Precursor lesions of CC, named cervical intraepithelial neoplasia (CIN), are classically divided into CIN1, CIN2, and CIN3, of which CIN3 is considered the most advanced precursor. Common practice is that all CIN2 and CIN3 are treated to prevent CC development. However, it is well known in the field that many of these CIN2 and some of CIN3 spontaneously regress, making treatment actually unwarranted. Current CIN classification is not able to identify which lesions will progress. The present treatment approach thereby leads to considerable overtreatment and cervical morbidity, including frequent preterm birth and cervical insufficiency in women at fertile age.
DNA methylation analysis of genes involved in CC development represents an important change in the concept of treatment of CIN2/3. A positive methylation test reflects a cancer-like methylation-high pattern. This methylation pattern can be used as a biomarker for the detection of advanced lesions, defined as CIN2/3 lesions associated with a duration of HPV infection >5years and having many chromosomal alterations. These advanced CIN lesions (i.e. part of the CIN2 and most CIN3 lesions) have a high short-term risk of progression to CC and are in need of treatment [Steenbergen et al. Nat Rev Cancer 2014]. This concept fits well with knowledge in the field that CIN2/3 lesions are heterogeneous, both in clinical behavior and with respect to (epi)genetic alterations. For instance, most CIN2/3 lesions at young age (<30 years) will not develop into cancer and mainly regress. This means that the methylation-negative CIN2 and CIN3 lesions, which are detected by current cytology and/or HPV testing, are in fact early lesions with a low chance of progression and may not need treatment within 1-3 years. The use of DNA methylation analysis can reduce overdiagnosis and overtreatment, which is especially important for women at fertile age. To translate this new view - which can be seen as a paradigm shift in the treatment of CIN lesions - to profound benefits to women and for the economics of healthcare, the Valid-screen project has played an important role. The project enabled the collaboration with several international European laboratory sites with well-documented clinical specimens to perform the necessary clinical validation studies to support the new concept and enforce the paradigm shift.
