LA TENDENCIA GENERAL AL FORMALISMO
RACIONALIDAD FORMAL» E IRRACIONALIDAD SUSTANTIVA
Faecal matter is easily collected and faecal occult blood testing is currently used as a screening tool in the UK which has limited sensitivity in part due to a reliance on the tumour being a bleeding phenotype (Young, Bosch 2011). Potential diagnostic molecular markers have been detected in faeces. In a case control study of 94 cancers and 198 healthy controls methylation of the vimentin gene had a sensitivity of 46% and a specificity of 90% for the detection of colorectal cancer (Chen, Han et al. 2005). Another group found sensitivity improved to 75% when vimentin was considered as part of a methylation panel inclusive of MGMT and hmlH1 specificity of 87% was comparable to the single marker study. This panel also detected adenoma with a sensitivity of 60% and may be useful in detection of premalignant disease (Baek, Chang et al. 2009). A panel of genes containing hypermethylated vimentin and mutation of KRAS and APC was found to be more sensitive for the detection of colorectal cancer than faecal occult blood testing (Ahlquist, Sargent et al. 2008). In future testing molecular markers may increase the sensitivity of the existing screening tools for colorectal carcinoma.
1.4.3.2 Urine
Urine is sterile, accessible and already has a place in clinical diagnostics being used for hormonal assays and screening for glucosuria and proteinuria which are early indicators of chronic disease. Promising molecular markers for the detection of urogenital cancers have now emerged in the literature. Promoter methylation of GSTP1 is tumour specific in prostate cancer and has been detected in the urine of patients with biopsy confirmed prostate cancer with a sensitivity of 75% and specificity of 98% (Woodson, O’Reilly et al.
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2008). In a case control study of 52 patients with prostate cancer and 91 age-matched controls the presence of at least one positive marker from a panel of four genes GSTP1, ARF, MGMT and P16 had a sensitivity of 87% and a specificity of 100% for the detection of biopsy proven prostate cancer (Hoque, Topaloglu et al. 2005). The same group also note that methylation of GSTP1 detected in tumours at primary surgery is a significant factor in the time to progression of the disease (Rosenbaum, Hoque et al. 2005) and may have a role as a prognostic marker.1.4.3.3 Sputum
Sputum is primarily used in lung cancer research and methylation at the promoter of P16
shows promise for the detection of lung cancer from sputum samples (Palmisano, Divine et al. 2000, Belinsky, Liechty et al. 2006, Belinsky, Grimes et al. 2007). A sensitivity of 66.7% for the detection of non-small-cell lung carcinoma (NSCLC) is reported using P16
methylation detected by MSP as a marker in the sputum of 50 patients. Chronic heavy smokers were used as a control group (n=100). Four percent had detectable P16 promoter methylation in sputum samples (Destro, Bianchi et al. 2004). No follow-up data is provided for this high risk group so it is unclear if they represent undiagnosed early cancer or a high risk group as P16 could be a marker of field cancerisation. More recently a large case control study of promoter methylation of P16, TERT, WT1 and RASSF1 inbronchial washings established this panel of biomarkers is more sensitive for the detection of lung cancer than cytological assessment which is currently part of the lung cancer diagnostic pathway in the UK (Nikolaidis, Raji et al. 2012).
1.4.3.4 Blood
The actual origin of free DNA in blood is unknown but there is a theory of phagocytic ingestion of solid tumour cells or circulating tumour cells that undergo necrosis and release DNA (Wong, Dennis Lo et al. 2001). Blood is non tissue specific and both serum and plasma have been used to detect molecular markers associated with solid tumours in various organs such as detection of ovarian cancer (De Caceres, Battagli et al. 2004), prostate cancer (Bryzgunova, Morozkin et al. 2008, Payne, Serth et al. 2009), colorectal cancer (Tänzer, Balluff et al. 2010) and HNSCC (Carvalho, Jeronimo et al. 2008). In addition to diagnostics, methylation markers in blood have also been used as predictive biomarkers in chemotherapy trials for solid tumours.
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Fiegl et al (Fiegl, Jones et al. 2008) investigated serum NEUROD 1 methylated DNA as a predictor of chemosensitivity in a cohort of 107 breast cancer patients using quantitative MSP. High levels of NEUROD 1 methylation in oestrogen receptor negative breast cancer tissue is associated with a 10.8 fold increase in response following neoadjuvant chemotherapy (sensitivity: 80% specificity: 72%). Oestrogen receptor negative patients with NEUROD 1 methylation present in pre and post treatment sera had a significantly worse relapse-free and overall survival compared with those who had become NEUROD 1
free in post treatment sera p=0.01. Pre-treatment and post-treatment plasma samples from multistage ovarian cancer patients receiving carboplatin taxoid chemotherapy as part of a stage III trial were collected. One hundred and thirty eight patients with relapse provided a matched pre-treatment and an at relapse plasma sample. 16/138 (12%) of patients were positive pre-treatment and 45/138 (33 %) at relapse which represents a significant increase (p<0.001) in hMLH1 methylation at relapse what is more the post- treatment acquisition of hypermethylated hMLH1 in plasma samples is associated with worsened survival (p=0.007) (Gifford, Paul et al. 2004).
In terms of translation into clinical use, surrogate derived epigenetic biomarker research is still evolving. This is in part because tissue epigenetic research continues to answer questions about tissue heterogeneity and normal levels of methylation. Currently in the HNSCC surrogate literature there are differences in sample collection, assay types and conditions and statistical analysis that make direct inter-study comparisons difficult and any definitive conclusions about specific genes difficult to draw.