#4052 Background: As cancer is a disease of ageing, factors involved in biological ageing may be informative in investigating the underlying mechanisms of cancer pathogenesis. How biological age is affected by epigenetic changes remains to be fully determined. This is pertinent to cancer pathogenesis, as epigenetic changes can increase the risk of neoplasia. We have investigated the biological age of breast tumours, using telomere length and the expression of sirtuin 7, a gene involved in the regulation of ribosome biosynthesis and previously demonstrated as potentially prognostic in breast cancer. We have evaluated these for association with epigenetic status.
 Materials and Methods: Telomere lengths and Sirtuin 7 (SIRT7) expression were determined using Q-PCR. Epigenetic status was determined using a Methylamp Global DNA methylation kit. Statistical analysis was performed using SPSS v15.
 Results: Chronological age was negatively associated with telomere length (p=0.013) and positively associated with methylation levels (p=0.007). Furthermore, telomere length showed a negative association with global methylation levels (p=0.002). Individuals with shorter telomeres were older and demonstrated higher levels of global DNA methylation. SIRT7 expression was positively associated with telomere length (p=0.01), but showed no association with methylation levels. Linear regression analysis indicated that SIRT7 expression accounted for 52.2% of the observed variability in telomere length (p=0.001) and methlyation for 33.4% (p<0.001). Multiple linear regression analysis indicated that methylation status and SIRT7 expression combined accounted for 69.4% of the observed variability in telomere length. Chronological age was not a significant contributor in either analysis.
 Discussion: Cells with critically short telomeres present a high risk of becoming neoplastic, as they are biologically aged. This study has demonstrated that both SIRT7 expression and global methylation levels significantly influence telomere attrition in breast cancer. This is consistent with a scenario whereby the rate of biological ageing in breast tumours is influenced by telomere mediated epigenetic changes and mechanistically by cellular proliferation requirements. The latter is manifest through SIRT7 regulated ribosome biogenesis. These findings support the use of SIRT7 as a potential prognostic tool and therapeutic target in breast cancer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4052.
#3088 Introduction: There has been a significant improvement in breast cancer survival in the UK in recent decades. Changes in the molecular epidemiology of breast cancers may have contributed to this, but the existing evidence may be confounded by heterogeneity of laboratory protocols. This study aimed to re-analyse the molecular profile of breast cancers from two different time periods using archived tissue. Methods: Archived tumour samples from all breast cancer patients at two Glasgow hospitals between 1984-86 and 1996-97 were sought, and linked to clinicopathologic, screening, demographic and survival data. Patients in the 1984-6 cohort would not have been offered mammographic screening but those in 1996-97 would have. Samples were placed in tissue microarrays and underwent immunohistochemistry for ER, PR and Her-2 status with strict standardisation. H&E sections were constructed to assess tumour grade. Statistical analysis included Kaplan-Meier survival analysis and Cox's regression. Results: 900 tumour samples underwent staining. In 1984-86, 8% of tumours were grade 1 and 42.9% grade 3 but in 1996-97 14.9% were grade 1 and 36.8% grade 3 (p=0.009). This effect appeared to be exerted by the presence of screen detected tumours in 1996-97 (p for difference in grade distribution between symptomatic patients between 1984-86 and 1996-97 = 2). In 1984-86 64.2% of tumours were ER positive and in 1996-97 71.5% were ER positive (p=0.042). This did not appear to be a function of the screening programme as there was a significant rise in ER positivity in symptomatic patients between the two cohorts (p=0.024). 44.9% of tumours in 1984-86 and 49.9% of tumours in 1996-97 were PR positive (p=0.181). 21.5% of tumours in 1984-86 and 20.6% of tumours in 1996-97 were Her-2 positive (p=0.772). 5-year survival in 1984-1986 patients was significantly lower than in 1996-1997 patients (p<0.001). When the effect of cohort on survival was adjusted for these changes in ER status and grade, cohort remained a significant independent factor. Conclusions: This study suggests a small but significant rise has occurred in the incidence of ER positive tumours in women in Glasgow. There has also been a shift in grade distribution of tumours, which is likely to be an effect of the NHS screening programme. The changes do not fully explain improvements in breast cancer survival but should be borne in mind when applying the results of clinical trials performed in the past to the women of today. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3088.
Background Systemic sclerosis is a immune mediated inflammatory disease culminating in vasculopathy and extensive fibrosis of the skin and internal organs. Telomere shortening has previously been described in small cohorts of SSc patients. Objectives To scrutinize previous findings in large cohort, investigate telomere shortening in multiple immune celltypes and scrutinize underlying aberrances in telosome gene expression. Methods We measured telomere length by qPCR in a cohort of 185 SSc patients and 100 healthy controls. Next we investigated plasmacytoid dendritic cells, T cells, B cells, monocytes and myeloid dendritic cells from 25 SSc patients for cell specific telomere attrition. Finally we investigated whether there were differences in expression of 31 genes involved in telomere pathways. Results A significant age related telomere attrition was observed in healthy controls and lcSSc patients (Both p< 0.001), but not in dcSSc patients. We observed significant shorter telomeres in B cells and myeloid dendritic cells of both lcSSc and dcSSc patients (B-Cells p=0.014, p=0.002 & myDCs p=0.019, p=0.004 respectively). PDCs and T cells had shorter telomeres in dcSSc patients only (p=0.001 and p=0.003). In addition, we observed in early SSc, that B cells exhibit a significant upregulation of the telosome genes SIRT6, RIF1 and WRN (after correction for multiple testing p=0.03, 0.006 and 0.048 respectively). In later disease there is a significant higher expression of HDAC9 in monocytes from dcSSc compared to lcSSc patients. Intriguingly, in PDCs of diffuse SSc patients, regardless whether it is early or progressed disease the expression of SIRT1 is significantly lower (p=0.002 in all comparisons). Image/graph Conclusions Aberrances in telomere shortening and biology are a feature of SSc, reflecting a difference in clinical subsets at the cellular level. Disclosure of Interest None Declared
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