Cleft lip/palate and CDH1/E-cadherin mutations in families with hereditary diffuse gastric cancer.

We report the association of CDH1/E-cadherin mutations with cleft lip, with or without cleft palate (CLP), in two families with hereditary diffuse gastric cancer (HDGC). In each family, the CDH1 mutation was a splicing mutation generating aberrant transcripts with an in-frame deletion, removing the extracellular cadherin repeat domains involved in cell-cell adhesion. Such transcripts might encode mutant proteins with trans-dominant negative effects. We found that CDH1 is highly expressed at 4 and 5 weeks in the frontonasal prominence, and at 6 weeks in the lateral and medial nasal prominences of human embryos, and is therefore expressed during the critical stages of lip and palate development. These findings suggest that alteration of the E-cadherin pathway can contribute to human clefting.

Chromosomal changes in human primary testicular nonseminomatous germ cell tumors.

A cytogenetic analysis of 14 primary testicular nonseminomatous germ cell tumors has been carried out after short term tissue culture. The modal chromosome numbers ranged from 53 to 113, in agreement with flow cytometric determination of the DNA content of the tumors. At least one copy of an i(12p) was present in 12 tumors. Two tumors, however, lacked that marker. Some chromosomes are apparently overrepresented, whereas others are underrepresented, although some differences between seminomas and nonseminomas were noticed.

Cytogenetic analysis of ten human seminomas.

A cytogenetic analysis of ten seminomas has been carried out after direct harvesting of the tumor cells. Modal chromosome numbers ranged from 63 to 112. These numbers were in agreement with flow cytometric determination of the DNA content of the tumors. Eight tumors had at least one copy of an i(12p) among other chromosomal abnormalities. Two seminomas lacked the i(12p).

Chromosomal changes in mature residual teratomas following polychemotherapy.

A cytogenetic analysis of 13 mature residual teratomas following chemotherapy revealed modal chromosome numbers ranging from 52 to 85, in agreement with the flow cytometric determination of the DNA content of the tumors. At least one copy of an i(12p) was present in 12 tumors. One tumor, however, lacked that marker. The comparison between the chromosomal abnormalities found in mature residual teratomas following chemotherapy and those from primary testicular nonseminomas suggests that residual teratomas result from selection of clones from the primary tumor with a less abnormal karyotype.

Four novel MSH2 / MLH1 gene mutations in portuguese HNPCC families.

Hereditary non-polyposis colorectal cancer (HNPCC) is considered to be determined by germline mutations in the mismatch repair (MMR) genes, especially MSH2 and MLH1. While screening for mutations in these two genes in HNPCC portuguese families, 3 previously unreported MSH2 and 1 MLH1 mutations have been identified in families meeting strict Amsterdam criteria. Hum Mutat 15:116, 2000.

Eleven novel APC mutations identified in Portuguese FAP families.

Germline mutations of the adenomatous polyposis coli (APC) gene are responsible for familial adenomatous polyposis (FAP), an autosomal dominant predisposition to colorectal cancer. In the present study we screened all of the exons of the APC gene in individuals belonging to 85 Portuguese FAP families. We here report eleven novel mutations which are predominantly frameshifts or single base substitutions, resulting in premature stop codons. Hum Mutat 16:178, 2000.

Analysis of FMR1 and flanking microsatellite markers in normal and fragile X chromosomes in Portugal: evidence for a "protector" haplotype.

In order to look for linkage disequilibrium between the fragile X locus and its flanking markers, we analysed the FRAXAC1 and DXS548 microsatellites in normal and fragile X individuals of Portuguese origin. We observed differences in allele and haplotype frequencies between these two samples. Four haplotypes (A-2, C-2, C-5 and D-6) accounted for 76% of all fragile X chromosomes, whereas a single haplotype (C-7) accounted for 70% of the normal population and less than 3% of the fragile X chromosomes. Among the four observed high-risk haplotypes, A-2 and D-6 had been previously reported in other studies, but C-2 and C-5 seem characteristic of Portuguese patients, as suggested by the high frequency (38%) in fragile X chromosomes and virtual absence in controls. In accordance with previous studies, a greater heterozygosity of the fragile X sample was noted when compared to that of controls. The high frequency of C-7 haplotype in the normal population and its virtual absence in the fragile X sample may reflect the existence of linkage disequilibrium between the two loci and/or selective advantage (protector effect) of this haplotype.

Molecular cytogenetic characterization of a small, familial supernumerary ring chromosome 7 associated with mental retardation and an abnormal phenotype.

A family is described in which a mother and two of her children were mosaic for a small supernumerary ring chromosome. As the origin of the ring chromosome could not be determined by routine cytogenetic studies, fluorescent in situ hybridization was performed, which indicated that the ring chromosome was derived from the pericentromeric region of chromosome 7. Further characterization with a YAC-probe showed the involvement of the proximal q-arm of chromosome 7. Both sibs had speech difficulties and were mildly mentally retarded whereas the mother's intelligence was at the lower end of the normal range. They all had an unusual face, characterized by a flat profile, short forehead, downslant of the palpebral fissures, high and broad nasal bridge, simply formed ears, and prognathia. This is the second report of a small supernumerary ring chromosome derived from the pericentromeric region of chromosome 7, and the described clinical phenotype differs from that delineated in the previous report.

Three cases of mosaicism for balanced reciprocal translocations.

Mosaicism for a balanced reciprocal translocation (BRTM) is rare. As far as we know only 26 cases of BRTM, demonstrated in lymphocyte cultures, have been described, five of which had an abnormal phenotype. Prenatally three confirmed cases with a normal phenotypic outcome have been described. Here we present three further cases of BRTM in lymphocyte cultures. The first was detected during a family study, the second after an abnormal karyotype in chorionic villus sampling, and the third because of a history of stillborn children. All three carriers have normal phenotypes. An inventory of the BRTM cases reported so far is made.

Angelman syndrome caused by loss of a marker chromosome: cytogenetic and fluorescence in situ hybridization analysis.

We report a cytogenetic and fluorescence in situ hybridization study of a family in which a female child showed all the main characteristics of Angelman syndrome. Her karyotype revealed a translocation between chromosomes 5 and 15 with a partial deletion from 15pter to the Angelman region. Several members of her family appeared to be carriers of the same translocation, but showed no symptoms. The karyotypes showed a marker chromosome, that was not present in the female with Angelman syndrome. Fluorescence in situ hybridization revealed that the marker chromosome corresponded to material from chromosome 15. The present study is in agreement with the suggestion that genomic imprinting is one of the mechanisms involved in Angelman syndrome.

Cytogenetic and fluorescence in situ hybridization studies in a case of anaplastic thyroid carcinoma.

Cytogenetic analysis of a case of anaplastic thyroid carcinoma revealed multiple numerical and structural chromosomal changes, including a der(9) add(9)(p22)hsr(9)(p?). Fluorescence in situ hybridization (FISH) studies performed to identify the genetic nature of this derivative chromosome showed that both the additional material and the hsr region were composed of only chromosome 9 sequences and that the C-ABL oncogene was not one of the genes harbored at the hsr region. We suggest that amplification of gene(s) located at chromosome 9, other than the C-ABL, may play a significant role in anaplastic evolution of thyroid carcinomas.

Familial gastric polyposis revisited. Autosomal dominant inheritance confirmed.

We update and review a large pedigree originally described by Santos and Magalhães with familial gastric polyposis and a high incidence of gastric cancer. The present observation of male-to-male transmission of the disease clearly demonstrates the autosomal dominant pattern of inheritance. The histologic review of the polyps present in several members of the family allowed the diagnosis of hyperplastic polyposis. Eight members of the family (two with concomitant gastric pathology) have severe cutaneous psoriasis. This finding may represent the existence of two different disorders segregating in the family or, alternatively, pleiotropic manifestations of the same gene.

Pathogenesis of adult testicular germ cell tumors. A cytogenetic model.

In essence, two models exist of the pathogenetic relationship between seminomas and nonseminomatous germ cell tumors (NSGCTs). In the first model, the histogenesis of seminomas is assumed to diverge from that of the other testicular germ cell tumors (TGCTs) at an early stage. The neoplastic pathway of seminomas and NSGCTs is different, with limited or no crossover. The second model suggests that seminomas and NSGCTs have a common origin with a single neoplastic pathway on which seminomas are an intermediate stage in development of NSGCTs. Our data on the cytogenetics and ploidy of seminomas, combined tumors, and NSGCTs lend support to the model of pathogenesis of seminomas and NSGCTs in which all TGCTs (with the possible exception of spermatocytic seminoma and infantile yolk sac tumor) have a single origin and neoplastic pathway, with seminomas representing an intermediate stage in development of NSGCT components, as opposed to the model in which seminomas and NSGCTs develop separately. The progression of TGCTs probably proceeds from high to lower numbers of chromosomes and is therefore accompanied by a net loss of chromosomal material. This decrease will be the end result of loss of specific chromosomes, gain of some other chromosomes (or part of chromosomes), and development of structural abnormalities.

Cytogenetic study of a combined germ cell tumor of the testis.

The cytogenetic findings in both components of a combined germ cell tumor of the testis are described. The only structural chromosomal abnormality in common was an i(12p).

Thyroid nodular hyperplasia: chromosomal studies in 14 cases.

Cytogenetic study of 14 thyroid nodular hyperplasias revealed a hyperdiploid karyotype in two cases (14%) and a normal chromosomal complement in the remaining cases. Some of the numerical alterations found were identical to the ones considered characteristic of a subset of thyroid adenomas (+5, +7, +9, +12, +14, and +16). Our findings suggest that the cytogenetic events involved in the pathogenesis of thyroid hyperplastic lesions and benign tumors may be closely related, which supports the hypothesis of a biologic "continuum" between these two types of lesions.

Cytogenetic study of a sclerosing stromal tumor of the ovary.

We describe a sclerosing stromal tumor (SST) of the ovary with monosomy of chromosome 16 and pathologic features consistent with a low-grade malignancy. So far, all described cases of SST were considered benign.

p53 alterations in gastric carcinoma: a study of 56 primary tumors and 204 nodal metastases.

We have looked for LOH, mutation, and expression of p53 in a series of 56 primary gastric carcinomas, using Southern blotting, constant denaturant gel electrophoresis (CDGE), direct sequencing, and immunohistochemistry. Two hundred-four lymph node metastases from 36 of these cases were also studied by immunohistochemistry. Loss of constitutional heterozygosity for the p53 locus was detected in five of 16 informative cases; in four of these cases there was a concurrent point mutation at the retained allele. Immunoreactivity for p53 product and mutation of p53 were observed in nine and 10 of the 56 tumors, respectively. There was no significant relationship between p53 immunoreactivity or mutation and pathologic features. The overall prevalence of p53 mutations, as detected by CDGE, was 18%. Direct sequencing confirmed p53 mutations (all G:C-A:T transitions) in seven cases, six of which were missense mutations; the remaining case was a silent mutation. In three of the cases with missense mutations, these occurred at CpG dinucleotides (codons 175, 273, and 282). Three cases with immunoreactivity for p53 product in the primary tumor also showed positive staining in the metastases. In two of these cases (with six and nine metastases, respectively) a positive staining was observed in all lymph node metastases, whereas in the remaining case only two of four nodal metastases were positively stained. In no single case was a positive staining observed in a metastasis where the primary tumor gave a negative staining result. Five of the six cases with p53 mutations and fresh material available for cell culture were successfully grown in vitro and all had abnormal karyotypes.

Loss of Y chromosome in gastric carcinoma. Fact or artifact?

Loss of chromosome Y has been reported in gastric cancer cells together with other chromosomal abnormalities. We noted loss of chromosome Y and near-diploid karyotypes in five cases of gastric adenocarcinoma, but DNA flow cytometry performed on fresh tumor tissue showed aneuploid peaks in four of them. Our findings suggest that loss of the Y chromosome in gastric cancer probably reflects the karyotype of a subpopulation of stromal cells and not a neoplasia-related chromosomal aberration.

Cytogenetic findings in 18 follicular thyroid adenomas.

Cytogenetic study of 18 follicular thyroid adenomas showed clonal chromosome changes in 12 tumors. These results suggest the existence of at least three cytogenetically distinct subgroups: a hyperploid group characterized by the presence of a cluster of numerical changes including +5, +7, and +12 as the most frequent anomalies and, less frequently, +4, +9, +14, +16, and +17; a pseudo- or near-diploid group characterized by simple karyotypic aberrations; and a cytogenetically normal group.