The cell-cell adhesion receptor gene E-cadherin (CDH1) is expressed by epithelial cells, in which it mediates adhesion and morphogenesis. Invasive lobular carcinoma (ILC) characteristically infiltrates diffusely as single cells; by immunohistochemistry, many of these tumours lack E-cadherin expression. In the present study we investigated various ways in which loss of function of the E-cadherin gene could occur in ILCs, namely, promoter methylation, mutation and allelic loss. We analysed 22 ILCs and found 12 (55%) E-cadherinnegative samples by immunohistochemical analysis. Methylation-specific polymerase chain reaction (PCR) showed that 17/22 (77%) of these tumours had methylation of the CDH1 promoter, including 11/12 (91%) of the E-cadherin-negative tumours. All 16 exons of E-cadherin (including intron-exon boundaries) were amplified from chromosomal DNA and screened for mutations by conformation-sensitive gel electrophoresis (CSGE). Bands with altered mobility were analysed by direct sequencing. We identified five frameshift mutations, which resulted in downstream stop codons and one splice site mutation in six different tumours (29%). Loss of heterozygosity (LOH) was assessed using microsatellite markers, and 9/18 (50%) informative tumours showed LOH. We conclude that most ILCs show genetic or epigenetic changes affecting the E-cadherin gene and that many of these tumours lack E-cadherin expression. In all cases in which there was loss of expression, this was consistent with biallelic inactivation of CDH1 by promoter methylation, mutation or allelic loss in any combination. © 2001 Wiley-Liss, Inc. Key words: breast lobular carcinoma; E-cadherin; LOH; promoter methylationE-cadherin is a transmembrane glycoprotein, expressed mainly in epithelial cells, which mediates calcium-dependent cell-cell adhesion through homophilic interactions while controlling cell polarity and morphogenesis. 1 An intracellular domain interacts with the catenins, and, through these proteins, E-cadherin is linked to the cytoskeleton. 2 The gene (CDH1, HSECAD) maps to 16q22.1 and consists of 16 exons. The CDH1 promoter, originally identified by Behrens et al., 3 has a high GC-rich region that may be implicated in transcriptional regulation.Downregulation of E-cadherin levels has been associated with reduced differentiation and poorer prognosis in breast cancer, 4 -6 although this has not been an universal finding. 7 Previous studies from our own institute and other centres have documented loss of E-cadherin expression, as determined by immunohistochemistry, in around 85% or more of invasive lobular carcinomas (ILCs) and lobular carcinoma in situ (LCIS). 8,9 Such findings suggest that the absence of expression of this molecule could play an important role in determining morphology as well as in mediating the distinct pattern of invasion of this tumour. A more recent report has shown simultaneous loss of ␣-and ␤-catenin expression in E-cadherinnegative lobular breast carcinomas. 10 Reduced immunoreactivity of any of the four proteins (E-ca...

Objective We reported the alveolar bone histology prior to dental extractions in cancer patients, who received bone‐targeting agents (BTA). Subjects and Methods Fifty‐four patients were included. Patients underwent extractions, and bone biopsies were taken. Results Extractions were performed due to pain, swelling, purulence, fistula, and numbness, not responding to treatment, in 40 patients (group A); extractions due to asymptomatic, non‐restorable teeth, were performed in 14 patients (group B). Complete alveolar jaw bone histological necrosis was observed in 28 of 40 (70%) patients of group A and none of group B (p < .001). The development of clinical osteonecrosis (MRON) was assessed in 44 patients; 10 patients, who were also treated with Low Level Laser Treatments‐LLLT, were excluded from this analysis, as the alternative therapies were a confounding factor. Twelve patients, with alveolar bone histological necrosis prior to extraction, developed medication‐related osteonecrosis of the jaw (MRONJ) compared with two patients with vital or mixed vital/non‐vital bone (p < .0007). BTAs >1 year and concurrent targeted therapy were also significantly associated with MRONJ (p = .016 and p = .050). Conclusion Pain, swelling, purulence, fistula, and numbness were significantly associated with complete bone histological necrosis prior to extractions and increased MRONJ development. Research is justified to explore whether histological necrosis represents an early stage of osteonecrosis.

We have screened 473 breast/ovarian cancer patients with family history, aiming to define the prevalence and enrich the spectrum of BRCA1/2 pathogenic mutations occurring in the Greek population. An overall mutation prevalence of 32% was observed. Six BRCA1 recurrent/founder mutations dominate the observed spectrum (58.5% of all mutations found). These include three mutations in exon 20 and three large genomic deletions. Of the 44 different deleterious mutations found in both genes, 16 are novel and reported here for the first time. Correlation with available histopathology data showed that 80% of BRCA1 carriers presented a triple-negative breast cancer phenotype while 82% of BRCA2 carriers had oestrogen receptor positive tumours. This study provides a comprehensive view of the frequency, type and distribution of BRCA1/2 mutations in the Greek population as well as an insight of the screening strategy of choice for patients of Greek origin. We conclude that the Greek population has a diverse mutation spectrum influenced by strong founder effects.

Grade I invasive ductal breast carcinomas have a specific pattern of genetic aberrations, namely gain of 1q and loss of 16q. This pattern is very similar to the changes seen in invasive lobular breast carcinomas (ILCs). The gene on 16q involved in ILC is known to be E-cadherin (CDH1). This study has investigated whether the same gene is responsible for grade I invasive ductal carcinoma (IDC), using allele imbalance analysis, mutation screening, and immunohistochemistry (IHC). The data suggest that despite the shared pattern of genetic aberrations seen in grade I IDC and ILC, CDH1 is not the target gene in low-grade ductal tumourigenesis.