (CT) tests. We found that 87% of Group A, 37% of Group B; and none of Group C had metastatic disease at surgery. The cure rates in these three groups with MEN-2A, as determined by stimulated CT measurement, was 0%, 51%, and 100%, respectively. From these results it may be concluded that screening can lead to the detection of MTC at an earlier stage which in turn could permit curative treatment and improvement of both prognosis and life expectancy. The need for supervision of affected families by central registration to guarantee the continuity of screening is stressed
Screening for BRCA2 mutations in 81 Dutch breast–ovarian cancer families
We have analysed 81 families with a history of breast and/or ovarian cancer for the presence of germline mutations in BRCA2 with a number of different mutation screening techniques. The protein truncation test (PTT) for exons 10 and 11 detected four different frame-shifting mutations in six of these families. Four of the remaining 75 families had given positive linkage evidence for being due to BRCA2. In these families the entire coding region was analysed by single-strand conformational polymorphism, leading to the detection of a non-sense and a splice-site mutation in two of them. While these studies were in progress, Southern analysis of BRCA1 revealed that in our study-population of 81 families, 15 families were segregating either the exon 13 or exon 22 deletion in BRCA1 (Petrij-Bosch et al (1997) Nat Genet17: 341–345). This prompted us to examine BRCA2 in the remaining 58 families by Southern analysis, using two different restriction enzymes. No aberrations were found in the restriction patterns. Thus, contrary to BRCA1, large genomic rearrangements within the BRCA2 gene do not represent a major mutation mechanism among Dutch breast cancer families. © 2000 Cancer Research Campaig
Penetrance of HNPCC-related cancers in a retrolective cohort of 12 large Newfoundland families carrying a MSH2 founder mutation: an evaluation using modified segregation models
<p>Abstract</p> <p>Background</p> <p>Accurate risk (penetrance) estimates for associated phenotypes in carriers of a major disease gene are important for genetic counselling of at-risk individuals. Population-specific estimates of penetrance are often needed as well. Families ascertained from high-risk disease clinics provide substantial data to estimate penetrance of a disease gene, but these estimates must be adjusted for possible specific sources of bias.</p> <p>Methods</p> <p>A cohort of 12 independently ascertained HNPCC families harbouring a founder MSH2 mutation was identified from a cancer genetics clinic in St. John's, Newfoundland, Canada. Carrier status was known for 247 family members but phenotype information on up to 85 additional relatives with unknown carrier status was available; using modified segregation models these additional individuals could be included in the analyses. Three HNPCC-related phenotypes were evaluated as age at diagnosis of: any HNPCC cancer (first cancer), colorectal cancer (CRC), and endometrial cancer (EC) for females.</p> <p>Results</p> <p>Lifetime (age 70) risk estimates for male and female carriers were similar for developing any HNPCC cancer (Males = 98.2%, 95% Confidence Interval (CI) = (93.8%, 99.9%); Females = 92.8%, 95% CI = (82.4%, 99.1%)) but female carriers experienced substantially reduced lifetime risk for developing CRC compared to male carriers (Females = 38.9%, 95% CI = (24.2%, 62.1%); Males = 84.5%, 95% CI = (67.3%, 91.3%)). Female non-carriers had very low lifetime risk for these two outcomes while male non-carriers had lifetime risks intermediate to the female carriers and non-carriers. Female carriers had a lifetime risk of developing EC of 82.4%. Relative risks for developing any HNPCC cancer (carriers relative to non-carriers) were substantially greater for females compared to their male counterparts (Females = 54.8, 95%CI = (4.4, 379.8); Males = 9.7, 95% CI = (0.3, 23.8)). Relative risks for developing CRC at age 70 were substantially greater for females compared to their male counterparts (Females = 23.7, 95%CI = (5.6, 137.9); Males = 6.8%, 95% CI = (2.3, 66.2)). However, the risk of developing CRC decreased with age among both genders.</p> <p>Conclusion</p> <p>The proposed modified segregation-based models used to estimate age-specific risks for HNPCC phenotypes can reduce bias due to ascertainment and missing genotype information as well as provide estimates of absolute and relative risks.</p
Pulmonary sclerosing hemangioma in a 21-year-old male with metastatic hereditary non-polyposis colorectal cancer: Report of a case
<p>Abstract</p> <p>Background</p> <p>Pulmonary sclerosing hemangioma (SH) is a rare tumor of the lung predominantly affecting Asian women in their fifth decade of life. SH is thought to evolve from primitive respiratory epithelium and mostly shows benign biological behavior; however, cases of lymph node metastases, local recurrence and multiple lesions have been described.</p> <p>Case Presentation</p> <p>We report the case of a 21-year-old Caucasian male with a history of locally advanced and metastatic rectal carcinoma (UICC IV; pT4, pN1, M1(hep)) that was eventually identified as having hereditary non-polyposis colorectal cancer (HNPCC, Lynch syndrome). After neoadjuvant chemotherapy followed by low anterior resection, adjuvant chemotherapy and metachronous partial hepatectomy, he was admitted for treatment of newly diagnosed bilateral pulmonary metastases. Thoracic computed tomography showed a homogenous, sharply marked nodule in the left lower lobe. We decided in favor of atypical resection followed by systematic lymphadenectomy. Histopathological analysis revealed the diagnosis of SH.</p> <p>Conclusions</p> <p>Cases have been published with familial adenomatous polyposis (FAP) and simultaneous SH. FAP, Gardner syndrome and Li-Fraumeni syndrome, however, had been ruled out in the present case. To the best of our knowledge, this is the first report describing SH associated with Lynch syndrome.</p
Detection of mismatch repair gene germline mutation carrier among Chinese population with colorectal cancer
<p>Abstract</p> <p>Background</p> <p>Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant syndrome. The National Cancer Institute (NCI) has recommended the Revised Bethesda guidelines for screening HNPCC. There has been a great deal of research on the value of these tests in other countries. However, literature about the Chinese population is scarce. Our objective is to detect and study microsatellite instability (MSI) and mismatch repair (MMR) gene germline mutation carriers among a Chinese population with colorectal cancer.</p> <p>Methods</p> <p>In 146 prospectively recruited consecutive patients with clinically proven colorectal cancer, MSI carriers were identified by analysis of tumor tissue using multiplex fluorescence polymerase chain reaction (PCR) using the NCI recommended panel and classified into microsatellite instability-low (MSI-L), microsatellite instability-high (MSI-H) and microsatellite stable (MSS) groups. Immunohistochemical staining for MSH2, MSH6 and MLH1 on tissue microarrays (TMAs) was performed, and methylation of the MLH1 promoter was analyzed by quantitative methylation specific PCR (MSP). Germline mutation analysis of blood samples was performed for MSH2, MSH6 and MLH1 genes.</p> <p>Results</p> <p>Thirty-four out of the 146 colorectal cancers (CRCs, 23.2%) were MSI, including 19 MSI-H CRCs and 15 MSI-L CRCS. Negative staining for MSH2 was found in 8 CRCs, negative staining for MSH6 was found in 6 CRCs. One MSI-H CRC was negative for both MSH6 and MSH2. Seventeen CRCs stained negatively for MLH1. MLH1 promoter methylation was determined in 34 MSI CRCs. Hypermethylation of the MLH1 promoter occurred in 14 (73.7%) out of 19 MSI-H CRCs and 5 (33.3%) out of 15 MSI-L CRCs. Among the 34 MSI carriers and one MSS CRC with MLH1 negative staining, 8 had a MMR gene germline mutation, which accounted for 23.5% of all MSI colorectal cancers and 5.5% of all the colorectal cancers. Five patients harbored MSH2 germline mutations, and three patients harbored MSH6 germline mutations. None of the patients had an MLH1 mutation. Mutations were commonly located in exon 7 and 12 of MSH2 and exon 5 of MSH6. Right colonic lesions and mucinous carcinoma were not common in MSI carriers.</p> <p>Conclusion</p> <p>Our data may imply that the characteristics of HNPCC in the Chinese population are probably different from those of Western countries. Application of NCI recommended criteria may not be effective enough to identify Chinese HNPCC families. Further studies are necessary to echo or refute our results so as to make the NCI recommendation more universally applicable.</p
Hereditary cancer registries improve the care of patients with a genetic predisposition to cancer:contributions from the Dutch Lynch syndrome registry
The Dutch Hereditary Cancer Registry was established in 1985 with the support of the Ministry of Health (VWS). The aims of the registry are: (1) to promote the identification of families with hereditary cancer, (2) to encourage the participation in surveillance programs of individuals at high risk, (3) to ensure the continuity of lifelong surveillance examinations, and (4) to promote research, in particular the improvement of surveillance protocols. During its early days the registry provided assistance with family investigations and the collection of medical data, and recommended surveillance when a family fulfilled specific diagnostic criteria. Since 2000 the registry has focused on family follow-up, and ensuring the quality of surveillance programs and appropriate clinical management. Since its founding, the registry has identified over 10,000 high-risk individuals with a diverse array of hereditary cancer syndromes. All were encouraged to participate in prevention programmes. The registry has published a number of studies that evaluated the outcome of surveillance protocols for colorectal cancer (CRC) in Lynch syndrome, as well as in familial colorectal cancer. In 2006, evaluation of the effect of registration and colonoscopic surveillance on the mortality rate associated with colorectal cancer (CRC) showed that the policy led to a substantial decrease in the mortality rate associated with CRC. Following discovery of MMR gene defects, the first predictive model that could select families for genetic testing was published by the Leiden group. In addition, over the years the registry has produced many cancer risk studies that have helped to develop appropriate surveillance protocols. Hereditary cancer registries in general, and the Lynch syndrome registry in particular, play an important role in improving the clinical management of affected families.</p
Guidelines for follow-up of women at high risk for inherited breast cancer: Consensus statement from the Biomed 2 Demonstration Programme on Inherited Breast Cancer
Protocols for activity aiming at early diagnosis and treatment of inherited breast or breast-ovarian cancer have been reported. Available reports on outcome of such programmes are considered here. It is concluded that the ongoing activities should continue with minor modifications. Direct evidence of a survival benefit from breast and ovarian screening is not yet available. On the basis of expert opinion and preliminary results from intervention programmes indicating good detection rates for early breast cancers and 5-year survival concordant with early diagnosis, we propose that women at high risk for inherited breast cancer be offered genetic counselling, education in ‘breast awareness’ and annual mammography and clinical expert examination from around 30 years of age. Mammography every second year may be sufficient from 60 years on. BRCA1 mutation carriers may benefit from more frequent examinations and cancer risk may be reduced by oophorectomy before 40–50 years of age. We strongly advocate that all activities should be organized as multicentre studies subjected to continuous evaluation to measure the effects of the interventions on long-term mortality, to match management options more precisely to individual risks and to prepare the ground for studies on chemoprevention
Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium 'care for CMMRD' (C4CMMRD)
Constitutional mismatch repair deficiency (CMMRD) syndrome is a distinct childhood cancer predisposition syndrome that results from biallelic germline mutations in one of the four MMR genes, MLH1, MSH2, MSH6 or PMS2. The tumour spectrum is very broad, including mainly haematological, brain and intestinal tract tumours. Patients show a variety of non-malignant features that are indicative of CMMRD. However, currently no criteria that should entail diagnostic evaluation of CMMRD exist. We present a three-point scoring system for the suspected diagnosis CMMRD in a paediatric/young adult cancer patient. Tumours highly specific for CMMRD syndrome are assigned three points, malignancies overrepresented in CMMRD two points and all other malignancies one point. According to their specificity for CMMRD and their frequency in the general population, additional features are weighted with 1-2 points. They include multiple hyperpigmented and hypopigmented skin areas, brain malformations, pilomatricomas, a second childhood malignancy, a Lynch syndrome (LS)-associated tumour in a relative and parental consanguinity. According to the scoring system, CMMRD should be suspected in any cancer patient who reaches a minimum of three points by adding the points of the malignancy and the additional features. The diagnostic steps to confirm or refute the suspected diagnosis are outlined. We expect that application of the suggested strategy for CMMRD diagnosis will increase the number of patients being identified at the time when they develop their first tumour. This will allow adjustment of the treatment modalities, offering surveillance strategies for second malignancies and appropriate counselling of the entire family
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