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H F Vasen

Publications and source records attributed to H F Vasen.

At least 73 records · Page 4Linked to original sources
PubMed1996

Thyroid carcinoma as first manifestation of familial adenomatous polyposis.

A 22-year-old female member of a family with familial adenomatous polyposis (FAP) presented with a thyroid nodule. Histology revealed a follicular carcinoma. The patient was on regular follow-up as part of the FAP screening program; 1.5 years after the thyroidectomy she appeared to have multiple adenomatous polyps in her colon and FAP was diagnosed. Thyroid-carcinoma is one of the extraintestinal manifestations of FAP and particularly women in the age of 25-35 years are at risk according to the literature.

Adenocarcinoma, Follicular↗
PubMed1996

Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis.

BACKGROUND & AIMS: Hereditary nonpolyposis colorectal cancer is characterized by early-onset colorectal cancer and the occurrence of various other cancers. The recent isolation of four mismatch repair genes responsible for hereditary nonpolyposis colorectal cancer allows for the identification of carriers within affected families. The purpose of this study was to assess the age-specific cancer risk in a large series of gene carriers. METHODS: Thirty-four families were studied by mutation analysis. In 19 of these families, pathogenic mutations were found at hMSH2 or hMLH1. Of 382 relatives, 124 had a mutation in hMLH1 and 86 in hMSH2. RESULTS: The lifetime risk of colorectal cancer was the same in both groups of gene carriers (80%). The risk of endometrial cancer was greater in hMSH2 gene carriers compared with hMLH1 gene carriers (61% vs. 42%), but the difference was not statistically significant. A very high relative risk of cancer of the small bowel (relative risk of >100) was observed in carriers of either gene. Only the carriers of hMSH2 mutations had a significantly increased relative risk of cancer of the urinary tract (kidney and ureter) (relative risk of 75.3), stomach (relative risk of 19.3), and ovaries (relative risk of 8.0). CONCLUSIONS: This study provides estimates of cancer risk that may contribute to the appropriate management of gene carriers within families with hereditary nonpolyposis colorectal cancer.

Adolescent↗
PubMed1996

The majority of 22 Dutch high-risk breast cancer families are due to either BRCA1 or BRCA2.

We have analyzed, by a combination of mutation and linkage analysis, the genetic basis of 22 breast cancer families in which at least 4 cases of either breast cancer diagnosed under the age of 60 or ovarian cancer had occurred. Chain-terminating mutations in BRCA1 were evidenced in 6 families, and posterior probabilities of > 0.90 of being linked to BRCA1 in 3. The breast versus ovarian cancer ratio in these 9 families was approximately 2:1. Among the remaining 13 families, significant linkage to markers flanking BRCA2 was established in the admixture test with a maximum multipoint lod score of 3.38, but there was no statistical evidence for genetic heterogeneity. The breast:ovarian cancer ratio in these families was 7:1, suggesting BRCA2 confers a much lower risk for ovarian cancer than does BRCA1. These results suggest that BRCA2 will explain a significant proportion of hereditary breast cancer in the Netherlands, and, together with BRCA1, account for the majority of all high-risk families.

BRCA2 Protein↗
PubMed1996

Genetic counseling in hereditary nonpolyposis colorectal cancer.

Recent identification of gene mutations responsible for hereditary nonpolyposis colorectal cancer (HNPCC) has made possible the presymptomatic diagnosis of at-risk family members. If DNA testing shows that a family member is a gene carrier, that individual's lifetime cancer risk is approximately 90%. If the test is negative, the family member's cancer risk drops to that of the general population. Presymptomatic DNA-based diagnosis consists of pretest counseling, the actual DNA test, and posttest counseling. Pretest counseling focuses on the benefits, limitations, and possible adverse effects of testing, and the advantages and drawbacks of screening methods. Posttest counseling sessions explore the test result, and family members' reactions to it. A multidisciplinary team approach is necessary for the management of HNPCC families.

Colorectal Neoplasms, Hereditary Nonpolyposis↗
PubMed1995

APC mutation in the alternatively spliced region of exon 9 associated with late onset familial adenomatous polyposis.

Germ-line mutations in the adenomatous polyposis coli (APC) gene are responsible for familial adenomatous polyposis (FAP). Genotype-phenotype correlation studies in patients with FAP have demonstrated associations of certain variants of the disease with mutations at specific sites within the APC gene. In a large FAP family, we identified a frameshift mutation located in the alternatively spliced region of exon 9. Phenotypic studies of affected family members showed that the clinical course of FAP was delayed, with gastrointestinal symptoms and death from colorectal carcinoma occurring on average 25 and 20 years later than usual, respectively. The numbers of colorectal adenomas differed markedly among affected individuals and the location of colorectal cancer lay frequently in the proximal colon. Our findings suggest that the exon 9 mutation identified in the pedigree is associated with late onset of FAP. The atypical phenotype may be explained by the site of the mutation in the APC gene. Analysis of the APC protein product indicated that the exon 9 mutation did not result in a detectable truncated APC protein. Given the location of the mutation within an alternatively spliced exon of APC, it is conceivable that normal APC proteins are produced from the mutant allele by alternative splicing.

Adenoma↗
PubMed1995

Age at diagnosis as an indicator of eligibility for BRCA1 DNA testing in familial breast cancer.

We searched for criteria that could indicate breast cancer families with a high prior probability of being caused by the breast/ovarian cancer susceptibility locus BRCA1 on chromosome 17. To this end, we performed a linkage study with 59 consecutively collected Dutch breast cancer families, including 16 with at least one case of ovarian cancer. We used an intake cut-off of at least three first-degree relatives with breast and/or ovarian cancer at any age. Significant evidence for linkage was found only among the 13 breast cancer families with a mean age at diagnosis of less than 45 years. An unexpectedly low proportion of the breast-ovarian cancer families were estimated to be linked to BRCA1, which could be due to a founder effect in the Dutch population. Given the expected logistical problems in clinical management now that BRCA1 has been identified, we propose an interim period in which only families with a strong positive family history for early onset breast and/or ovarian cancer will be offered BRCA1 mutation testing.

Adult↗
PubMed1995

Rapid detection of BRCA1 mutations by the protein truncation test.

More than 75% of the reported mutations in the hereditary breast and ovarian cancer gene, BRCA1, result in truncated proteins. We have used the protein truncation test (PTT) to screen for mutations in exon 11, which encodes 61% of BRCA1. In 45 patients from breast and/or ovarian cancer families we found six novel mutations: two single nucleotide insertions, three small deletions (1-5 bp) and a nonsense mutation identified two unrelated families. Furthermore, we were able to amplify the remaining coding region by RT-PCR using lymphocyte RNA. Combined with PTT, we detected aberrantly spliced products affecting exons 5 and 6 in one of two BRCA1-linked families examined. The protein truncation test promises to become a valuable technique in detecting BRCA1 mutations.

BRCA1 Protein↗
PubMed1995

Hereditary medullary thyroid carcinoma.

The most well-known form of familial thyroid cancer is hereditary medullary thyroid carcinoma (MTC). This neoplasm is often associated with pheochromocytoma and hyperparathyroidism, a combination known as the multiple endocrine neoplasia syndrome type 2A (MEN 2A). The rare association of MTC and pheochromocytoma with multiple mucosal neuromas is called multiple endocrine neoplasia syndrome type 2B (MEN 2B). Of those who present with clinical signs and symptoms, almost half die of the disease and others may suffer significant morbidity. By contrast, early diagnosis by screening of family members allows for treatment with thyroidectomy and/or adrenalectomy, which are often curative. Measurement of serum calcitonin before and after stimulation with pentagastrin and/or calcium is mandatory for the diagnosis of MTC. Testing of first-degree relatives of patients with MTC should be started by the age of 3 to 5 years. In families with the MEN 2B syndrome, screening should be started during the first year after birth and include a search for the characteristic phenotype. The mapping of the MEN 2A gene to the centromeric region of chromosome 10 has provided an alternative approach to the diagnosis of MEN 2A gene carriers. Genetic screening using linked markers can now be done with an accuracy of 95% in informative families. Surgery is the treatment of choice for cases of MEN 2, but the extent of surgical resection of the involved endocrine organs is still a subject of debate.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

[Periodic examination of families with hereditary nonpolyposis colorectal carcinoma in The Netherlands: a study of 41 families].

OBJECTIVE: To determine characteristics of hereditary nonpolyposis colorectal cancer (HNPCC) and the implications for screening and treatment. DESIGN: Longitudinal. SETTING: Nationwide. METHOD: Genealogic studies were performed in 114 families referred to the Netherlands Foundation for Detection of Hereditary Tumours because of a suspected inherited form of colorectal cancer. RESULTS: Forty-one families met the criteria for HNPCC: These families included 194 patients with colorectal cancer (84 females and 110 males). The mean age at diagnosis was 44 years (range: 16-74). In 92% the tumour was diagnosed before the age of 60 years. Fifty-eight per cent were located in the proximal colon. Twenty-three per cent of the patients had multiple primary colorectal cancer. The cumulative risk of developing a second colorectal cancer was 23% after 10 years of follow up. Cancer of the endometrium, stomach and urinary tract were the most frequent extracolonic cancers. CONCLUSIONS: Periodic examination of first-degree relatives of patients from HNPCC families should start between the ages of 20 and 25 years. The recommended interval between consecutive examinations is 2-3 years. After the age of 60 years screening may be performed at a lower frequency. The right colon in particular should be investigated. A subtotal colectomy is indicated at the time of diagnosis of the initial colon cancer, because of the risk of multiple primary tumours.

Adolescent↗
PubMed1994

Endometrial cancer in four sisters: report of a kindred with presumed cancer family syndrome.

Hereditary nonpolyposis colorectal cancer (HNPCC, synonyms: cancer family syndrome, Lynch syndrome) is characterized by the occurrence of colorectal cancer and other primary tumors in susceptible family members. Inheritance is autosomal dominant with high penetrance. Endometrial cancer is the most frequent extracolonic malignancy in gene carriers. The criteria for the diagnosis HNPCC include the occurrence of colorectal cancer in three close relatives. However, not only colorectal cancer but also endometrial cancer may indicate HNPCC. We present a family diagnosed as a probable HNPCC kindred after endometrial cancer was observed in four sisters. One of these patients and the father of the four sisters had had colorectal cancer. This kindred illustrates the importance of recording the family history in patients with endometrial cancer.

Adenocarcinoma↗
PubMed1994

The risk of endometrial cancer in hereditary nonpolyposis colorectal cancer.

PURPOSE: Hereditary nonpolyposis colorectal cancer (HNPCC) is characterized by increased risk for cancer, especially colorectal cancer. It has been recommended that colon cancer control programs for family members be expanded to include endometrial cancer, the commonest extracolonic cancer observed in HNPCC families. We estimated the age-specific and cumulative endometrial cancer risk for women at high risk for HNPCC. PATIENTS AND METHODS: Family history data from three large HNPCC registries were combined for this study. High risk family members were identified without regard to extracolonic cancer. Life table methods were used to calculate estimates of risk. RESULTS: One thousand eighteen women from 86 families were included in the study. Cumulative incidence was 20% by age 70, compared to 3% in the general population. Risk was highest in women most likely to carry the HNPCC gene (P < 0.001). In this group, during the highest risk years (age 40 to 60), average annual risk exceeded 1%. There was no significant difference among the registries, despite different ascertainment practices regarding endometrial cancer. CONCLUSION: Interventions to reduce endometrial cancer morbidity and mortality are justified by the risk levels observed. Prophylactic total hysterectomy and bilateral salpingo-oophorectomy should be recommended to women in HNPCC families who have a syndrome cancer or offspring with a syndrome cancer. Endometrial cancer screening should be available to women at high risk. Studies of screening protocols are needed.

Colorectal Neoplasms, Hereditary Nonpolyposis↗
PubMed1994

Clinical heterogeneity of familial colorectal cancer and its influence on screening protocols.

The age at onset of non-polyposis colorectal cancer (CRC) was investigated in 49 families with at least three relatives affected in two successive generations. Forty one of these families satisfy the accepted minimum criteria for hereditary non-polyposis CRC. The remaining eight families were distinguished by a late age of disease onset and, hence, could not be included in the group. The condition in these latter families has been designated provisionally, as late onset familial CRC. The hereditary non-polyposis CRC families include 194 patients, 110 men and 84 women (mean age at diagnosis: 44 years; range: 16-74 years). Ninety two per cent of the patients were diagnosed by age 60. Colorectal cancer was diagnosed at progressively earlier ages in successive generations (p < 0.0005). The late onset CRC families comprised 30 patients, 20 men and 10 women (mean age at diagnosis: 62 years; range: 51-77 years). Fifty eight per cent of the CRCs in the patients belonging to the hereditary non-polyposis CRC families were located in the right colon compared with 13% in the late onset familial CRC group (p < 0.001). Multiple CRCs were found in 23% of the cases in the former but in only 3% in the latter families (p < 0.05). Adenomas associated with CRC were reported in 14.5% of the cases in the hereditary non-polyposis CRC families and in 30% of the cases in the late onset familial CRC group (p = NS). Extracolonic cancers, frequently encountered in hereditary non-polyposis CRC, were not found in the late onset CRC families. These findings indicate that there is a distinct clinical entity of non-polyposis CRC in which colorectal cancer develops at a more advanced age than in hereditary non-polyposis CRC. Future molecular genetic studies should confirm this hypothesis. In the meantime, recognition of these late onset familial CRC families, which will rest on clinical observations, is important because of the implications for the screening protocol.

Adolescent↗
PubMed1994

Increased prevalence of colonic adenomas in patients with acromegaly.

Forty-nine acromegalics and 57 controls matched for age and sex underwent colonoscopy. The control group consisted of patients investigated because of atypical abdominal complaints compatible with irritable bowel syndrome or constipation. The exclusion criteria for both groups included: age over 75 years, previous colonic polyps or cancer, previous colonic surgery, rectal blood loss, anemia, previous abdominal radiation, sigmoidoscopy, colonoscopy or barium enema performed for any indication within 3 years prior to the present study. Colonoscopy was successful in reaching the cecum in 72 and 77% of the controls and acromegalics, respectively (p = NS). Eleven (22%) of 49 acromegalics had biopsy-proven colonic adenomas versus only five (9%) of the control group (p < or = 0.05). Multiple adenomas were found in three of the 11 acromegalics and in none of the controls. In five of these 11 patients and in only one of the controls, at least one adenoma was located in the right colon. In addition, acromegalics tended to have larger adenomas. The group of acromegalics with and without adenomas did not differ significantly in age or duration of active disease. In conclusion, the present study shows that acromegalic patients have an increased risk of developing colonic adenomas.

Acromegaly↗
PubMed1994

Screening in breast cancer families: is it useful?

In 5% of the cases of breast cancer, the condition is attributable to a genetic predisposition. The clinical relevance of inherited forms of cancer lies in the fact that periodic screening of close relatives of patients may prevent disease and death due to cancer. Although surveillance programmes for hereditary cancers have been recommended for many years, there is still little or no evidence that surveillance will improve the prognosis. In particular, screening for breast and ovarian cancers gives rise to many problems, because there is no precursor lesion that can easily be identified, such as an adenomatous polyp in familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer. This means that prospective controlled studies are urgently needed to assess the value of the recommended screening protocols. National and regional hereditary cancer registries may play an important role in the evaluation of the effect of long-term surveillance. Presymptomatic testing based on DNA technology will probably become feasible for breast cancer in the near future. A major advantage of DNA analysis in this context is that screening can be focused on high-risk individuals and the family members at low risk can be less rigorously followed. Because of unanticipated consequences associated with DNA analysis, much research remains to be done to define the psychosocial implications of presymptomatic DNA diagnosis.

Breast Neoplasms↗
PubMed1993

Non-allelic heterogeneity of familial adenomatous polyposis.

Linkage studies on familial adenomatous polyposis (FAP) reported so far suggest that FAP is a genetically homogeneous disease. Recently, we found that the putative gene for Turcot syndrome, an apparently autosomal recessive clinical variant of FAP, is not allelic to FAP. Here we describe another family, segregating for an autosomal dominant disease clinically indistinguishable from FAP but genetically not linked to the APC locus, adding further evidence for the occurrence of non-allelic heterogeneity of FAP. These observations have implications to the linkage-based genetic counselling of persons at risk for FAP especially when they are drawn from small families giving insufficient information.

Adenomatous Polyposis Coli↗