Anna Berardi

High Incidence of Familial Gastric Cancer in Tuscany, a Region in Italy

Objectives: Only 1% of diffuse gastric cancers occur in families with autosomal dominant gastric cancer susceptibility. Germline mutations in the E-cadherin gene account for the hereditary diffuse gastric cancer (HDGC) syndrome. We studied a large cohort of gastric cancer patients from Tuscany, a region in Italy, to evaluate the presence of familial clustering of gastric cancer. Methods: 238 pedigrees were retrospectively studied by structured interviews. All probands with diagnosed gastric cancer were contacted in-person or by phone and tumor types were assessed in first- and second-degree relatives. Familial aggregation was investigated in order to search for families with suspected HDGC. Results: Familial aggregation for gastric cancer was observed in 79 of 238 cases (33.2%). Among these, there were 64 families (81%) with one gastric cancer other than the proband, 10 families with two gastric cancers (12.7%) and 5 families with three gastric cancers (6.3%). Fourteen families fulfilled the HDGC clinical criteria, one of them presenting with a pathogenic germline mutation in the E-cadherin gene (7.1%). Conclusions: The prevalence of familial HDGC appears extremely high. Since only one pathogenic germline mutation was noted in a family fulfilling the HDGC clinical criteria, factors other than E-cadherin gene mutations may contribute to the familial clustering of HDGC.

Central nervous system imaging in reevaluation of patients with neurofibromatosis type 1

We report the results of the reevaluation of 24 patients with neurofibromatosis type 1 (NF1) using central nervous system (CNS) imaging techniques. The first examination by computed tomography (CT) or magnetic resonance imaging (MRI) indicated the presence of optic glioma in three cases, “unidentified bright objects” (UBOs) in six, and a suspected right frontal tumor in one. In two patients optic glioma and UBOs were both present and in one of them a bulbar tumor was also suspected. Later imaging examinations revealed the appearance of optic glioma in three more cases and UBOs in nine. In two of these patients both optic glioma and UBOs were present. This study indicates that the likelihood of detecting imaging abnormalities in patients with NF1 increases when systematic follow-up is performed. Optic gliomas are characteristic of pediatric patients; they rarely give rise to clinical manifestations (1/6 cases) and in general progress very slowly. For these reasons, therapeutic strategy must be carefully considered and individually decided. UBOs are very frequent findings in pediatric patients with NF 1 and therefore they must be considered diagnostically relevant. They are not related to clinical manifestations and spontaneous regression has been observed. The nature of these imaging abnormalities is still unknown, but because they do not behave like tumors, useless and dangerous therapeutic procedures should not be employed.

CDH1 C-160A promoter polymorphism and gastric cancer risk.

The objective of this study was to find out whether C-160A single nucleotide polymorphism of the promoter region of the E-cadherin gene might be a potential genetic marker for identifying individuals at risk for gastric cancer (GC). To test this hypothesis, 412 GC patients and 408 controls were analyzed statistically. A PCR-restriction fragment length polymorphism assay was adopted for C-160A single nucleotide polymorphism detection. No statistical differences were found among CC, CA, and AA genotypes and the risk of GC, even stratifying according to age, sex, and area of residence. Similarly, genotype was not associated with intestinal or diffuse histotypes, or with cardia or noncardia carcinomas. In conclusion, the C-160A polymorphism is not associated with GC risk in the Italian population.

Quantification of psychosine in the serum of twitcher mouse by LC-ESI-tandem-MS analysis.

Globoid cell leukodystrophy or Krabbe disease is an inherited autosomal recessive disorder caused by mutations in the galactosylceramidase (GALC) gene. Deficiency of GALC results in the accumulation of a highly cytotoxic metabolite galactosylsphingosine (psychosine). In the present study, we describe the development and validation of a sensitive and specific LC-ESI-tandem-MS method for the determination of psychosine in the serum of twitcher mice, the naturally occurring animal model of this disease. The method was validated in terms of accuracy, precision, specificity, linearity and sensitivity. Calibration plots were linear over the concentration range of 2.5-50ng/mL. Recovery of psychosine from serum was in the range 94.20-98.02%. The results of this study show that in the affected mice the concentration of psychosine (ranging from 2.53 to 33.27ng/mL) increased significantly with the progression of the disease. The maximum level (33.27ng/mL) was detected in the serum of one of the twitcher mice sacrificed at 40PND. Psychosine was not detected at significant levels in wild type mice. These results clearly demonstrate that this noninvasive, rapid, and highly sensitive LC-ESI-tandem-MS method is a very useful approach for the detection of psychosine in serum.

Influence of age on soluble E-cadherin serum levels prevents its utility as a disease marker in gastric cancer patients

TO THE EDITOR: E-cadherin is one of the most important candidate genes in gastric carcinogenesis. The reduction of E-cadherin expression in cancer tissue seems to be associated with the aggressiveness and metastatic ability of the tumour [1]. Although, the role of circulating forms of E-cadherin has not been completely elucidated, several investigators have reported the presence of soluble E-cadherin in patients with malignancies [2], particularly in tumours of epithelial origin such as gastric cancer, suggesting a possible role as a tumour marker of diagnostic and prognostic value [2 5].

Diagnosis of neurofibromatosis type 1 using RFLPs tightly linked to gene

This study reports the results of a linkage analysis in nine families with members who had neurofibromatosis type 1 (NF1), using five restriction fragment length polymorphisms (RFLPs) tightly linked to the NF1 locus. The purpose of this analysis was to determine whether the at-risk individuals were carrying the NF1 allele and whether the nine families would be informative for prenatal testing. The families included 25 patients with NF1, 3 individuals at risk for NF1, and 11 unaffected subjects, with a total of 39 family members and 12 matings. In 6 matings two or more flanking probes were informative, in 3 matings only one probe was informative, and in the other 3 no probe was informative. DNA linkage analysis showed with more than 98% probability that the 3 at-risk individuals did not carry the NF1 mutation. No recombination events were observed. In 6 families it will be possible to do a DNA prenatal diagnosis if this type of test is requested. The NF1 gene has been identified and direct testing for the NF1 mutation is now possible. Linkage testing, however, will probably remain useful and complementary to direct analysis of the NF1 gene to reveal intragenic recombination events and for diagnosis in families in which the detection of mutation is difficult.

Purification and Characterization of UDP-GAL: Ceramide Galactosyltransferase and Reconstitution of its Activity by Incorporation into Liposomes

The UDP-gal: ceramide galactosyltransferase (CGalT) (EC 2.4.1.45) catalyzes the last step in the synthesis of the myelin- characteristic lipid, galactosylceramide (Morell and Radin, 1969). The Oligodendroglia and Schwann cells are the primary site of localization of this enzyme, and its presence in myelin has been firmly established biochemically and (Neskovic et al., 1973; Costantino-Ceccarini and Suzuki, 1975; Koul and Jungalwala, 1981; Roussel et al., 198ssel et al., 1987). While considerable amounts of information are available regarding the properties of the enzyme in the literature, the majority of these studies were carried out with membrane-bound enzyme preparations, and to date, nothing is known about in vivo regulation of the activity of this enzyme during development. The question of regulation of the synthesis of galactosylceramide and other myelin lipids must be considered in a wider context of regulation of synthesis of the myelin membrane. Considerable progress has been made in the understanding of synthesis of myelin-specific proteins at the molecular level. Similar studies with respect to the myelin-specific lipids have been hampered by the difficulties encountered in the purification of the respective synthetic enzymes due to the highly hydrophobic nature of these proteins.