RESUMEN
BACKGROUND: Over 95% of all thyroid malignancies are non-medullary thyroid carcinomas (NMTC). Familial NMTC are more aggressive and mortality is higher as compared with sporadic carcinomas. Known genetic factors do not explain all familial NMTC. Recently, thyroid disorders have been observed in families with germline mutations in aryl hydrocarbon receptor interacting protein (AIP) but, due to frequent occurrence of these conditions in the population, the significance of this co-occurrence is not clear. AIM, SUBJECTS AND METHODS: To examine whether AIP is involved in familial NMTC, we performed AIP mutation screening in 93 familial NMTC cases. In addition, the AIP status was studied in one follicular thyroid adenoma patient with a known AIP mutation from an additional cohort. RESULTS: No potentially pathogenic changes were identified, but two likely rare polymorphisms were detected. AIP mutation-positive patient's follicular thyroid adenoma showed no loss of heterozygosity or lack of immunohistochemical AIP staining. CONCLUSION: Our study indicates that germline AIP mutations are rare or do not exist in familial NMTC.
Asunto(s)
Adenoma/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Neoplasias de la Tiroides/genética , Adolescente , Adulto , Anciano , Niño , Análisis Mutacional de ADN , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal/fisiología , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Adulto JovenRESUMEN
Hereditary non-polyposis colorectal cancer (HNPCC) is caused by germline mutations in mismatch repair (MMR) genes, mostly MLH1 and MSH2. Somatic inactivation of the wild-type allele of the respective MMR gene is required for tumor development. Unexpectedly, a recent study utilizing DNA from paraffin-embedded tissue material detected frequent loss of the mutant MMR gene allele in HNPCC tumors. Dual role for loss of heterozygosity (LOH) was proposed. If somatic loss of the wild-type MMR gene allele had occurred through point mutation or promoter hypermethylation, frequent somatic deletions at the region of the MMR gene locus, perhaps targeting other relevant cancer genes, could quite commonly lead to loss of the mutant allele. To test this hypothesis, we studied a population-based series of 25 fresh-frozen HNPCC tumors with a germline mutation in MLH1 or MSH2 for LOH. Fourteen of the 25 tumors (56%) showed LOH at the respective locus, and all 14 losses targeted the wild-type allele (P=0.00006). These results strongly support the traditional two-hit model of HNPCC gene inactivation.
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Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Pérdida de Heterocigocidad/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/etiología , Humanos , Mutación PuntualRESUMEN
Germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene were recently observed in patients with pituitary adenoma predisposition (PAP). Though AIP mutation-positive individuals with prolactin-, mixed growth hormone/prolactin-, and ACTH-producing pituitary adenomas as well as non-secreting pituitary adenomas have been reported, most mutation-positive patients have had growth hormone-producing adenomas diagnosed at relatively young age. Pituitary adenomas are also component tumors of some familial endocrine neoplasia syndromes such as multiple endocrine neoplasia type 1 (MEN1) and Carney complex (CNC). Genes underlying MEN1 and CNC are rarely mutated in sporadic pituitary adenomas, but more often in other lesions contributing to these two syndromes. Thus far, the occurrence of somatic AIP mutations has not been studied in endocrine tumors other than pituitary adenomas. Here, we have analyzed 32 pituitary adenomas and 79 other tumors of the endocrine system for somatic AIP mutations by direct sequencing. No somatic mutations were identified. However, two out of nine patients with prolactin-producing adenoma were shown to harbor a Finnish founder mutation (Q14X) with a complete loss of the wild-type allele in the tumors. These results are in agreement with previous studies in that prolactin-producing adenomas are component tumors in PAP. The data also support the previous finding that somatic AIP mutations are not common in pituitary adenomas and suggest that such mutations are rare in other endocrine tumors as well.
Asunto(s)
Adenoma/genética , Carcinoma/genética , Neoplasias de las Glándulas Endocrinas/genética , Mutación , Proteínas/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Bases , Análisis Mutacional de ADN , Femenino , Humanos , Péptidos y Proteínas de Señalización Intracelular , Masculino , Persona de Mediana EdadRESUMEN
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a tumour predisposition syndrome caused by heterozygous germline mutations in the fumarate hydratase (FH) gene. The condition is characterised by predisposition to benign leiomyomas of the skin and the uterus, renal cell carcinoma (RCC), and uterine leiomyosarcoma (ULMS). To comprehensively examine the cancer risk and tumour spectrum in Finnish FH mutation positive families, genealogical and cancer data were obtained from 868 individuals. The cohort analysis of the standardised incidence ratios (SIR) was analysed from 256 individuals. FH mutation status was analysed from all available individuals (n = 98). To study tumour spectrum in FH mutation carriers, loss of the wild type allele was analysed from all available tumours (n = 22). The SIR was 6.5 for RCC and 71 for ULMS. The overall cancer risk was statistically significantly increased in the age group of 15-29 years, consistent with features of cancer predisposition families in general. FH germline mutation was found in 55% of studied individuals. Most RCC and ULMS tumours displayed biallelic inactivation of FH, as did breast and bladder cancers. In addition, several benign tumours including atypical uterine leiomyomas, kidney cysts, and adrenal gland adenomas were observed. The present study confirms with calculated risk ratios the association of early onset RCC and ULMS with FH germline mutations in Finns. Some evidence for association of breast and bladder carcinoma with HLRCC was obtained. The data enlighten the organ specific malignant potential of HLRCC.
Asunto(s)
Fumarato Hidratasa/genética , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Neoplasias/genética , Adolescente , Adulto , Factores de Edad , Anciano , Carcinoma de Células Renales/diagnóstico , Carcinoma de Células Renales/genética , Estudios de Cohortes , Femenino , Finlandia , Humanos , Neoplasias Renales/diagnóstico , Neoplasias Renales/genética , Leiomiomatosis/diagnóstico , Leiomiomatosis/genética , Masculino , Persona de Mediana Edad , Neoplasias/diagnóstico , Fenotipo , Factores de RiesgoRESUMEN
BACKGROUND: LKB1/STK11 germline mutations cause Peutz-Jeghers syndrome (PJS). The existence of a second PJS locus is controversial, the evidence in its favour being families unlinked to LKB1 and the low frequency of LKB1 mutations found using conventional methods in several studies. Exonic and whole gene deletion or duplication events cannot be detected by routine mutation screening methods. OBJECTIVE: To seek evidence for LKB1 germline deletions or duplications by screening patients meeting clinical criteria for PJS but without detected mutations on conventional screening. METHODS: From an original cohort of 76 patients, 48 were found to have a germline mutation by direct sequencing; the remaining 28 were examined using multiplex ligation dependent probe amplification (MLPA) analysis to detect LKB1 copy number changes. RESULTS: Deletions were found in 11 of the 28 patients (39%)--that is, 14% of all PJS patients (11/76). Five patients had whole gene deletions, two had the promoter and exon 1 deleted, and in one patient exon 8 was deleted. Other deletions events involved: loss of exons 2-10; deletion of the promoter and exons 1-3; and loss of part of the promoter. No duplications were detected. Nine samples with deletions were sequenced at reported single nucleotide polymorphisms to exclude heterozygosity; homozygosity was found in all cases. No MLPA copy number changes were detected in 22 healthy individuals. CONCLUSIONS: These results lessen the possibility of a second PJS locus, as the detection rate of germline mutations in PJS patients was about 80% (59/76). It is suggested that MLPA, or a suitable alternative, should be used for routine genetic testing of PJS patients in clinical practice.
Asunto(s)
Exones , Eliminación de Gen , Síndrome de Peutz-Jeghers/genética , Proteínas Serina-Treonina Quinasas/genética , Quinasas de la Proteína-Quinasa Activada por el AMP , Estudios de Cohortes , Análisis Mutacional de ADN/métodos , Mutación de Línea Germinal , Humanos , Síndrome de Peutz-Jeghers/diagnósticoRESUMEN
Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant cancer predisposition syndrome caused by germ-line mutations in DNA mismatch repair genes. It is relevant to identify HNPCC patients because colonoscopic screening of individuals with HNPCC mutations reduces cancer morbidity and mortality. Microsatellite instability (MSI) is characteristic of HNPCC tumors. A panel of five markers (BAT25, BAT26, D2S123, D5S346, and D17S250, the so-called Bethesda markers) has been proposed for screening for MSI. To test a hypothesis that the use of BAT26 alone is feasible in screening for MLH1/MSH2 mutation-positive HNPCC patients, we compared the MSI results of 494 colorectal cancer patients obtained using BAT26 with results obtained using the Bethesda markers. BAT26 was able to identify all 27 mutation-positive individuals in this series. The marker failed to identify 2 high MSI tumors and 20 low MSI tumors, all of which expressed MLH1, MSH2, and MSH6 when scrutinized by immunohistochemistry.
Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Proteínas de Unión al ADN , Repeticiones de Microsatélite/genética , Proteínas Adaptadoras Transductoras de Señales , Adulto , Anciano , Anciano de 80 o más Años , Proteínas Portadoras , Pruebas Genéticas/métodos , Mutación de Línea Germinal , Humanos , Persona de Mediana Edad , Homólogo 1 de la Proteína MutL , Proteína 2 Homóloga a MutS , Proteínas de Neoplasias/genética , Proteínas Nucleares , Proteínas Proto-Oncogénicas/genéticaRESUMEN
LKB1 serine/threonine kinase is a gene for Peutz-Jeghers cancer predisposition syndrome. Most studies have detected a low frequency of LKB1 defects in sporadic cancer. A notable exception is a recent report describing frequent, mostly missense type, LKB1 mutations in Korean distal colorectal tumors. To clarify the role of LKB1 in colon cancer, we scrutinized 50 left-sided Korean and Finnish specimens. No somatic mutations were found. The seven Korean somatic missense mutations reported previously were functionally analyzed, and five were found not to alter LKB1 kinase activity. One of these changes was found to be a germ-line polymorphism. LKB1 involvement in distal colorectal cancer is not common.
Asunto(s)
Neoplasias Colorrectales/etiología , Síndrome de Peutz-Jeghers/genética , Proteínas Serina-Treonina Quinasas/genética , Quinasas de la Proteína-Quinasa Activada por el AMP , Neoplasias Colorrectales/genética , Humanos , Mutación Missense , Proteínas Quinasas/metabolismoRESUMEN
BACKGROUND: Defects in the DNA repair system lead to genetic instability because replication errors are not corrected. This type of genetic instability is a key event in the malignant progression of HNPCC and a subset of sporadic colon cancers and mutation rates are particularly high at short repetitive sequences. Somatic deletions of coding mononucleotide repeats have been detected, for example, in the TGFbetaRII and BAX genes, and recently many novel target genes for microsatellite instability (MSI) have been proposed. Novel target genes are likely to be discovered in the future. More data should be created on background mutation rates in MSI tumours to evaluate mutation rates observed in the candidate target genes. METHODS: Mutation rates in 14 neutral intronic repeats were evaluated in MSI tumours. Bioinformatic searches combined with keywords related to cancer and tumour suppressor or CRC related gene homology were used to find new candidate MSI target genes. By comparison of mutation frequencies observed in intronic mononucleotide repeats versus exonic coding repeats of potential MSI target genes, the significance of the exonic mutations was estimated. RESULTS: As expected, the length of an intronic mononucleotide repeat correlated positively with the number of slippages for both G/C and A/T repeats (p=0.0020 and p=0.0012, respectively). BRCA1, CtBP1, and Rb1 associated CtIP and other candidates were found in a bioinformatic search combined with keywords related to cancer. Sequencing showed a significantly increased mutation rate in the exonic A9 repeat of CtIP (25/109=22.9%) as compared with similar intronic repeats (p< or =0.001). CONCLUSIONS: We propose a new candidate MSI target gene CtIP to be evaluated in further studies.
Asunto(s)
Neoplasias Colorrectales/genética , Predisposición Genética a la Enfermedad/genética , Repeticiones de Microsatélite/genética , Neoplasias Colorrectales/diagnóstico , Análisis Mutacional de ADN , ADN de Neoplasias/química , ADN de Neoplasias/genética , Pruebas Genéticas , Humanos , Intrones/genética , MutaciónRESUMEN
We have compared the steroid regulation of human genes encoding prostatic acid phosphatase (hPAP), prostate-specific antigen (hPSA), and prostate-specific glandular kallikrein (hK2) at the level of transcription. Reporter constructs of hPAP promoter covering the region -734/+467 were functional in both prostatic (LNCaP and PC-3) and nonprostatic (CV-1) cell lines in transient transfections. hPAP -231/+50 with eight identified transcription factor-binding sites showed the highest, and hPAP -734/+467 showed the lowest transcriptional activity in CV-1 cells. The hPAP promoter could not be induced with androgen, glucocorticoid, or progesterone, contrary to the hPSA (-620/+40) and hK2 (-493/+27) promoters in PC-3 cells cotransfected with the respective steroid receptor expression vector. Therefore, steroids cannot directly regulate hPAP gene expression via receptor binding to steroid response elements at -178 and +336, which have been shown to have androgen receptor-binding ability in vitro. Glucocorticoid was the most powerful activator of the hPSA construct at 10-nM steroid concentrations. On the contrary, glucocorticoid stimulation of the transcriptional activity of the hK2 construct was the weakest among the tested steroids. The results indicate that the steroid response elements in the proximal promoters of hPSA and hK2 genes are not androgen specific, offering the molecular basis for the expression of these genes outside the prostate in tissues containing steroid receptors.
Asunto(s)
Fosfatasa Ácida/genética , Regulación de la Expresión Génica/efectos de los fármacos , Calicreínas/genética , Antígeno Prostático Específico/genética , Próstata/enzimología , Esteroides/farmacología , Andrógenos/farmacología , Animales , Línea Celular , Cloranfenicol O-Acetiltransferasa/genética , Huella de ADN , Glucocorticoides/farmacología , Haplorrinos , Humanos , Masculino , Progesterona/farmacología , Regiones Promotoras Genéticas , Próstata/metabolismo , Neoplasias de la Próstata/metabolismo , Transcripción Genética/efectos de los fármacos , Transfección , Células Tumorales CultivadasRESUMEN
In the Finnish breast and ovarian cancer families six BRCA1 and five BRCA2 mutations have been found recurrently. Some of these recurrent mutations have also been seen elsewhere in the world, while others are exclusively of Finnish origin. A haplotype analysis of 26 Finnish families carrying a BRCA1 mutation and 20 families with a BRCA2 mutation indicated that the carriers of each recurrent mutation have common ancestors. The common ancestors were estimated to trace back to 7-36 generations (150-800 years). The time estimates and the geographical clustering of these founder mutations in Finland are in concordance with the population history of this country. Analysis of the cancer phenotypes showed differential ovarian cancer expression in families carrying mutations in the 5' and 3' ends of the BRCA1 gene, and earlier age of ovarian cancer onset in families with BRCA1 mutations compared with families with BRCA2 mutations. The identification of prominent and regional BRCA1 and BRCA2 founder mutations in Finland will have significant impact on diagnostics in Finnish breast and ovarian cancer families. An isolated population with known history and multiple local founder effects in multigenic disease may offer distinct advantages also for mapping novel predisposing genes.
Asunto(s)
Neoplasias de la Mama/genética , Efecto Fundador , Genes BRCA1/genética , Mutación/genética , Proteínas de Neoplasias/genética , Neoplasias Ováricas/genética , Factores de Transcripción/genética , Adulto , Anciano , Proteína BRCA2 , Neoplasias de la Mama/patología , Familia , Femenino , Finlandia/epidemiología , Genotipo , Haplotipos , Humanos , Persona de Mediana Edad , Proteínas de Neoplasias/metabolismo , Neoplasias Ováricas/patología , Fenotipo , Factores de Tiempo , Factores de Transcripción/metabolismoRESUMEN
Since the identification of the BRCA1 and BRCA2 breast-ovarian cancer susceptibility genes, mutation analyses have been carried out in different populations. Here we screened 15 Turkish breast and breast-ovarian cancer families for mutations in both genes by conformation-sensitive gel electrophoresis (CSGE) and the protein truncation test (PTT), followed by DNA sequencing. Three families included a male breast cancer case, one without family history. Three germline mutations were identified, two in BRCA1 and one in BRCA2. The two BRCA1 mutations, 5382insC and 5622C-->T, were found in breast-ovarian cancer families. The BRCA2 3414delTCAG is a novel mutation detected in a site-specific breast cancer family that included 1 case of male breast cancer. These first results of Turkish families show that the frequency of germline BRCA1 or BRCA2 mutations appears to be high in families with at least 3 breast and/or ovarian cancer cases.
Asunto(s)
Neoplasias de la Mama Masculina/genética , Genes BRCA1/genética , Mutación de Línea Germinal/genética , Proteínas de Neoplasias/genética , Factores de Transcripción/genética , Edad de Inicio , Proteína BRCA2 , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Neoplasias Ováricas/genética , Linaje , Proyectos Piloto , Turquía/epidemiologíaRESUMEN
Mutations in BRCA1 and BRCA2 account for a large portion of the inherited predisposition to breast and ovarian cancer. It was recently discovered that mutations in these two genes are less common in the Finnish population than expected. Because the genetic background of breast cancer, in particular, is largely obscure, it became necessary to search for mutations in other susceptibility genes. Because seven of our BRCA1 and BRCA2 mutation-negative families fulfilled the criteria of either Li-Fraumeni syndrome (LFS) or Li-Fraumeni-like syndrome (LFL), we decided to screen them for germ-line TP53 mutations in exons 5-8 using a dual-temperature single-strand conformation polymorphism assay (SSCP). Two missense mutations (Asn235Ser and Tyr220Cys) were identified. The clinical significance of these findings was evaluated by comparison to previously reported germ-line TP53 mutation data, and by using the tumor loss of heterozygosity (LOH) analysis. In addition, an immunohistochemical analysis of tumor specimens from mutation-positive individuals was performed. Our results suggest that the observed missense mutations confer susceptibility to cancer, and that germ-line TP53 mutations would therefore explain an additional fraction of hereditary breast cancer in Finland.
Asunto(s)
Genes BRCA1 , Genes p53 , Mutación de Línea Germinal , Síndrome de Li-Fraumeni/genética , Proteínas de Neoplasias/genética , Neoplasias/genética , Factores de Transcripción/genética , Proteína BRCA2 , Femenino , Finlandia , Humanos , Masculino , Neoplasias/etnología , Linaje , Polimorfismo Conformacional Retorcido-SimpleRESUMEN
Tumor specimens from 78 epithelial ovarian cancer patients were examined for loss of heterozygosity (LOH) at 11 microsatellite markers at chromosomes 3p14.2, 6q27, 8p12, 11p15.5, 11q23.1-q24, 16q24.3, and 17p13.1, to evaluate the involvement, possible clustering, and prognostic significance of these lesions in the progression of the disease. The LOH analysis was performed on polymerase chain reaction (PCR)-amplified DNA from sections of paraffin-embedded tumor and normal tissue pairs. In addition to primary tumors, specimens of metastatic tissues were studied from 19 patients. In the combined results from primary and metastatic tumors, LOH frequencies varied between 31% (6q27) and 69% (17p13.1). Only LOH at chromosomal regions 3p14.2 (D3S1300), 11p15.5 (D11S1318), 11q23.3-q24 (D11S1340 and D11S912), 16q24.3 (D16S476 and D16S3028), and 17p13.1 (D17S938) was associated with an adverse disease course. Our results indicate that LOH at 17p13.1 occurs independently from the other chromosomal sites studied, and is an early event in ovarian tumorigenesis. The LOH at 16q24.3, 11q23.3/q24, and 11p15.5 seems to occur later. The LOH at 11p15.5 and 11q23.3 was associated with reduced cancer-specific survival time; therefore, the studied markers could be located close to genes with influence on patient survival. Of the studied chromosomal regions, the most important tumor suppressor genes involved in the evolution of ovarian cancer appear to be located on chromosomes 11, 16, and 17. The genetic heterogeneity observed in primary and metastatic specimens demonstrates that there are multiple pathways involved in the progression of ovarian cancer.
Asunto(s)
Cromosomas Humanos , Pérdida de Heterocigocidad , Neoplasias Ováricas/genética , Deleción Cromosómica , Femenino , Humanos , Neoplasias Ováricas/patologíaAsunto(s)
Cadherinas/genética , Neoplasias Gástricas/genética , Secuencia de Bases , ADN/química , ADN/genética , Análisis Mutacional de ADN , Salud de la Familia , Femenino , Mutación de Línea Germinal , Humanos , Masculino , Mutación , Mutación Missense , Linaje , Polimorfismo Genético , Polimorfismo Conformacional Retorcido-SimpleAsunto(s)
Neoplasias de la Mama/genética , Pruebas Genéticas , Mutación de Línea Germinal/genética , Proteínas Serina-Treonina Quinasas/genética , Adulto , Proteínas de la Ataxia Telangiectasia Mutada , Proteínas de Ciclo Celular , Preescolar , Análisis Mutacional de ADN , Proteínas de Unión al ADN , Exones/genética , Femenino , Finlandia , Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Humanos , Masculino , Linaje , Polimorfismo Genético/genética , Proteínas Supresoras de TumorAsunto(s)
Aconitato Hidratasa/genética , Alelos , Deleción Cromosómica , Cromosomas Humanos Par 22/genética , Neoplasias Colorrectales/genética , Pérdida de Heterocigocidad/genética , Mutación/genética , Secuencia de Bases , Análisis Mutacional de ADN , Exones/genética , Humanos , Polimorfismo Genético/genéticaRESUMEN
Germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene were recently identified in individuals with pituitary adenoma predisposition (PAP). These patients have prolactin (PRL) or growth hormone (GH) oversecreting pituitary adenomas, the latter exhibiting acromegaly or gigantism. Loss-of-heterozygosity (LOH) analysis revealed that AIP is lost in PAP tumours, suggesting that it acts as a tumour-suppressor gene. Aryl hydrocarbon receptor interacting protein is involved in several pathways, but it is best characterised as a cytoplasmic partner of the aryl hydrocarbon receptor (AHR). To examine the possible role of AIP in the genesis of common cancers, we performed somatic mutation screening in a series of 373 colorectal cancers (CRCs), 82 breast cancers, and 44 prostate tumour samples. A missense R16H (47G>A) change was identified in two CRC samples, as well as in the respective normal tissues, but was absent in 209 healthy controls. The remaining findings were silent, previously unreported, changes of the coding, non-coding, or untranslated regions of AIP. These results suggest that somatic AIP mutations are not common in CRC, breast, and prostate cancers.
Asunto(s)
Neoplasias de la Mama/genética , Neoplasias Colorrectales/genética , Mutación , Neoplasias de la Próstata/genética , Proteínas/genética , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Aminoácidos , Humanos , Péptidos y Proteínas de Señalización Intracelular , Pérdida de Heterocigocidad , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Proteínas/química , Homología de Secuencia de AminoácidoRESUMEN
Mutations in LKB1 lead to Peutz-Jeghers syndrome (PJS). However, only a subset of PJS patients harbours LKB1 mutations. We performed a mutation analysis of three genes encoding novel LKB1-interacting proteins, BRG1, STRADalpha, and MO25alpha, in 28 LKB1-negative PJS patients. No disease-causing mutations were detected in the studied genes in PJS patients from different European populations.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras del Transporte Vesicular/genética , Mutación , Proteínas Nucleares/genética , Síndrome de Peutz-Jeghers/genética , Factores de Transcripción/genética , ADN Helicasas , Humanos , Intrones , Polimorfismo GenéticoRESUMEN
The pvB370 BamHI tandemly repeated satellite DNA family was isolated and analyzed in eight species of the Drosophila virilis group and is probably common to all its members. Unexpectedly, the satellite DNA family showed similar levels of intra- and interspecific sequence variability. An EMBL gene-bank search revealed a high degree of similarity between the members of the pvB370 BamHI satellite DNA sequence family and the direct terminal repeats of the mobile dispersed genetic pDv elements described in D. virilis and other species of the group. However, no similarity was observed to the transcribed and translated part of the pDv elements. It is suggested that the satellite DNA repeats are phylogenetically older than the mobile dispersed genetic pDv element and that the functional pDv elements might have derived from the satellite DNA family through an insertion of a tandemly repeated 36-bp transcription unit.
Asunto(s)
Elementos Transponibles de ADN , ADN Satélite/genética , Drosophila/genética , Evolución Molecular , Secuencias Repetitivas de Ácidos Nucleicos , Animales , Secuencia de Bases , Southern Blotting , Desoxirribonucleasa BamHI , Drosophila/clasificación , Biblioteca Genómica , Modelos Genéticos , Datos de Secuencia Molecular , Filogenia , Análisis de Secuencia de ADN , Homología de Secuencia de Ácido Nucleico , Especificidad de la Especie , Transcripción GenéticaRESUMEN
Microsatellite instability (MSI) is characteristic of hereditary nonpolyposis colorectal cancer, and occurs in a subset (10 to 15%) of unselected colorectal cancer cases. In hereditary nonpolyposis colorectal cancer, MSI is caused by defects in five mismatch repair genes, and in sporadic cases the main cause seems to be somatic MLH1 promoter methylation. Most likely additional hereditary nonpolyposis colorectal cancer genes remain to be discovered. Genes with simple repeats in their coding region are often targets for deletions in MSI-positive tumors. Several genes (TGFbeta RII, IGFIIR, MSH3, MSH6, BAX, MBD4) with significance in tumorigenesis harbor repeats in their coding regions and are often somatically inactivated because of deletions causing frameshifts. Recently, a novel human mismatch repair gene, MLH3, was cloned and shown to be involved in mammalian mismatch repair. To evaluate the possible role of MLH3 in hereditary cancer, we performed germline single-strand conformation polymorphism-analysis for 52 patients displaying features of inherited colorectal cancer. Forty-six of these had been diagnosed with MSI-positive tumors. No germline mutations were found. Similar to MSH3 and MSH6, MLH3 harbors mononucleotide repeats, ie, (A(6))-(A(9)), in its coding region, which makes it a putative target for somatic mutations in MSI-positive tumors. To evaluate its somatic inactivation we performed a deletion search focusing on eight exonic MLH3 mononucleotide repeats in a series of 93 MSI-positive tumors. Somatic deletions were found in 8.6% of the samples, a frequency similar to one detected in neutral noncoding mononucleotide repeats. No evidence of involvement of MLH3 in MSI tumorigenesis was obtained.