Showing papers by "Fred H. Menko published in 1999"

Familial endometrial cancer in female carriers of MSH6 germline mutations

Abstract: Hereditary non-polyposis colorectal cancer (HNPCC) is a common autosomal dominant condition characterized by early onset colorectal cancer as well as other tumour types at different anatomical sites1. HNPCC tumours often display a high level of genomic instability, characterized by changes in repeat numbers of simple repetitive sequences (microsatellite instability, MSI), which reflects the malfunction of the DNA mismatch repair machinery2, 3. Accordingly, HNPCC was shown to be caused by germline mutations in the DNA mismatch repair genes (MMR) MSH2, MLH1, PMS1, PMS2 and MSH6 (refs 3, 4, 5, 6). So far, more than 220 predisposing mutations have been identified, most in MSH2 and MLH1 and in families complying with the clinical Amsterdam criteria3, 7, 8 (AMS+). Many HNPCC families, however, do not fully comply with these criteria, and in most cases the causative mutations are unknown.

Characteristics of small breast and/or ovarian cancer families with germline mutations in BRCA1 and BRCA2.

Abstract: For families with a small number of cases of breast and/or ovarian cancer, limited data are available to predict the likelihood of genetic predisposition due to mutations in BRCA1 or BRCA2. In 104 families with three or more affected individuals (average 3.8) seeking counselling at family cancer clinics, mutation analysis was performed in the open reading frame of BRCA1 and BRCA2 by the protein truncation test and mutation-specific assays. In 31 of the 104 families tested, mutations were detected (30%). The majority of these mutations (25) occurred in BRCA1. Mutations were detected in 15 out of 25 families (60%) with both breast and ovarian cancer and in 16 out of 79 families (20%) with exclusively cases of breast cancer. Thus, an ovarian cancer case strongly predicted finding a mutation (P < 0.001). Within the group of small breast-cancer-only families, a bilateral breast cancer case or a unilateral breast cancer case diagnosed before age 40 independently predicted finding a BRCA1 or BRCA2 mutation (P = 0.005 and P = 0.02, respectively). Therefore, even small breast/ovarian cancer families with at least one case of ovarian cancer, bilateral breast cancer, or a case of breast cancer diagnosed before age 40, should be referred for mutation screening.

Accumulation of p53 protein is frequent in ovarian cancers associated with BRCA1 and BRCA2 germline mutations.

Abstract: BACKGROUND: Mutations in the BRCA1 or BRCA2 genes are responsible for up to 95% of hereditary ovarian cancer cases. Both genes function as tumour suppressor genes, and development of a cancer is thought to require an accumulation of somatic genetic events in addition to the inherited germline predisposition. It is unknown whether these somatic events in BRCA associated ovarian cancer are similar to or distinct from those in sporadic cases. The most frequent somatic genetic event in ovarian cancer is a mutation of the p53 gene. AIM: To study the role of p53 in hereditary ovarian cancer, by analysing accumulation of the p53 protein in ovarian cancers which occurred in BRCA1 or BRCA2 germline mutation carriers and comparing the results with a panel of ovarian cancers from patients who tested negative for both BRCA1 and BRCA2. METHODS: The study group consisted of 39 ovarian cancer patients in whom a BRCA mutation had been confirmed previously. p53 Immunohistochemistry was performed on archival tissue using a standard microwave antigen retrieval technique. The rate of p53 accumulation was compared with 40 ovarian cancer cases who tested negative for BRCA1 and BRCA2 germline mutations. RESULTS: P53 Accumulation was similar in BRCA related ovarian cancers and BRCA negative controls. Overall 27 of 39 BRCA1 or BRCA2 positive cases (69%) had evidence of p53 accumulation, compared with 24 of 40 invasive ovarian cancer cases (60%) which tested negative for BRCA1 and BRCA2 germline mutations. BRCA1 related ovarian cancers showed p53 accumulation in 22 of 30 cases (73%); p53 accumulation was present in five of nine BRCA2 related ovarian cancers. CONCLUSIONS: In addition to germline BRCA1 and BRCA2 mutations, somatic p53 alterations leading to p53 accumulation are an important event in hereditary ovarian cancer and are as frequent as in non-BRCA-related ovarian cancer.

[Genetics of colorectal cancer. I. Non-polyposis and polyposis forms of hereditary colorectal cancer].

Abstract: About 5% of colorectal cancer cases are due to an autosomal dominant genetic predisposition with high penetrance. In this condition, the patient is carrier of a pathogenic gene mutation present in all body cells which can be transmitted to descendants, a so-called germ line mutation. The mutation is usually present in a tumour suppressor gene. Three subgroups of hereditary colorectal cancer can be distinguished on the basis of the clinical characteristics: (a) syndromes without polyposis (mostly hereditary non-polyposis colorectal carcinoma; HNPCC), (b) syndromes with adenomatous polyposis (mostly familial adenomatous polyposis; FAP) and (c) syndromes with hamartomatous polyposis. Recently, the main gene defects which underlie these syndromes were identified. Consequently, it is possible in approximately half the families with HNPCC or FAP in patients with colorectal cancer to demonstrate the causative gene defect and subsequently, by blood testing of healthy relatives to determine who is and is not a carrier of this hereditary condition. Thus, preventive measures can be directed toward family members with a demonstrable high risk of large bowel cancer.

Periodiek colonoscopisch onderzoek bij personen met een belaste familieanamnese voor colorectaal carcinoom

Abstract: Individuals with one first-degree relative with colorectal cancer diagnosed before age 45 years and those with two first-degree relatives with colorectal cancer run a significantly increased risk (relative risk: 4-6) of developing colorectal cancer. Based on calculation of the mortality due to colorectal cancer for the age group 50-70 years (which is higher than the mortality due to breast cancer) surveillance may be justified, e.g. by colonoscopy at 5-year intervals from the age of 45-50. The total number of people in the Netherlands in this high risk group is estimated at 10,000. The authors conclude that prospective studies are needed to assess the cost-effectiveness of such a programme.

Genetics of colorectal cancer. II. Hereditary background of sporadic and familial colorectal cancer

Abstract: About 15% of patients with colorectal cancer have a positive family history: 5% have hereditary colorectal cancer (hereditary non-polyposis colorectal carcinoma (HNPCC), familial adenomatous polyposis (FAP) or some other hereditary syndrome), while in 10% no clear hereditary pattern can be recognized ('familial colorectal cancer'). In sporadic and in familial intestinal cancer, a demonstrable hereditary predisposition may undoubtedly exist. HNPCC is often characterized by microsatellite instability, i.e. an increased number of short DNA sequences in the DNA indicating a disorder in DNA repair and a mutation in a DNA 'mismatch repair' (MMR) gene. Indicative of hereditary bowel cancer on the basis of such an MMR gene mutation are: (a) presence of bowel cancer in > or = 3 relatives, (b) early age at the time of the diagnosis of 'bowel cancer', (c) multiple primary bowel tumours, (d) uterine cancer in the family and (e) bowel and uterine cancer in a woman. Recent data demand a new subdivision of hereditary bowel cancer, based upon both the clinical picture and the results of DNA-tests. The genetic alterations in colonic adenomas and carcinomas are known to a large extent. In future these insights may be important in clinical practice, such as a more individual determination of the patient's prognosis and accordingly, of the treatment and follow-up.

Familial breast cancer: clinical services in The Netherlands.

Abstract: The incidence of breast cancer in the Netherlands ranks among the highest in Europe. In 1995 9476 new cases were diagnosed. Age at diagnosis was < 40 years for 584 (6.2%) patients. About 10–15% of cases report a positive family history [1]. An increasing number of patients and family members is referred for genetic counselling, on the basis of young age at diagnosis and/or a positive family history.