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Biomedical subjects

M Nilbert

Publications and source records attributed to M Nilbert.

At least 19 recordsLinked to original sources
PubMed2006

Increased risk of malignancies in a population-based study of 818 soft-tissue sarcoma patients.

Soft-tissue sarcomas (STS) have been associated with various rare cancer syndromes and occur at increased frequencies in survivors of childhood cancer. Also adult patients with STS have been suggested to be at an increased risk of additional malignancies. After exclusion of syndrome-associated and radiation-induced sarcomas, we studied multiple primary malignancies in a population-based cohort of 818 patients with primary STS of the extremities and the trunk wall. In total, 203 other malignancies developed in 164 (20%) patients median 10 (0-32) years before and median 4 (0-35) years after the sarcoma diagnosis. Standardised morbidity ratios (SMRs) were determined for primary malignancies following a STS. Hereby individuals who had developed a STS were identified to be at increased risk of second primary malignancies (SMR for all malignant tumours=1.3; 95% CI=1.0-1.5; P=0.02) with STS being the only specific tumour type that occurred at an increased risk (SMR=17.6; 95% CI=8.1-33.5; P<0.001). Hence, this population-based series demonstrates a high frequency of second primary tumours among STS patients and indicates a particularly increased risk of developing a new STS.

Adolescent↗
PubMed2004

One in 10 ovarian cancer patients carry germ line BRCA1 or BRCA2 mutations: results of a prospective study in Southern Sweden.

At least 10% of all ovarian cancers are estimated to have a hereditary background. Hereditary breast-ovarian cancer (HBOC) due to mutations in the BRCA genes is a major cause of hereditary ovarian cancer, although its frequency and relationship to age and family history in unselected series of ovarian cancers is not completely known. We report here the results of a full mutational screening analysis for germ line BRCA1 and BRCA2 mutations in 161 patients with invasive epithelial ovarian carcinomas. Age at diagnosis ranged from 22 to 82 years (mean 59 years). Deleterious (frame-shift, nonsense and missense) mutations were detected in 13/161 (8%) of the patients and affected BRCA1 in 12 cases and BRCA2 in one case. Four additional missense variants (one in BRCA1 and three in BRCA2) with a possible association with an increased risk ovarian cancer were revealed, resulting in a total frequency of BRCA gene alterations of 17/161 (11%). The 13 patients with deleterious mutations had a mean age of 57 years (range 41-76 years) and only three of these patients were below 50 years of age. A family history of at least one breast cancer and/or ovarian cancer was reported in all but 1 of the patients with BRCA mutations compared with only 24% of patients without mutations. Our findings in this prospective study confirm approximately 1 in 10 patients with ovarian cancer carry a germ line BRCA gene mutation associated with HBOC, and also indicate that a large number of these patients are over 50 years of age at diagnosis.

Adult↗
PubMed2004

Association between preoperative plasma levels of tissue inhibitor of metalloproteinases 1 and rectal cancer patient survival. a validation study.

The level of the tissue inhibitor of metalloproteinases 1 (TIMP-1) has previously been demonstrated to predict the survival of early stage colorectal cancer patients. The present study was undertaken to further validate plasma TIMP-1 as a prognostic marker in rectal cancer. Preoperative plasma from 352 rectal cancer patients were analysed using an immunoassay for TIMP-1. The TIMP-1 immunoassay demonstrated robustness and good reproducibility with low interassay coefficients of variation (CV). The rectal cancer patients had a mean plasma TIMP-1 level of 184 microg/l (standard deviation (SD): 70 microg/l). There were no significant differences in TIMP-1 levels between patients with Dukes' stage A, B or C disease, whereas Dukes' stage D patients had significantly increased TIMP-1 levels (P<0.0001); however, high levels of TIMP-1 were not restricted to those with advanced disease. Univariate analysis demonstrated an increasing risk of mortality with increasing TIMP-1 levels Hazard Ratio (HR)=2.9; 95% Confidence Interval (CI): 1.7-5.0; P<0.0001). Including additional covariates, multivariate analysis identified plasma TIMP-1 as an independent prognostic marker (HR=2.2; 95% CI: 1.2-4.1 (P=0.01). This study showed a highly significant and independent association between preoperative plasma TIMP-1 levels and survival in rectal cancer patients, thus confirming our previous findings. Furthermore, the TIMP-1 immunoassay proved to be stable and reproducible in this confirmatory study.

Adult↗
PubMed2004

Experiences from tissue microarray in soft tissue sarcomas.

The tissue microarray (TMA) technology was introduced in 1998 as a tissue preserving, high-throughput technique that allows studies of multiple markers in large sample sets. TMA slides can be analyzed using techniques such as immunohistochemistry and in situ hybridization and represents a powerful tool for the investigation of potential diagnostic and prognostic markers identified in DNA microarray studies. We review the TMA method, its reproducibility, advantages, limitations and future perspectives with specific focus on soft tissue sarcomas.

Biomarkers, Tumor↗
PubMed2004

Lessons from genetic profiling in soft tissue sarcomas.

Soft tissue sarcomas represent a heterogeneous group of tumors and include over 50 histotypes. Some of these tumor types are characterized by specific chromosomal translocations, whereas other types show complex genetic aberrations. The recent developments within gene expression technologies have now been applied to studies of soft tissue sarcomas (STS) and the first results indicate that genetic signatures are useful for classification and diagnosis. Distinctive expression profiles have been found in e.g. gastrointestinal stromal tumors (GISTs), synovial sarcomas, malignant peripheral nerve sheath tumors (MPNSTs), and in subsets of liposarcomas. The more pleomorphic tumor types, such as high-grade variants of leiomyosarcomas, malignant fibrous histiocytomas (MFHs), fibrosarcomas, and subtypes of liposarcomas, show a greater variability among the expression profiles, but interestingly subsets with distinctive expression profiles can be identified also among these tumors. The data available place many of the genes hypothesized to be involved in the development of a certain type of STS, such as the KIT gene in GIST development, among the top discriminating genes. Thereby expression profiling provides novel insights into the pathogenesis of STS. Although much work remains to be done to validate the data and to define optimal discriminating gene lists, the current lessons from gene expression studies in STS are encouraging and imply that genetic signatures may serve as diagnostic and prognostic markers and may help identify novel therapeutic strategies.

Chromosome Aberrations↗
PubMed2004

Familial risk of tumors associated with hereditary non-polyposis colorectal cancer: a Swedish population-based study.

BACKGROUND: Familial clustering, which may be due to inherited predisposition, is seen in several common cancer types. The aim of this study was to assess the familial risk of tumors that are associated with hereditary non-polyposis colorectal cancer (HNPCC), a familial cancer syndrome that confers an increased risk of several cancer types, and is associated with a low age at onset. METHODS: The National Swedish Cancer Registry and population registers were utilized to identify all tumors among the offspring of individuals who had developed any of the diagnoses included in the Amsterdam II criteria for HNPCC. In all, 204,358 offspring of 102,814 individuals with cancer of the colorectum, endometrium, upper urinary tract or small intestine were identified. RESULTS: Significantly increased risks for several tumor types were demonstrated. If the parent was below age 50 at diagnosis, the offspring Standard Incidence Ratios (SIRs) were 3.6 for colon cancer, 3.8 for rectal cancer, 2.8 for gastric cancer, and 2.3 for ovarian cancer. Offspring who had both a parent and a sibling with HNPCC-associated cancer showed even higher SIRs for cancer of the colorectum, endometrium, ovary, and urinary tract. The highest values were observed in the subgroup whose parent had developed multiple primary tumors; SIR 34.0 for colon cancer, 17.9 for rectal cancer, 21.8 for endometrial cancer, and 5.8 for ovarian cancer. CONCLUSIONS: The study demonstrates that there is an increased risk for several tumor types among individuals whose parents developed HNPCC-associated tumors, where a young age at diagnosis and development of multiple tumors in the parents lead to the highest SIRs.

Adult↗
PubMed2003

Defective mismatch-repair in patients with multiple primary tumours including colorectal cancer.

Individuals with an inherited predisposition to cancer development are at an increased risk of developing multiple tumours. Hereditary non-polyposis colorectal cancer (HNPCC) is one of the most common hereditary cancer syndromes and is estimated to account for approximately 2% of colorectal cancers. However, HNPCC individuals are at an increased risk of developing other tumour types such as cancers of the endometrium, urothelium and small intestine. We have utilised a population-based regional cancer registry to identify all patients with double primary colorectal cancers and at least one additional malignancy and characterised the tumour spectrum in this patient group. We subsequently selected those 47 individuals who had developed at least four malignancies, including two colorectal cancers, for studies of the tumour characteristics associated with HNPCC. In total, these individuals developed 209 tumours, 156 of which were successfully retrieved. Microsatellite instability (MSI), a phenomenon caused by defective mismatch-repair (MMR), was identified in 63/154 (41%) evaluable tumours with a MSI-high pattern in 59 and a MSI-low pattern in four tumours. All tumours were immunohistochemically stained for the MMR proteins MLH1 and MSH2, with loss of expression in 55/63 (87%) MSI tumours and in 2/89 (2%) microsatellite stable (MSS) tumours. This loss affected MLH1 in 24 tumours and MSH2 in 33 tumours. A concordant loss of expression for the same MMR protein in several tumours from the same individual, a pattern that strongly suggests an underlying germline MMR gene mutation, was found in 17/45 (38%) patients and affected MLH1 in 8 patients and MSH2 in 9 patients. We conclude that the development of multiple primary tumours, including synchronous or metachronous colorectal cancers, is associated with an increased frequency of MSI and loss of immunohistochemical expression of MLH1 and MSH2.

Adult↗
PubMed2001

Beta-catenin activation through mutation is rare in rectal cancer.

Increased transcriptional activation through beta-catenin stabilization plays a central role in colorectal tumorigenesis. Alterations of phosphorylation sites within the CTNNB1 gene, which codes for beta-catenin has been reported to occur in about one-half of colorectal tumors without APC-gene mutations. We assessed the importance of mutations in the regulatory domain, located within exon 3 of CTNNB1, in 103 rectal carcinomas and correlated these data with presence of microsatellite instability, somatic frame-shift alterations of the TCF-4 gene, and APC-gene mutations in the tumors. No mutation was detected in exon 3 of the CTNNB1 gene and our results thus demonstrate that beta-catenin activation through mutation rarely contributes to the development of sporadic and microsatellite instability stable rectal cancer.

Adenocarcinoma↗
PubMed2001

Prognostic importance of the soluble plasminogen activator receptor, suPAR, in plasma from rectal cancer patients.

Colorectal cancer is one of the most common tumour types with approximately one third of the tumours located within the rectum. Rectal cancer differs somewhat from colon cancer, e.g. regarding the method of operation and the use of preoperative radiotherapy due to a tendency for local tumour recurrence. Proteolytic enzymes have been identified as key molecules in tumour invasion and metastasis, and factors within the urokinase-plasminogen activation (uPA) system have been associated with prognosis in several tumour types, including colorectal cancer. Recently, methods have been developed to analyse the soluble fraction of the plasminogen activator receptor (suPAR) in blood samples. An association between elevated suPAR levels and poor prognosis has recently been demonstrated in colorectal cancer. We have measured suPAR levels in pretreatment plasma samples from 173 rectal cancer patients in order to confirm its prognostic strength in this clinical entity. suPAR levels were determined in ethylenediamine tetraacetic acid (EDTA) plasma by a kinetic enzyme-linked immunosorbent assay (ELISA) and analysed with respect to sex, age, Dukes' stage, tumour differentiation grade and survival. In a univariate analysis, continuous suPAR plasma levels were associated with survival (P<0.001) with shorter survival among patients with high suPAR values. Patients with suPAR values within the upper quartile had significantly shorter survival (hazard ratio (HR) 2.2, 95% confidence interval (CI) 1.3-43.7, P=0.002). In a multivariate Cox analysis, increasing suPAR values predicted shorter survival independent from Dukes' stage and tumour differentiation grade with an adjusted HR of 2.2 per ng/ml suPAR (95% CI 1.2-4.0, P=0.01). This study thus confirms that measurement of suPAR in preoperative plasma samples gives independent prognostic information in rectal cancer patients, higher values being associated with shorter survival.

Adult↗
PubMed2001

Tissue microarray technique in soft tissue sarcoma: immunohistochemical Ki-67 expression in malignant fibrous histiocytoma.

Malignant fibrous histiocytoma (MFH) represents a heterogeneous soft tissue sarcoma entity. The authors compared different methods to determine immunohistochemical staining in whole tissue sections, evaluated the tissue microarray technique, and assessed immunohistochemical heterogeneity using the proliferation marker Ki-67 in 47 histopathologic tumor blocks from 11 MFHs. Whole tissue sections were assessed counting 400 cells along a line and counting all cells in 10 high-power fields (0.16 mm2) with mean Ki-67 expression levels of 13% and 11%, respectively. For the tissue microarray technique, two to three 0.6-mm diameter biopsies were studied from each of the 47 tumor blocks. Good correlation was obtained between whole tissue immunohistochemistry and tissue microarray with the microarray method, giving on average 8.6% greater Ki-67 expression levels than the reference method. Immunohistochemical tumor heterogeneity, evaluated using the high-power field method, showed a median standard deviation of 2.3% within the tumor blocks and 2.5% between the blocks from the same tumor. The authors concluded that the tissue microarray technique yields good quality staining and expression levels for Ki-67 comparable with whole tissue methods in MFH, but because of tumor heterogeneity, several tumor blocks ideally should be studied and, because of loss of material in the microarray process, multiple biopsies should be taken. The feasibility of tissue microarray for immunohistochemical studies of soft tissue sarcomas offers new possibilities to study multiple markers in large tumor materials.

Aged↗
PubMed2000

Somatic frameshift alterations in mononucleotide repeat-containing genes in different tumor types from an HNPCC family with germline MSH2 mutation.

Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by a germline mutation in one of several DNA repair genes, which in the tumors is reflected as microsatellite instability (MSI). MSI+ tumors have been found to carry somatic frameshift mutations in mononucleotide repeats within the coding regions of several genes involved in growth control, apoptosis, and DNA repair, e.g., TGFBRII, BAX, IGFIIR, TCF4, MSH3, and MSH6. We have studied the occurrence of somatic frameshift alterations in these mononucleotide repeat-containing genes in 24 tumors (15 colorectal cancers, 1 colon adenoma, 4 endometrial cancers, 1 ovarian cancer, 1 gastric cancer, 1 urothelial cancer, and 1 duodenal cancer) from 14 individuals in an HNPCC family with germline hMSH2 mutation. Such somatic frameshift mutations occurred at a variable frequency; the long mononucleotide repeats that characterize intronic MSI markers were mutated in the majority of tumors, 13 of the tumors displayed alterations in the (A)(10) tract of TGFBII, eight tumors (all of gastrointestinal origin) had alterations in the (A)(9) repeat of TCF4, and one to five tumors had somatic frameshift alterations in the shorter mononucleotide repeats of IGFIIR, BAX, MSH3, and MSH6. Thus, longer mononucleotide repeats were more frequently affected by somatic frameshift mutations. The pattern of alterations varied between the tumors from different family members as well as between different tumors from the same individual. To what extent this variable pattern depends on the widespread mismatch repair deficiency induced by the underlying MSH2 mutation, or represents alternative ways whereby the tumors can achieve a tumorigenic phenotype, is unknown. We suggest, however, that the accumulation of somatic frameshifts, rather than the specific loci in which these occur, drives the development of the tumorigenic phenotype in HNPCC.

Aged↗
PubMed2000

Lack of activating c-SRC mutations at codon 531 in rectal cancer.

Cellular SRC (c-SRC), which is the human homolog of the Rous sarcoma viral oncogene, v-src, is highly activated in colorectal cancer. Recently, a subset of colon cancers have shown a nonsense mutation at codon 531, which truncates c-SRC directly C-terminal to the c-SRC kinase regulatory domain. This specific mutation has been demonstrated to be activating, transforming, and tumorigenic and to promote metastasis. We investigated 100 rectal cancers, half of which had tumor spread outside the rectum, for this mutation by using direct sequencing. None of these tumors displayed any genetic alteration at this locus, and we thus conclude that the codon 531 mutation is a rare cause of c-SRC activation in rectal cancer.

Adenocarcinoma↗
PubMed2000

Involvement of adenomatous polyposis coli (APC)/beta-catenin signalling in human breast cancer.

We studied the relevance of adenomatous polyposis coli (APC)/beta-catenin signalling in the development of breast cancer by analysing the expression of beta-catenin in 54 primary breast tumours (34 ductal and 20 lobular). We showed that 13% of the tumours exhibited upregulated levels of beta-catenin in the cytosol suggesting that defects in APC/beta-catenin signalling components had lowered the rate of beta-catenin degradation. No mutations were observed in the amino-terminal region of beta-catenin, which comprises conserved serine residues important for phosphorylation-dependent degradation of the protein, but the APC protein was altered in 6% of the tumours. Tyrosine phosphorylation of beta-catenin was detected in only one tumour and could, therefore, not have been responsible for the observed increased levels of this protein. Although 9% of the tumours displayed upregulation of c-MYC protein, there was no correlation with beta-catenin overexpression, suggesting that increased beta-catenin expression is not the major cause of c-myc gene activation in breast cancer. It is imperative that elements that selectively drive the oncogenic activity of beta-catenin in breast cancer be identified.

Adenomatous Polyposis Coli Protein↗
PubMed2000

Novel germline APC mutations in Swedish patients with familial adenomatous polyposis and Gardner syndrome.

BACKGROUND: Familial adenomatous polyposis (FAP) is a familial cancer syndrome in which affected individuals develop multiple adenomatous polyps and are thereby at greatly increased risk of developing colorectal cancer. Gardner syndrome is a variant of FAP, in which the patients also develop extraintestinal tumors, in particular osteomas and desmoid tumors. An attenuated form of the disease (AFAP) is associated with fewer polyps, but still a high risk for colorectal cancer. Germline mutations in the adenomatosis polyposis coli (APC) gene cause FAP and Gardner syndrome and have recently been associated also with the development of AFAP. METHODS: We have analysed the entire APC gene for germline mutations in 7 patients with FAP and in 6 patients with suspected AFAP. Mutation screening was performed by direct sequencing of exons 1-14 and using the protein truncation test for analysis of exon 15. RESULTS: Novel disease-causing germline mutations, all of which resulted in truncation of the APC protein, were identified in 6 of the 7 patients with FAP or Gardner syndrome. No APC mutation was detected in any of the 6 patients with suspected AFAP. CONCLUSIONS: This study reports novel FAP- and Gardner syndrome-causing mutations in the APC gene. The lack of APC mutations in patients with multiple polyps at young age indicates that other genetic defects may cause this phenotype.

Adenomatous Polyposis Coli↗
PubMed1999

hMLH1, hMSH2 and hMSH6 mutations in hereditary non-polyposis colorectal cancer families from southern Sweden.

We have screened 17 Southern Sweden individuals/families with suspected hereditary non-polyposis colorectal cancer (HNPCC) for mutations in the DNA-mismatch repair genes hMLH1, hMSH2 and hMSH6 using denaturing gradient gel electrophoresis, protein truncation test and direct DNA sequencing. The families were selected on the basis of a family history of HNPCC-related tumors or the occurrence of metachronous colorectal cancer/endometrial cancer at young age in an individual with a weak family history of cancer. Furthermore, we required that tumor tissue from at least one individual in the family had to display microsatellite instability. We identified germ-line mutations in 9 individuals from 8 families. Five families had mutations in hMLH1, 4 of which were splice site mutations, 2 had frameshift mutations in hMSH2 and 1 patient with metachronous endometrial and rectal cancer but with a weak family history of cancer had a nonsense mutation in hMSH6. Our results present novel germ-line DNA-repair gene mutations, one of these in hMSH6, and demonstrate the diversified mutation spectrum in Sweden, where no founder mutation has so far been identified.

Adaptor Proteins, Signal Transducing↗
PubMed1999

A somatic BRCA2 mutation in RER+ endometrial carcinomas that specifically deletes the amino-terminal transactivation domain.

Mismatch repair deficiency and replication errors (RERs) occur in approximately 20% of sporadic endometrial carcinomas. Frameshift mutations in several cancer predisposing genes, especially in their mononucleotide repeats, are seen in RER+ tumors. In a survey of hereditary breast cancer genes in gynecological cancer, we analyzed the entire coding sequence of BRCA1 and BRCA2 in 51 endometrial tumors, of which 12 were RER+. Seven somatic mutations were identified in six (50%) of the RER+ tumors, but none in RER- tumors. A novel base pair deletion at a (T)10 tract in BRCA2 intron 2, causing an in-frame splice deletion of exon 3, was observed in four tumors, one of which contained a second, truncating BRCA2 mutation. Two tumors exhibited frameshift mutations at polyA tracts in BRCA1 and BRCA2 exon 11, both predicted to result in premature translation termination. Whereas most mutations in BRCA1 and BRCA2 are known to affect the more carboxy-terminal regions interacting with RAD51, and the transactivating BRCT domains of BRCA1, this is the first demonstration of a recurrent BRCA2 mutation that specifically deletes the amino-terminal transactivation domain. Moreover, our results suggest that somatic mutations in BRCA2(and to some extent BRCA1) may confer a growth advantage in RER+ endometrial carcinomas.

BRCA1 Protein↗
PubMed1999

Microsatellite instability is rare in rectal carcinomas and signifies hereditary cancer.

We analysed microsatellite instability (MSI) in a consecutive series of 165 rectal carcinomas. Data on a personal and/or family history of cancer were collected from all patients and revealed metachronous cancer in 9 patients, 2 of whom had developed colorectal cancer, and a suspected familial aggregation of colorectal cancer in three families. Only three of the 165 (2%) rectal cancers showed MSI. The patients whose tumours displayed MSI had clinical histories suggesting hereditary cancer--a family history of colorectal cancer and/or synchronous colorectal cancers. Denaturing gradient gel (DGGE) analysis was used to screen the MSI+ patients for mutations in the hMLH1 and hMSH2 genes and revealed two new germline mutations; a 1 bp deletion in exon 10 of hMSH2 creating a premature stop-codon and a splice donor site mutation in intron 16 of hMLH1. Considering colorectal carcinomas as a group, MSI has been reported to occur in approximately 10-20% of the tumours and thus can not, per se be used for clinical detection of hereditary tumours. This study shows, however, that MSI is rare in rectal carcinomas and when present strongly suggests a hereditary predisposition for colorectal cancer development.

Adaptor Proteins, Signal Transducing↗