Biomedical subjects

D K Bartsch

Publications and source records attributed to D K Bartsch.

25 records · Page 2Linked to original sources

PubMed2001

A novel insulinoma tumor suppressor gene locus on chromosome 22q with potential prognostic implications.

The molecular mechanisms contributing to the tumorigenesis of insulinomas are still poorly understood. As moderate to high rates of LOH have been found on chromosome 22q in gastrinomas, we performed a finer deletion mapping study of chromosome 22q with 8 microsatellite markers in 15 insulinomas (4 malignant and 11 benign). Fourteen of 15 (93%) insulinomas revealed LOH on chromosome 22q, whereas the shortest region of overlap implicated a deletion of approximately 700 kb at 22q12.1-q12.2 with an LOH rate of up to 57% (8 of 14). Although the expressed sequence tag marker A006E25 that is localized in the hSNF5/INI1 gene on 22q11.2 revealed LOH in 50% of informative cases (7 of 14), no alterations in this gene could be identified by single strand conformational polymorphism analysis, direct DNA sequencing, or RNA expression analysis. Remarkably, the four malignant tumors showed a common deleted region between markers D22S345 and D22S1144 compared with none of the 11 benign insulinomas. The observed high frequency of chromosome 22q12 deletions in insulinomas is suggestive for a region compatible with harboring a tumor suppressor gene. The hSNF5/INI1 gene is most likely not the candidate gene, because no alterations could be identified. The distinct pattern of allelic loss identified in this chromosomal region appears to be an attractive candidate marker for further evaluation with regard to the discrimination between benign and malignant insulinomas.

Adult↗

PubMed2000

Management of nonfunctioning islet cell carcinomas.

Tumors arising from the pancreatic islet cells are rare and represent a heterogeneous group of benign or malignant lesions. Most tumors present with well characterized syndromes, whereas others appear to be nonfunctioning. The clinical features of 11 men and 7 women with nonfunctioning islet cell carcinomas operated on between 1983 and 1998 were reviewed. The median patient age was 53.5 years (range 26-74 years). The most frequent presenting symptoms were abdominal pain (13 patients), weight loss (7 patients), and obstructive jaundice (4 patients). Gut hormone profiles were normal in all patients. Abdominal sonography and computed tomography localized the tumor in 17 patients, and correct prediction of an endocrine tumor was achieved in 12 patients. Six of seven patients showed a hypervascular tumor upon angiography, and seven of eight patients preoperatively had positive somatostatin receptor scintigraphy. At operation, regional or distant metastases were present in 15 (83%) and 6 (33%) patients, respectively. Eleven patients underwent potentially curative resections, and the remaining seven patients were managed palliatively by resection (four patients) or bypass procedures (three patients). Three patients had up to three more resection for metastases. Eight patients received postoperative octreotide, interferon alpha therapy, or both. The overall cumulative 5- and 10-year survival rates were 65.4% and 49.1%, respectively. Of the 11 patients who underwent curative resection, 10 were alive after a median follow-up of 63 months (range 7-180 months), but only 5 are free from disease. Although surgical cure is rare in nonfunctioning islet cell carcinomas, significant long-term palliation can be achieved in a large proportion of patients with an aggressive surgical approach and, when indicated, additional medical therapy.

Adult↗

PubMed2000

A RET double mutation in the germline of a kindred with FMTC.

Activating germline mutations of the RET proto-oncogene are found in more than 90% of families with multiple endocrine neoplasia type 2a (MEN 2a) and familial medullary thyroid carcinoma (FMTC). The majority of patients with these hereditary tumors carry germline mutations that result in the substitution of one of five cysteine residues in exon 10 and 11. Different mutations in exons 13, 14 and 15 affecting non-cysteine residues have also been described but are considered to be rare. We now for the first time report a double mutation of the RET proto-oncogene occurring in the germline of a kindred with FMTC. Both mutations occur within the tyrosine kinase domain in exon 14 and lead to the substitution of valine 804 by methionine and arginine 844 by leucine. Since the double mutated allele cosegregated with the disease and was not identified in 200 unrelated normal probands, we conclude that they represent mutations that predispose the individual to the development of FMTC with a mild phenotype.

Adolescent↗

PubMed2000

Pancreaticoduodenal endocrine tumors in multiple endocrine neoplasia type 1: surgery or surveillance?

BACKGROUND: The management of pancreaticoduodenal endocrine tumors (PETs) remains controversial in multiple endocrine neoplasia type 1 (MEN 1). METHODS: Twenty-one patients with MEN 1 and PETs were analyzed for outcome of surgery and surveillance with special regard to the genotype based on MEN1 gene mutation analysis. RESULTS: Nine patients had gastrinomas, 5 had nonfunctioning tumors, 4 had insulinomas, 2 had insulinomas and gastrinomas, and 1 had a VIPoma. Seven patients (33%) had malignant tumors. Sixteen patients (76%) were initially treated by pancreatic resections or tumor enucleations or both. Six patients underwent reoperations for recurrences or lymph node metastases or both. Fifteen of the 16 operated patients are alive, and 12 have no evidence of disease after a median follow-up of 78 months (range, 1-198 months). Five patients with gastrinomas or nonfunctioning tumors, but no symptoms, underwent surveillance; 1 of them developed lymph node metastases. Patients with truncating mutations in the N- or C-terminal region (exons 2, 9, or 10) of the MEN1 gene had a significantly higher rate of malignant tumors (55% vs 10%; P <.05) than patients with other mutations. CONCLUSIONS: An aggressive surgical approach is justified for PETs in patients with MEN 1. However, MEN1 gene mutations in exons 3 to 8 seem to be associated with mild behavior of PETs, possibly allowing surveillance in asymptomatic patients.

Adult↗

PubMed2000

Multiple primaries in pancreatic cancer patients: indicator of a genetic predisposition?

BACKGROUND: The genetic basis of several familial cancers including breast and colon cancers has been identified recently. The occurrence of multiple cancers in one individual is also suggestive of a genetic predisposition. To evaluate inherited predisposition in pancreatic cancer we compared the clinical data of pancreatic cancer patients with and without multiple primaries as well as the frequency of malignancies among their relatives. METHODS: Detailed data on 69 pancreatic cancer patients included survival time and TNM-classification. Index case data were separated into two groups. The first group (group 1) developed only pancreatic cancer during their lifetime, whereas the second group (group 2) developed additional primary tumours. A systematic family history was taken from 59 of these pancreatic cancer patients using a standardized questionnaire. The pancreatic cancers and the multiple primaries of the 59 patients were histologically proven. RESULTS: Of the 69 pancreatic cancer patients, 13 (18.8%) had multiple primaries. Neither the clinical data nor the survival data of the index cases revealed differences between the two groups (all nominal P-values >0.05). In the family history study blood relatives developed a malignancy in 51% (24 of 47) of the families in group 1 compared to 75% (9 of 12) in group 2. The risk of relatives in group 2 of developing a malignant tumour was significantly higher (P = 0.034) than in group 1 after adjustments for family size and age of disease onset of the index case. The cancer spectrum of the 59 families mainly included tumours of the digestive tract and the reproductive organs. CONCLUSIONS: A multiple primary cancer history is a common condition among pancreatic cancer patients. Relatives of these patients seem to have an increased risk for the development of distinct malignant solid tumours, which might be caused by an inherited predisposition. Clinical and genetic investigation of pancreatic cancer patients with multiple primaries and their families might lead to the identification of predisposing gene defects providing a new goal for the understanding of a shared genetic basis of different solid tumours.

Aged↗

PubMed2000

Multiple primary tumors as an indicator for p16INK4a germline mutations in pancreatic cancer patients?

Multiple primary tumors in pancreatic cancer patients might indicate a genetic predisposition to the development of malignancies. In this study we evaluated whether the mutation rate of the TP53 and p16INK4a genes of pancreatic cancers differs in pancreatic cancer patients with and without multiple primaries. Furthermore, we investigated whether pancreatic cancer patients with multiple primaries carry germline mutations in either p16INK4a, TP53, or BRCA2 tumor suppressor genes to detect a genetic alteration that predisposes to the development of different primaries. Fourteen (23%) of 60 pancreatic cancer patients developed histologically verified additional primaries during their lifetimes. Normal constitutional and tumor DNA of the 14 patients with a positive cancer history, but negative family history, were analyzed for p16INK4a, TP53, and BRCA2 mutations by single-strand conformational variant (SSCV) analysis and direct sequencing. Hypermethylation of the p16INK4a promoter region in pancreatic cancers was identified by methylation-specific polymerase chain reaction (PCR; MSP). Four of 14 pancreatic carcinomas carried somatic intragenic p16INK4a mutations, and another four tumors revealed hypermethylation of the p16INK4a promoter region. Somatic intragenic TP53 mutations were identified in six of 14 tumors. None of the pancreatic cancer patients carried TP53 or BRCA2 germline mutations. In contrast, one of 14 pancreatic cancer patients with multiple primaries carried the p16INK4a mutation A68V in his germline. This mutation was localized in the conserved second ankyrin repeat of p16INK4a and did not occur in 100 control patients. The frequency of somatic TP53 and p16INK4a mutations in pancreatic cancer is similar in patients with and without multiple primaries. TP53 and BRCA2 germline mutations seem not to be significantly associated with the occurrence of multiple primaries in pancreatic cancer patients. However, p16INK4a germline mutations might be causative for tumor development in some pancreatic cancer patients with multiple primaries. The genetic investigation of patients with accumulation of different cancers even without a positive family history may be a new approach for the understanding of the relation of different cancers.

Adult↗

PubMed2000

Low frequency of p16(INK4a) alterations in insulinomas.

BACKGROUND/AIMS: The molecular mechanisms contributing to the tumorigenesis of insulinomas are poorly understood. Disruption of the cell cycle due to inactivation of the p16(INK4a) tumor-suppressor gene was identified in a variety of human tumors, including gastrinomas and nonfunctioning endocrine pancreatic carcinomas. In this study the role of p16(INK4a) in the tumorigenesis of insulinomas was evaluated. METHODS: Seventeen insulinomas (14 benign, 3 malignant) were analyzed for genetic alterations in the p16(INK4a) tumor-suppressor gene by SSCP, PCR-based deletion and methylation-specific assays. p16 expression was determined by immunohistochemistry. RESULTS: One malignant insulinoma showed a homozygous deletion of p16(INK4a) and another two benign insulinomas revealed aberrant methylation of the p16(INK4a) promoter region. All three tumors lacked p16 expression according to immunohistochemistry. None of the insulinomas carried intragenic p16(INK4a) mutations. In total, 17% of insulinomas had p16(INK4a) alterations. CONCLUSIONS: The p16(INK4a) tumor-suppressor gene contributes to tumorigenesis in only a small subset of insulinomas.

Cell Cycle↗