In Drosophila, the Slit gene product, a secreted glycoprotein, acts as a midline repellent to guide axonal development during embryogenesis. Three human Slit gene orthologues have been characterised and recently we reported frequent promoter region hypermethylation and transcriptional silencing of SLIT2 in lung, breast, colorectal and glioma cell lines and primary tumours. Furthermore, re-expression of SLIT2 inhibited the growth of cancer cell lines so that SLIT2 appears to function as a novel tumour suppressor gene (TSG). We analysed the expression of SLIT3 (5q35 -34) and SLIT1 (1q23.3 -q24) genes in 20 normal human tissues. Similar to SLIT2 expression profile, SLIT3 is expressed strongly in many tissues, while SLIT1 expression is neuronal specific. We analysed the 5 0 CpG island of SLIT3 and SLIT1 genes in tumour cell lines and primary tumours for hypermethylation. SLIT3 was found to be methylated in 12 out of 29 (41%) of breast, one out of 15 (6.7%) lung, two out of six (33%) colorectal and in two out of (29%) glioma tumour cell lines. In tumour cell lines, silenced SLIT3 associated with hypermethylation and was re-expressed after treatment with 5-aza-2 0 -deoxycytidine. In primary tumours, SLIT3 was methylated in 16% of primary breast tumours, 35% of gliomas and 38% of colorectal tumours. Direct sequencing of bisulphite-modified DNA from methylated tumour cell lines and primary tumours demonstrated that majority of the CpG sites analysed were heavily methylated. Thus, both SLIT2 and SLIT3 are frequently methylated in gliomas and colorectal cancers, but the frequency of SLIT3 methylation in lung and breast cancer is significantly less than that for SLIT2. We also demonstrated SLIT1 promoter region hypermethylation in glioma tumour lines (five out of six; 83%), the methylation frequency in glioma tumours was much lower (two out of 20; 10%). Hence, evidence is accumulating for the involvement of members of the guidance cues molecules and their receptors in tumour development.
The degree of nodal involvement in a consecutive series of 400 patients with invasive ductal breast cancer is presented. A positive correlation was observed between the number of metastatic nodes identified and the number of axillary nodes examined for poorly but not moderately differentiated tumours. The relevance of this observation to breast cancer trials is discussed.
Germline loss-of-function mutations in BRCA1 are associated with a high lifetime risk of breast and ovarian cancer. Most mutations in the gene are 'truncating': in the main these induce premature termination codons, resulting in nonsense-mediated decay, loss of the transcript and/or the entire protein. The improved screening methods now in use across the UK will identify many carriers of unclassified BRCA1 variants. These are chiefly missense mutations, introducing an amino acid change in the context of an expressed protein. Indeed more than one-quarter of entries recorded in the Breast Cancer Information Core dataset of BRCA1 sequence variants collected from patients worldwide are unclassified missense alterations (http://research.nhgri.nih.gov/bic/). Currently, discovery of the majority of missense variants leaves both variant carriers and their families in an ambiguous position.
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