Chromosomal abnormalities in a pineocytoma

Letter to the editor.-- El pdf es la versión post-print.-- et al.This work was performed at the Department of Genetics, Fundación Jiménez Díaz (Madrid).Peer Reviewe

Chromosome aberrations in metastatic ovarian cancer: Relationship with abnormalities in primary tumors

Twenty malignant effusions secondary to ovarian cancer have been cytogenetically analyzed directly and after short in vitro culture. With the exception of one sample characterized by trisomy 3, all cases displayed clonal structural rearrangements. Chromosomes 1 and 3 were most frequently involved in the genesis of markers. Abnormalities of chromosomes 5, 6, 9, 11 and 12 were also recurrently found, and double minutes (DM) were observed in 2 samples. Our results agree with previous findings on the preferential involvement of chromosomes 1, 3 and 6 in ovarian carcinomas, and suggest that rearrangements of certain chromosomes are non-random but are secondary to the malignant progression of these tumors.Funded by The Comisión Asesora para la Investigación Científica y Técnica (CAICYT) and Fundación Conchita Rábago de Jiménez Diaz.Peer Reviewe

III. Oligodendrogliomas: Molecular biology

[ES]: Las dificultades inherentes al diagnóstico, tratamiento y evolución clínica de oligodendrogliomas representan un complejo problema reflejado en la ausencia de factores predictivos reproductibles, con capacidad de identificación de las formas agresivas. La utilización de nuevas metodologías de análisis biológico permite la exploración de características tumorales hasta ahora difícilmente abordables, de tal forma que un detallado conocimiento de los acontecimientos moleculares responsables del desarrollo tumoral de oligodendrogliomas (del proceso neoplásico en general) es un prerrequisito para el establecimiento de nuevos métodos terapéuticos, encaminados a mejorar el pronóstico y, en última instancia, la curación de los enfermos. En este artículo revisamos los datos actuales acerca de los mecanismos moleculares implicados en la patogénesis de oligodendrogliomas, que suponen la acumulación secuencial de diversas alteraciones genéticas que producen activación de oncogenes o inactivación de genes oncosupresores o genes reparadores de ADN, así como la alteración de las vías de muerte celular programada.[EN]: Accurate and reproducible identification of the aggressive subset of oligodendrogliomas is difficult, and this determination of new biological characteristics of these tumors may prove helpful in predicting postoperative survivals. Detailed knowledge of the molecular events participating in brain tumor growth may be an important aspect for the development of new therapeutic strategies to improve prognosis. This article reviews the data available on the molecular mechanisms involved in the pathogenesis of oligodendrogliomas, that imply a sequential accumulation of anomalies leading to oncogene activation and inactivation of genes involved in reparation of DNA replication errors or tumor suppressor genes. These anomaliesgenerate growth factor loops, inactivation of sorne regulatory genes involved in control of cell cycle or alteration of apoptotic pathways.Peer Reviewe

hRAD54 gene and 1p high-resolution deletion-mapping analyses in oligodendrogliomas

The hRAD54 protein belongs to a superfamily of DNA helicases, and mutations in genes with DNA helicase function have been found to be responsible for cancer-prone syndromes (xeroderma pigmentosum, Bloom syndrome, Werner syndrome). hRAD54 thus could be a candidate modifier gene in tumors characterized by allelic imbalance at 1p32, the chromosome region in which this gene is located. Using a panel of 38 1p and five 1q markers, we therefore performed deletion-mapping analysis on a series of 35 oligodendrogliomas, which were also studied for mutations in the hRAD54 gene. Deletions of the short arm of chromosome 1 were evidenced in 26 tumors, mostly involving 1p36-1p13; all thus displayed loss of the 1p32 region. We used PCR/SSCP to examine all 18 exons of the hRAD54 gene for mutations in 25 tumors, but the mobility shifts detected corresponded to previously identified polymorphic changes: T-to-C transition at nucleotide 2865 (with no amino acid change) and at nucleotide 3008, at the 3' untranslated region. We conclude that hRAD54 gene alterations are not required for malignant transformation of oligodendrogliomas. Copyright (C) 1999 Elsevier Science Inc.This work was supported by funds from grant no. 98/1349 from FIS, Ministerio de Sanidad.Peer Reviewe

Allelic loss at 1 p is associated with tumor progression of meningiomas

Next to chromosome 22 anomalies, deletions of the short arm of chromosome I have previously been described as the most frequent alteration detected by cytogenetic analysis of meningiomas. To determine the incidence of these deletions, we have analyzed a series of 50 meningiomas for the loss of alleles at four chromosome I loci. Thirteen samples displayed LOH for the markers studied; in one instance, the results were compatible with loss of the entire chromosome I, whereas in the other 12 samples deletions of the short arm were observed. Eleven of the meningiomas had previously been shown to have loss of alleles on chromosome 22, and 12 of them were characterized by increased tumor aggressiveness. These findings suggest that deletion of lp (or the alteration of a locus located there) might represent a secondary, but nonrandom alteration in meningiomas, perhaps contributing to meningioma tumor progression.Funded by Comunidad Autónoma de Madrid. Grant Numbers: C267190, C367/92 and Ministerio de Educación y Ciencia, Grant Number: SAF-92-0182.Peer Reviewe

DNA mismatch repair gene methylation in gastric cancer in individuals from northern Brazil

7 páginas, 3 tablas, 1 figura.-- et al.Gastric cancer is one of the most common malignancies. DNA methylation is implicated in DNA mismatch repair genes deficiency. In the present study, we evaluated the methylation status of MLH1, MSH2, MSH6 and PMS2 in 20 diffuse- and 26 intestinal-type gastric cancer samples and 20 normal gastric mucosal of gastric cancer patients from Northern Brazil. We found that none of the nonneoplastic samples showed methylation of any gene promoter and 50% of gastric cancer samples showed at least one methylated gene promoter. Methylation frequencies of MLH1, MSH2, MSH6 and PMS2 promoter were 21.74%, 17.39%, 0% and 28.26% respectively in gastric cancer samples. MLH1 and PMS2 methylation were associated with neoplastic samples compared to nonneoplastic ones. PMS2 methylation was associated with diffuse- and intestinal-type cancer compared with normal controls. Intestinal-type cancer showed significant association with MLH1 methylation. Diffuse-type cancer was significantly associated with MSH2 methylation. Our findings show differential gene methylation in tumoral tissue, which allows us to conclude that methylation is associated with gastric carcinogenesis. Methylation of mismatch repair genes was associated with gastric carcinogenesis and may be a helpful tool for diagnosis, prognosis and therapies. However, MSH6 does not seem to be regulated by methylation in our samples.This study was supported by grants from FAPESP, FAEPA, CAPES, CNPq and Financiadora de Estudos e Projetos (FINEP/CT-INFRA 0927-03).Peer Reviewe

Loss of heterozygosity for distal markers on 22q in human gliomas

Loss of constitutional heterozygosity as determined through the analysis of restriction-fragment-length polymorphism (RFLP) on tumoral and constitutional DNA has proven to be helpful to delimit the location of tumor-suppressor genes in the human genome. In malignant gliomas this approach indicates that chromosomes 9p, 10, 17p, and 22 may contain genes of this category involved in its origin and/or progression. Regarding chromosome 22, the data so far provided by molecular studies confirmed those previously reported by cytogenetic studies, suggesting the existence of a sub-group of malignant gliomas characterized by monosomy of this chromosome. However, the precise location of the putative glioma suppressor gene on chromosome 22 remains ambiguous. We have perormed a combined cytogenetic and RFLP study on a series of 31 gliomas, looking for structural abnormalities of this chromosome. In 3 instances, terminal deletions of the long arm of chromosome 22 were observed by both methodologies, suggesting that the band q13 region distal to the D22S80 marker might be the critical domain non-randomly involved in tumor suppression of gliomas.Comunidad Autonoma de Madrid, Grant. Grant Number: C267/90 from PB 88-0079.Peer Reviewe

Molecular analysis of chromosomh 1 abnormalities in human gliomas reveals frequent loss of 1p in oligodendroglial tumors

Alterations of the short arm of chromosome I are recurrently found in cytogenetic analysis of malignant gliomas, and deletions of Ip36-p32 region characterize at least the higher-grade tumors, glioblastoma multiforme. Molecular analysis of tumor-derived and normal genomic DNA from 57 cases of gliomas, using a panel of chromosome I-specific DNA probes showed LOH in 16 tumors. Allelic losses on I p were primarily restricted to glioblastoma multiforme (2/11) and to tumors with a major oligodendroglial component: grade 11 oligodendrogliomas (6/6), grade 111 anaplastic oligodendrogliomas (5/6) and grade II-III mixed oligo-astrocytomas (2/3). Losses for Iq markers were detected in only I tumor (glioblastoma multiforme). Our data suggest that anomalies of Ip primarily characterize oligodendrogliomas, whereas they are rare events in astrocytic tumors and indicate that a tumor-suppressor gene on Ip36-p32 is involved in the development of brain tumors with oligodendroglial differentiation.Funded by Comunidad Autónoma de Madrid. Grant Numbers: C267/90, C367/92, Ministerio de Educación y Ciencia. Grant Number: SAF-92-0182 and Fundación Cientifica de la Asociación Española contra el Cáncer.Peer Reviewe

NF2 gene mutations and allelic status of 1p, 14q and 22q in sporadic meningiomas

Formation of meningiomas and their progression to malignancy may be a multi-step process, implying accumulation of genetic mutations at specific loci. To determine the relationship between early NF2 gene inactivation and the molecular mechanisms that may contribute to meningioma tumor progression, we have performed deletion mapping analysis at chromosomes 1, 14 and 22 in a series of 81 sporadic meningiomas (54 grade I (typical), 25 grade II (atypical) and two grade III (anaplastic)), which were also studied for NF2 gene mutations. Single-strand conformational polymorphism analysis was used to identify 11 mutations in five of the eight exons of the NF2 gene studied. All 11 tumors displayed loss of heterozygosity (LOH) for chromosome 22 markers; this anomaly was also detected in 33 additional tumors. Twenty-nine and 23 cases were characterized by LOH at 1p and 14q, respectively, mostly corresponding to aggressive tumors that also generally displayed LOH 22. All three alterations were detected in association in seven grade II and two grade III meningiomas, corroborating the hypothesis that the formation of aggressive meningiomas follows a multi-step tumor progression model.Peer Reviewe