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A Borg

Publications and source records attributed to A Borg.

At least 109 records · Page 6Linked to original sources
PubMed1997

Amplification of cyclin D1 in squamous cell carcinoma of the head and neck and the prognostic value of chromosomal abnormalities and cyclin D1 overexpression.

BACKGROUND: Abnormalities of chromosome band 11q13 are frequent in squamous cell carcinoma of the head and neck (SCCHN). The oncogene CCND1 is located at 11q13 and encodes cyclin D1, a cell cycle-regulating protein. The authors investigated the clinical relevance and associations between amplification and overexpression of cyclin D1 and 11q13 rearrangements. METHODS: The study involved two series of patients. In Series 1, overexpression of cyclin D1 and 11q13 rearrangements, assessed by immunohistochemistry and cytogenetics, respectively, were compared with clinical data in 75 patients with SCCHN. Patients were monitored for at least 18 months or until death. In another 23 patients (Series 2), the authors investigated the association between DNA amplification (by slot blot hybridization), overexpression of cyclin D1, and cytogenetics. RESULTS: In Series 1, 9 of 75 tumors (12%) had 11q13 aberrations, 6 of which manifested elevated expression of cyclin D1. Patients with tumors strongly positive for cyclin D1 (n = 9) and those with tumors showing 11q13 rearrangements had poorer survival (P = 0.047 and 0.005, respectively). However, the correlation between these two variables was weak (P = 0.12). In Series 2, 17 of 23 tumors (74%) showed elevated cyclin D1 protein expression, and 6 of these showed gene amplification as well. Of these six, only one revealed 11q13 rearrangements. CONCLUSIONS: Overexpression of cyclin D1 and 11q13 rearrangements are independent prognostic factors for SCCHN. In general, DNA amplification results in overexpression of cyclin D1, but additional genetic mechanisms are involved in the deregulation. Furthermore, oncogenes at 11q13 besides CCND1 may be involved in the tumorigenesis.

Adult↗
PubMed1997

Identification of TP53 gene mutations in uterine corpus cancer with short follow-up.

The involvement of the TP53 tumor suppressor gene in uterine corpus cancer was investigated by single-stranded conformation polymorphism and sequence analysis of its exons 4 to 10. Mutations were found in 12 (18.5%) of 65 cases. Ten of these 12 were single-base substitutions (8 missense and 2 nonsense mutations), whereas 2 were frame-shifting mutations. TP53 gene mutations correlated significantly with advanced surgical stage of disease (P = 0.006) and unfavorable tumor histology types (P = 0.003), whereas the association to myometrial wall invasion did not reach statistical significance (P = 0.054). TP53 gene mutations also correlated significantly with allelic loss at TP53 locus (P = 0.024), absence of estrogen (P = 0.045) and progesterone receptors (P = 0.001), DNA nondiploidy (P = 0.002), and high S-phase fraction values (P = 0.002). Our results suggest that inactivation of the TP53 checkpoint function is associated with disease transition into a stage of rapid progression and spread.

Aged↗
PubMed1997

Tumour biological features of BRCA1-induced breast and ovarian cancer.

BRCA1 mutations, although implicated in disease predisposition in a major part of the hereditary breast cancer population, do not seem to be crucially involved in tumorigenesis of sporadic breast and ovarian cancers. This suggests that tumours arising in BRCA1 mutation carriers may differ from BRCA1 negative hereditary and sporadic cancer in genetic and biological features, as well as in clinical behaviour. Prior to BRCA1 analysis, 79 breast and 19 ovarian tumours from 57 breast and breast-ovarian cancer families, and 170 tumours from a comparison group of stage II breast cancers were studied with regard to histopathological features; immunohistochemistry [c-erbB-2, p53, oestrogen receptor (ER) and progesterone receptor (PR)], DNA flow cytometry and S-phase fraction. BRCA1 mutations were found in 40 breast and 15 ovarian tumours. The BRCA1 positive breast tumours were significantly more often of ductal type, histological grade III and manifested a heavy lymphocyte infiltration. Additionally, as compared to BRCA1 negative tumours, the BRCA1 positive tumours were significantly more often ER, PgR and c-erbB-2 negative. Furthermore, they were significantly more often DNA non-diploid, as well as being characterised by higher S-phase fraction values. These results suggest that BRCA1-induced breast cancers may manifest distinct tumour biological features of clinical importance.

Adult↗
PubMed1997

Correlation between p53 mutation and cyclin D1 amplification in had and neck squamous cell carcinoma.

Mutations in the p53 tumour suppressor gene and amplification of the cyclin D1 (CCND1) oncogene have been commonly reported in various malignancies. In the present study of 39 squamous cell carcinomas of the head and neck, p53 mutations were manifest in 11 (28%) of the cases, whereas CCND1 amplification was seen in 6 (16%) of 37 analysed tumours. The 10 mutations occurring in coding sequences of p53 were found in exon 5 (4 cases), exon 6 (3 cases),f and exon 8 (3 cases). No mutation was found in exon 7. Eight of the 10 exon nucleotide substitutions were missense mutations and two were nonsense mutations. All six tumours with CCND1 amplification also had p53 mutations, while an additional five tumours manifested p53 mutations in the absence of CCND1 amplification. There was a statistically significant positive correlation between these two gene alterations. This raises the possibility that mutation of p53 precedes CCND1 amplification in carcinogenesis.

Adult↗
PubMed1997

Reduced testosterone, 17 beta-oestradiol and sexual hormone binding globulin, and increased insulin-like growth factor-1 concentrations, in healthy nulligravid women aged 19-25 years who were first and/or second degree relatives to breast cancer patients.

Differences in hormonal and constitutional parameters between women with at least one first and/or second degree relative with breast cancer (RBC) and women without such affected relatives were studied in a group of healthy, nulligravid women aged 19-25 years. Present oral contraceptive (OC) users were analysed separately. In women not presently exposed to OCs we found significant correlations between RBC and reduced concentrations of testosterone during both the follicular (P < 0.001) and luteal menstrual cycle phases (P = 0.016). 17 beta-oestradiol was also significantly negatively correlated with RBC in the follicular (P = 0.044) and in the luteal phase (P = 0.027). RBC was significantly correlated with a lower waist/hip ratio (P = 0.044) compared with women without such a history. In multivariate analyses, the results for testosterone but not 17 beta-oestradiol remained significant. In these analyses high IGF-1 (P = 0.05) in the follicular phase and low sexual hormone-binding globulin (SHBG) (P = 0.04) in the luteal phase were also related to RBC. Including all 66 women in a multivariate model that analysed the specific effects from OCs and RBC on plasma testosterone showed that plasma testosterone was significantly lower among present OC users (P = 0.004) and in women with RBC (P = 0.005) during cycle days 5-10, with a significant positive two-way interaction between present OC use and RBC (P = 0.007). During cycle days 18-23 plasma testosterone showed a significant negative relationship with present OC use (P < 0.001) and RBC (P = 0.016) no significant interaction was seen during cycle days 18-23. Factors not significantly related to RBC were height, weight, breast size, age at menarche, p-progesterone and p-prolactin. It is concluded that a family history of breast cancer significantly lowered plasma testosterone concentrations in both cycle phases among healthy, nulligravid women compared with women without such history.

Adult↗
PubMed1997

Loss of heterozygosity at 7q31 in breast cancer: results from an International Collaborative Study Group. The Breast Cancer Somatic Genetics Consortium.

Loss of heterozygosity (LOH) at 7q31 has been claimed to occur in over 80% of all breast cancers and to be of prognostic significance. This would make this genetic alteration the most common event observed in breast cancer to date. Others, however, have been unable to confirm this high incidence. In this multicenter study, we have complied LOH scorings for three polymorphic markers for 7q31-q32 in 683 breast tumors. Although some significant differences between centers existed, no center reported more than 40% LOH, and the average rate was 19%. Disease-free and overall survival of the patients whose tumors carried LOH at 7q31 did not differ significantly from those patients whose tumors showed retention of heterozygosity at 7q31. In a double-blind scoring of a subset of the raw data, an average discordant rate of LOH scoring of 12% was observed. While startling in itself, this was unable to explain the variation among centers, nor the difference with the initially reported high rate of LOH. We conclude that LOH at 7q31 is not important as a genetic alteration in breast cancer as originally suggested, nor a strong determinant of disease outcome.

Breast Neoplasms↗
PubMed1997

Moderate frequency of BRCA1 and BRCA2 germ-line mutations in Scandinavian familial breast cancer.

Previous studies of high-risk breast cancer families have proposed that two major breast cancer-susceptibility genes, BRCA1 and BRCA2, may account for at least two-thirds of all hereditary breast cancer. We have screened index cases from 106 Scandinavian (mainly southern Swedish) breast cancer and breast-ovarian cancer families for germ-line mutations in all coding exons of the BRCA1 and BRCA2 genes, using the protein-truncation test, SSCP analysis, or direct sequencing. A total of 24 families exhibited 11 different BRCA1 mutations, whereas 11 different BRCA2 mutations were detected in 12 families, of which 3 contained cases of male breast cancer. One BRCA2 mutation, 4486delG, was found in two families of the present study and, in a separate study, also in breast tumors from three unrelated males with unknown family history, suggesting that at least one BRCA2 founder mutation exists in the Scandinavian population. We report 1 novel BRCA1 mutation, eight additional cases of 4 BRCA1 mutations described elsewhere, and 11 novel BRCA2 mutations (9 frameshift deletions and 2 nonsense mutations), of which all are predicted to cause premature truncation of the translated products. The relatively low frequency of BRCA1 and BRCA2 mutations in the present study could be explained by insufficient screening sensitivity to the location of mutations in uncharacterized regulatory regions, the analysis of phenocopies, or, most likely, within predisposed families, additional uncharacterized BRCA genes.

Adult↗
PubMed1996

The FHIT and PTPRG genes are deleted in benign proliferative breast disease associated with familial breast cancer and cytogenetic rearrangements of chromosome band 3p14.

We have used nested reverse transcription-PCR (RT-PCR) and PCR on genomic DNA to search for aberrations in the FHIT and PTPRG genes, both located in chromosomal band 3p14.2, in specimens from cytogenetically analyzed benign breast lesions (three samples with atypical hyperplasia and one with fibroadenosis) from two women belonging to breast cancer families. The transcription analysis showed that the FHIT gene was either not expressed or that its expression was dramatically reduced to a level not detectable by nested RT-PCR in the samples with atypical hyperplasia. Genomic analysis of exons 3 and 5 of FHIT and exon 12 of PTPRG provided evidence that these DNA segments were homozygously deleted in the majority of the cells. These data are in line with the histopathological features and cytogenetic findings in the three samples; none contained normal parenchyma, and all had chromosomal aberrations involving band 3p14. RT-PCR analysis of the fibroadenosis specimen, which had a normal karyotype, detected the expected 856-bp fragment as well as an additional alternative transcript variant of FHIT with 1014 bp. The additional 158-bp sequence, which may add 38 amino acids to the NH2-terminal part of the previously described FHIT protein, was inserted between exons 4 and 5 and seems to be a new exon located in intron 4 of FHIT.

Acid Anhydride Hydrolases↗
PubMed1996

High prevalence of the 999del5 mutation in icelandic breast and ovarian cancer patients.

Studies on Icelandic breast cancer families have shown that most of them segregate a 999del5 BRCA2 mutation. Here, we report the frequency of the 999del5 BRCA2 mutation in an Icelandic control population and four different groups of cancer patients diagnosed with (a) breast cancer; (b) ovarian cancer; (c) prostate cancer (patients younger than 65 years); and (d) other cancer types. The proportions of individuals carrying the mutation were 0.4% in the control population and in the patient groups 8.5%, 7.9%, 2.7%, and 1.0%, respectively. Our results indicate that BRCA2 confers a very high risk of breast cancer and is responsible for a substantial fraction of breast and ovarian cancer in Iceland, but only a small proportion of other cancers.

Adult↗
PubMed1996

A novel p53 germline alteration identified in a late onset breast cancer kindred.

Germline mutations in the p53 tumor suppressor gene are associated with the Li-Fraumeni syndrome, characterized by childhood sarcoma, leukemia and early onset breast cancer and has occasionally been found also in familial breast-ovarian cancer. Most mutations found are of missense type and located in the central region of the gene (exons 5 to 8). In the present study, a germline p53 alteration was identified in a late onset breast cancer family (kindred Lund 5; mean age 58 years) using single stranded conformation polymorphism and sequence analysis. The mutation (a CCG to CTG transition) at codon 82 in exon 4, resulting in a proline to leucine substitution, has not previously been reported and was not present in a control set of 60 healthy individuals. Three of five woman with breast cancer (45, 57 and 65 years) were carriers of the alteration. Loss of heterozygosity at the p53 locus was not seen in the primary tumors of these women, but appeared as a partial loss of the wildtype allele in subsequent recurrent lesions of two gene carriers. The family manifested no linkage to the p53 gene (a two-point LOD-score of -0.41), and has previously also been excluded for linkage to the BRCA1 and BRCA2 loci, as well as being carrier of a BRCA1 germline mutation. Although it seems unlikely that the p53 germline mutation is the major cause of disease predisposition in Lund 5, the data suggest that some p53 alteration may confer a subtle influence on breast cancer development and progression.

Aged↗
PubMed1996

Novel germline p16 mutation in familial malignant melanoma in southern Sweden.

The p16 (CDKN2/MTS1/INK4a) malignant melanoma susceptibility gene was analyzed in 10 melanoma kindreds from southern Sweden using single-stranded conformation polymorphism analysis of all three exons and flanking intron regions followed by sequence analysis. A novel germline mutation, constituting an in-frame 3-bp duplication at nucleotide 332 in exon 2, was identified in two families (Lund M2 and M9). The mutation results in an insertion of Arg at codon 105, which interrupts the last of the four ankyrin repeats of the p16 protein, motifs which have been demonstrated as important in binding and inhibiting the activity of cyclin D-dependent kinases 4 and 6 in cell cycle G1 phase regulation. All five tested individuals of Lund M2 and M9 affected by melanoma were mutation carriers, as were five melanoma-free individuals. Other malignancies observed in gene carriers or obligate carriers included cervical, breast, and pancreatic carcinomas and a non-Hodgkin's lymphoma. Analysis of microsatellite markers adjacent to the p16 gene at chromosomal region 9p21 revealed that both families share a common haplotype, in keeping with a common ancestor.

Carrier Proteins↗
PubMed1996

Chromosome aberrations in prophylactic mastectomies from women belonging to breast cancer families.

Short-term cultures of samples from eight prophylactic mastectomies from five unrelated women who were genetically predisposed to breast cancer were analyzed cytogenetically. Clonal chromosome abnormalities were detected in five breasts. Three samples from two women had aberrations involving the short arm of chromosome 3, with a breakpoint in 3p14 in common. Three samples from three women had rearrangements of 1q. Two of them, one of which also displayed a 3p14 rearrangement, shared a breakpoint in 1q41. Both 1q41 and, in particular, 3p14 have been reported to be rearranged frequently in malignant breast proliferations. Whether alterations of genes in these bands are essential in mammary tumorigenesis and, if so, whether they are equally important in sporadic and in hereditary cases remains to be explored.

Adult↗
PubMed1996

Urokinase plasminogen activator, a strong independent prognostic factor in breast cancer, analysed in steroid receptor cytosols with a luminometric immunoassay.

Urokinase plasminogen activator (uPA) is involved in the activation of different proteases which participate in the degradation of extracellular matrix, thereby enhancing the invasive capacity of tumour cells. uPA has been shown to be of prognostic importance in breast cancer. We have analysed uPA with a new luminometric immunoassay (LIA), applicable in cytosol samples routinely used for oestrogen-receptor (ER) and progesterone-receptor (PgR) analyses. At a cut-off value of 0.62 ng uPA/mg protein, 33% (230/688) samples were classified as representing high uPA tumours. High uPA content was found to be associated with shorter recurrence-free survival (median observation time: 42 months), ER and PgR negativity, increased p53 expression, DNA non-diploidy and a high S-phase fraction (SPF), but not with lymph node involvement or tumour size (< or = 20 mm versus > 20 mm). In the subgroup of patients not treated with systemic adjuvant therapy, multivariate analysis showed uPA to be an independent prognostic factor together with lymph node status and SPF. If these results can be reproduced, uPA may be a factor suitable for inclusion in a prognostic index.

Antineoplastic Agents, Hormonal↗
PubMed1996

Multiple splicing variants of the estrogen receptor are present in individual human breast tumors.

Transcript variants of the estrogen receptor (ER) were investigated in 109 primary breast tumors using reverse transcription-polymerase chain reaction (RT-PCR) and primers allowing analysis of each internal exon. A high incidence of different ER variants was observed, each individual tumor often manifesting multiple variants coexisting with corresponding wildtype (wt) ER. These variants, by sequence analysis confirmed to represent exon splicing deletions, included ER deltaE2 (found in 41% of the tumors examined), ER deltaE3 (74%), ER deltaE4 (72%), ER deltaE5 (66%), and ER deltaE7 (88%). No evidence of transcripts lacking exon 6 was found, although a ER deltaE5,7 variant manifesting simultaneous deletion of exons 5 and 7 was observed. The presence of specific ER variants was not significantly correlated to the status of ER and progesterone receptor (PgR) protein expression, as assessed by routine analysis, although a trend towards a higher incidence of ER deltaE3 and increased expression of ER deltaE7 in ER+/PgR- tumors was observed, suggesting a dominant inhibitory effect on normal ER function to be involved. Moreover, ER deltaE4 was more common in ER+ tumors, possibly due to a cytoplasmic sequestring of this variant lacking a nuclear localization sequence. The presence of ER variants was not associated to clinicopathological variables, and equally frequent in tumors from patients having recurred or remained recurrence-free during adjuvant tamoxifen therapy. In conclusion, although ER splicing variants are abundant in breast cancer, the present study provides no evidence for a direct role of these ER variants in tumor development and tamoxifen resistance. It remains possible, however, that minor cell clones within the tumor, undetected by analysis of tumor homogenates, displaying extreme difference in content of ER variants, could be selected for during therapy or metastasis.

Adult↗
PubMed1996

Allelic loss at chromosome 13q12-q13 is associated with poor prognosis in familial and sporadic breast cancer.

Loss of heterozygosity (LOH) was analysed in 84 primary tumours from sporadic, familial and hereditary breast cancer using five microsatellite markers spanning the chromosomal region 13q12-q13 which harbours the BRCA2 breast cancer susceptibility gene, and using one other marker located within the RBI tumour-suppressor gene at 13q14. LOH at the BRCA2 region was found in 34% and at RBI in 27% of the tumours. Selective LOH at BRCA2 occurred in 7% of the tumours, whereas selective LOH at RBI was observed in another 7%. Moreover, a few tumours demonstrated a restricted deletion pattern, suggesting the presence of additional tumour-suppressor genes both proximal and distal of BRCA2. LOH at BRCA2 was significantly correlated to high S-phase values, low oestrogen and progesterone receptor content and DNA non-diploidy. LOH at BRCA2 was also associated, albeit non-significantly, with large tumour size and the ductal and medullar histological types. No correlation was found with lymph node status, patient age or a family history of breast cancer. A highly significant and independent correlation existed between LOH at BRCA2 and early recurrence and death. LOH at RBI was not associated with the above mentioned factors or prognosis. The present study does not provide conclusive evidence that BRCA2 is the sole target for deletions at 13q12-q13 in breast tumours. However, the results suggest that inactivation of one or several tumour-suppressor genes in the 13q12-q13 region confer a strong tumour growth potential and poor prognosis in both familial and sporadic breast cancer.

Adult↗
PubMed1996

Successful treatment of HTLV-1-associated acute adult T-cell leukaemia lymphoma by allogeneic bone marrow transplantation.

HTLV-1-associated acute adult T-cell leukaemia-lymphoma (ATL) is a highly aggressive malignant disorder with a median survival of 6 months or less. We describe an Afro-Caribbean female with very poor prognosis ATL who underwent chemotherapy with a 4 d infusion schedule of cyclophosphamide, doxorubicin and etoposide, followed by successful allogeneic bone marrow transplantation (BMT) from her HTLV-1-negative histocompatible sister. The patient remains in complete remission 23 months after BMT and has 100% donor haemopoiesis with no evidence of HTLV-1 infection on PCR testing. We suggest that allo-BMT can prolong disease free survival or may even be curative in HTLV patients.

Adult↗