[The first breast cancer gene isolated. Safer risk assessment for affected families].
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Breast Implants↗
Biomedical subjects
A Lindblom
Publications and source records attributed to A Lindblom.
High allele loss rates at 17q12-q21 in breast and ovarian tumors from BRCAl-linked families. The Breast Cancer Linkage Consortium.
Loss of heterozygosity (LOH) was evaluated in 174 breast and ovarian tumors derived from 94 families with at least 3 first-degree relatives affected with either of these cancers. By linkage analysis 26 families were identified as having a high posterior probability of being due to BRCAl (the breast/ovarian cancer susceptibility locus on 17q12-21) with lod scores varying from 0.51 to 9.49. Tumor genotypes were determined at at least 2 constitutionally heterozygous markers flanking BRCAl in a total of 58 tumors from these families. These tumors were derived from 52 patients, the BRCAl mutation carrier status of which was evidenced by DNA sequencing in 20, and inferred by reconstructing haplotypes in the remainder. LOH was detected in 50 (86%) tumors, and invariably involved the wild-type allele. Where informative, this allele was of paternal origin in 33 cases and of maternal origin in 10 cases. These results strongly suggest that BRCAl is a tumor suppressor gene and that LOH is greatly favored to fully inactivate it.
Alleles↗
Familial breast cancer and genes involved in breast carcinogenesis.
Breast cancer has often been reported to run in families, and the most important risk factor for the disease is a family history of breast cancer. Numerous pedigrees and segregation analyses have suggested an autosomal dominant transmitted susceptibility to breast cancer. Familial breast cancer occurs alone or associated with other cancers in clinically distinguishable syndromes. Such cases may be characterized by early onset, bilateral disease, prolonged survival, and anticipation, mainly seen as a higher penetrance or earlier onset in subsequent generations. Studies of patients and tumors from these families as well as sporadic cases have led to localization and/or identification of a number of genes implicated in breast carcinogenesis of familial and sporadic breast cancer.
Breast Neoplasms↗
Finnish mutations in Swedish HNPCC families.
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Adaptor Proteins, Signal Transducing↗
Sequence variability of a prolonged tetranucleotide repeat.
A tetranucleotide repeat located in intron 20 of the RB gene consists of 16-26 CTTT(+/- T) repeats in 99% of the alleles. In the remaining 1% of alleles the segment is extended to a length of > 60 repeats. Sequence analysis revealed that the prolonged alleles either consisted of perfect CTTT(+/- T) repeats or irregular repeat sequences with variable combinations of C and T. The data provide clues to the mechanisms causing unstable expansions of repeats.
Alleles↗
[Insufficient "proof-reading" after replication. Newly discovered mechanism of colon cancer].
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Colonic Neoplasms↗
Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer.
The human DNA mismatch repair gene homologue hMSH2, on chromosome 2p is involved in hereditary non-polyposis colon cancer (HNPCC). On the basis of linkage data, a second HNPCC locus was assigned to chromosome 3p21-23 (ref. 3). Here we report that a human gene encoding a protein, hMLH1 (human MutL homologue), homologous to the bacterial DNA mismatch repair protein MutL, is located on human chromosome 3p21.3-23. We propose that hMLH1 is the HNPCC gene located on 3p because of the similarity of the hMLH1 gene product to the yeast DNA mismatch repair protein, MLH1, the coincident location of the hMLH1 gene and the HNPCC locus on chromosome 3, and hMLH1 missense mutations in affected individuals from a chromosome 3-linked HNPCC family.
Adaptor Proteins, Signal Transducing↗
Chromosomal deletions in anaplastic meningiomas suggest multiple regions outside chromosome 22 as important in tumor progression.
Meningioma is a common, usually benign, sporadic and solitary tumor of the meninges covering the central nervous system. Meningiomas can become malignant, and such anaplastic tumors are associated with a high rate of recurrence and death from the disease. We analyzed 16 sporadic, anaplastic meningiomas for loss of alleles on the majority of chromosomal arms, in order to define regions in the genome which may be important for tumor progression. Loss of genetic material was observed on all but 2 chromosomes studied. While loss of heterozygozity (LOH) from chromosome 22 was the most frequent finding, LOH from the short arm of chromosome I was the second most common lesion occurring preferentially in tumors from men, and at a frequency almost as high as for LOH on chromosome 22. This suggests the existence of a tumor-suppressor locus on Ip involved in meningioma carcinogenesis. Three tumor samples from one large, anaplastic tumor, each with distinct histopathological characteristics, were studied. All 3 samples showed deletions on 22q and Ip. However, only one tumor sample, with the most malignant histopathological phenotype, displayed, in addition to 22q and Ip, deletions on 9q and 17p. This case suggests that the latter 2 chromosomal regions may harbor genes which contribute to the progression of meningioma.
Chromosome Aberrations↗
Characterization of native laminin from bovine kidney and comparison with other laminin variants.
A comprehensive characterization of laminin isoforms requires access to native preparations of laminins of a defined subunit composition. For this purpose an optimized isolation procedure was developed and shown to be broadly applicable to normal mammalian tissues. The protocol does in addition yield side fractions highly enriched in collagens XII and XIV. The major laminin purified from bovine kidney is indistinguishable from mouse Engelbreth-Holm-Swarm (EHS) tumor laminin in electron microscopy, but contains an A chain that migrates in a position intermediate to the Ae and the Am chains on SDS/PAGE. Antisera raised against mouse EHS-tumor laminin crossreact with B chains, but not with the A chain, of kidney laminin. Further, this A chain is not recognized by antisera raised against the Am chain. Laminins from heart and kidney both contain a significant subpopulation with a 190-kDa polypeptide identified as the B1s chain. The Am-containing laminins from heart and placenta differ morphologically from the Ae-containing EHS laminin in having one short arm that does not have the characteristic globule-rod-globule appearance. Further, the Am-containing laminins show a significantly higher thermal stability of the coiled-coil alpha-helical region in the long arm than does Ae-containing EHS laminin, indicating that certain combinations of laminin chains interact more strongly than others.
Animals↗
Laminin isoforms promote attachment of hepatocytes via different integrins.
Three isoforms of laminin were compared for the ability to promote adhesion of primary rat hepatocytes. In tests of initial attachment to these substrates, kidney laminin (alpha k, beta 1, gamma 1, and alpha k, beta 2, gamma 1) was shown to be a more efficient substrate than Engelbreth Holm Swarm (EHS) (alpha 1, beta 1, gamma 1) or heart laminin (alpha 2, beta 1, gamma 1, and alpha 2, beta 2, gamma 1). Hepatocyte attachment to EHS laminin and heart laminin was completely inhibited by antibodies specific for the integrin subunit beta 1, while a combination of beta 1 integrin antibodies and GRGDS peptide was needed for total inhibition of hepatocyte attachment to kidney laminin. Antiserum directed to the integrin subunit beta 3 could not substitute for the GRGDS peptide in this inhibition. Antibodies against the integrin subunit alpha 1 efficiently blocked adhesion of hepatocytes to collagen type I and to the P1 domain of EHS laminin. However, this antibody had essentially no effect on the attachment to kidney laminin and had only a minor inhibitory effect on attachment to heart laminin, to intact EHS laminin, or to the isolated fragment E8 of EHS laminin. Combining the alpha 1 integrin antibody with GRGDS peptide gave no further inhibition on these substrates. These results show that a recently described isoform of laminin from bovine kidney is an efficient substrate for initial attachment of hepatocytes, interacting with at least one beta 1-containing integrin and an RGD-dependent integrin not containing beta 1 or beta 3 subunits. Native EHS laminin uses integrin alpha 1 beta 1 for hepatocyte binding to the center of the cross (fragment P1) and other beta 1 integrin(s) in addition to alpha 1 beta 1 as receptors for the distal part of the long arm (fragment E8).
Animals↗
Sublocalization of a locus at 3p21.3-23 predisposing to hereditary nonpolyposis colon cancer.
Hereditary nonpolyposis colon cancer (HNPCC) is a heterogeneous disease caused by at least three different genes on chromosomes 2 and 3, and one or more additional chromosomes. We used 19 dinucleotide markers in order to sublocalize further the 3p locus linked to HNPCC, and to order the markers into one map resulting in a panel of markers suitable for linkage studies. Human chromosome 3 mouse hybrids were used to determine the chromosomal position of the markers. Haplotype analysis in two families where the disease is linked to chromosome 3p21-23 was used in order to sublocalize further the region in which the gene is located. Based on our results, the gene has now been localized to the region 3p21.3-23.
Animals↗
Loss of heterozygosity studies in tumors from families with breast-ovarian cancer syndrome.
A gene (BRCA1) predisposing for familial breast and ovarian cancer has been mapped to chromosome band 17q12-21. Based on the observation that ovarian tumors from families with breast and ovarian cancer lose the wild-type allele in the region for the BRCA1 locus, it has been suggested that the gene functions as a tumor suppressor gene. We have studied chromosomal deletions in the BRCA1 region in seven breast tumors, three ovarian tumors, one bladder cancer, and one colon cancer from patients in six families with breast-ovarian cancer, in order to test the hypothesis of the tumor suppressor mechanism at this locus. We have found a low frequency of loss of heterozygosity at this region, and our results do not support the idea that BRCA1 is a tumor suppressor gene. Alternatively, the disease segregating in these families is linked to one or more different loci.
Breast Neoplasms↗
Nitrous oxide for colonoscopy discomfort: a randomized double-blind study.
The possibility of reducing recovery time after colonoscopy was studied using patient-administered nitrous oxide and comparing it with our standard treatment of ketobemidone plus midazolam. Fifty consecutive colonoscopy patients were randomized to receive either (i) intravenous ketobemidone hydrochloride 2.5 mg, midazolam 2.5 mg, and breathing air from a face mask with a demand valve (KHM) or (ii) intravenous saline and a breathing mixture of even parts of oxygen and nitrous oxide (Entonox) from the same valve setup. Patient discomfort during colonoscopy was assessed using visual analogue scales. All patients were allowed to stay for recovery as long as they wanted, and the time was measured. Modified recollection tests were performed prior to colonoscopy and when the patients left the Endoscopy Unit, in order to study the degree of mental impairment induced by the procedure and the medication. All patients had complete colonoscopies of the same duration in both groups. Discomfort during colonoscopy was rated the same in both groups (2p = 0.6413). Both groups of patients scored identically in the precolonoscopy recollection test. Most patients had a lower score after colonoscopy, but Entonox-treated patients scored significantly better than those with KHM (2p = 0.0250). Patients treated with Entonox opted to leave the Unit directly after the procedure (median 0 minutes; interquartile range 0-5 minutes) compared to 38 minutes for those with KHM (interquartile range 10-75 min), 2p < 0.001. It seems from our data that nitrous oxide gives pain relief equal to that in our standard treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Distinct and overlapping ligand specificities of the alpha 3A beta 1 and alpha 6A beta 1 integrins: recognition of laminin isoforms.
The ligand specificity of the alpha 3A beta 1 integrin was analyzed using K562 cells transfected with full-length alpha 3A cDNA and was compared with that of alpha 6A beta 1 in similarly transfected K562 cells. Clones were obtained that showed comparable surface expression of either alpha 3A beta 1 or alpha 6A beta 1 integrins. Those expressing alpha 3A beta 1 attached to and spread on immunopurified human kalinin and cellular matrices containing human kalinin, which is a particular isoform of laminin. In addition, alpha 3A transfectants adhered to bovine kidney laminins possessing a novel A chain variant. Binding to kalinin was blocked by a monoclonal antibody against the A chain constituent of kalinin and adhesion to both kalinin and kidney laminins by anti-alpha 3 and beta 1 monoclonal antibodies. The alpha 3A transfected cells bound more strongly to kalinin and bovine kidney laminins after treatment with the beta 1 stimulatory antibody TS2/16. A distinctly weaker and activation-dependent adhesion of alpha 3A transfectants was observed on human placental laminins possessing the Am chain variant (merosin), and no adhesion occurred on bovine heart laminins and murine EHS tumor laminin. Further inactive substrates were fibronectin, nidogen, and collagen types IV and VI, indicating that the alpha 3A beta 1 integrin is a much less promiscuous receptor than thought before. By contrast, alpha 6A transfected cells adhered to all laminin isoforms when stimulated with TS2/16. Adhesion also occurred only on bovine kidney laminins in the absence of TS2/16. These results demonstrate that both alpha 3A beta 1 and alpha 6A beta 1 integrins are typical laminin receptors but that their affinity and activation dependence for binding to various laminin isoforms differ considerably.
Amino Acid Sequence↗
Genetic rearrangements in sporadic and familial gastric carcinomas detected with microsatellite markers.
Ten gastric carcinomas were studied for loss of heterozygosity by analysis of 21 microsatellite markers from 14 different chromosomes. Four patients had a family history of gastro-intestinal cancer, and six tumours were considered sporadic. We also studied a new mechanism in tumourigenesis recently reported in hereditary non polyposis colon cancer, a defect in mismatch repair that is seen as gain of new bands by the use of dinucleotide repeat markers. Loss of heterozygosity was detected with two markers in one primary tumour and with the majority of markers in one metastasis from a sporadic gastric tumour. Gain of microsatellite bands was seen in one tumour from a gene carrier in a family with hereditary non-polyposis colon cancer and in one sporadic tumour. Two tumours from patients with a family history of gastric cancer showed no rearrangements. Our results suggest that different types of genes are involved in initiation and progression of gastric cancer in sporadic and familial gastric cancer.
Adult↗
Predisposition for breast cancer in carriers of constitutional translocation 11q;22q.
A translocation between the long arms of chromosomes 11 and 22, t(11;22)(q23;q11), is the most frequent constitutional reciprocal translocation in man. This chromosome abnormality has not previously been reported to be associated with an increased risk for neoplasia. The observation of one patient with a constitutional translocation t(11q;22q) and breast cancer prompted us to study the relationship between these two conditions. The incidence of breast cancer was determined in carriers of t(11q;22q). The karyotypes were determined by QFQ-banding, and the breakpoints were then further characterized by fluorescent in situ hybridization. Eight families with a total of 22 balanced carriers were found. In five of these families there was one case of breast cancer each. In another family a case of an unknown malignancy was reported in one member. No other malignancies were found among these patients. The number of breast cancer cases was significantly higher than expected among the translocation carriers (P < .001). The chromosomal breakpoints showed the same localization with the markers used, in the seven families studied. The association of constitutional translocation t(11q;22q) and breast cancer identifies a subset of patients with a highly increased risk for breast cancer who would benefit from counseling and screening. It also suggests the involvement of genes on 11q and/or 22q, in the tumorigenesis of breast cancer.
Breast Neoplasms↗
Loss of heterozygosity in familial breast carcinomas.
Three loci have been implicated in the etiology of familial breast cancer; the BRCA1 locus on 17q, the p53 gene on 17p, and the androgen receptor gene on the X chromosome. However, it has been estimated that in approximately 50% of all breast cancer families the predisposing genetic defect is not linked to any of these three loci. In an attempt to identify chromosomal regions harboring putative breast cancer genes we performed allelotyping in 82 familial breast carcinomas. Polymorphic markers representing 45 different loci were analyzed and the most frequently involved chromosomal arms were 8p, 16q, 17p, 17q, and 19p.
Adult↗
Deletions on chromosome 16 in primary familial breast carcinomas are associated with development of distant metastases.
Genetic alterations that occur in human breast cancers are believed to be of importance for initiation as well as progression of the disease. In order to find a genetic alteration that may be used as a prognostic marker, 82 familial breast carcinomas were analyzed for loss of constitutional heterozygosity at polymorphic loci on all chromosomes. Frequently occurring allele losses were compared to estrogen receptor expression, lymph node metastases, tumor size at the time of operation, and distant metastases at the time of follow-up 2-15 years later. Loss of heterozygosity (LOH) on the long arm of chromosome 16 in the tumor at the time of operation was significantly correlated (P < 0.001) with the occurrence of distant metastases 1-13 years after the operation. In addition, LOH at 16q was not correlated with estrogen receptor status, lymph node positivity, or tumor size, nor was the occurrence of distant metastases correlated with any of these parameters. The results suggest the existence of a tumor suppressor gene on 16q that facilitates hematogenic spread of breast cancer and that LOH at this locus is an independent prognostic marker in breast cancer.
Breast Neoplasms↗