BackgroundAs screening methods for colorectal cancer (CRC) are limited by uptake and adherence, further options are sought. A blood test might increase both, but none has yet been tested in a screening setting.ObjectiveWe prospectively assessed the accuracy of circulating methylated SEPT9 DNA (mSEPT9) for detecting CRC in a screening population.DesignAsymptomatic individuals ≥50 years old scheduled for screening colonoscopy at 32 US and German clinics voluntarily gave blood plasma samples before colon preparation. Using a commercially available assay, three independent blinded laboratories assayed plasma DNA of all CRC cases and a stratified random sample of other subjects in duplicate real time PCRs. The primary outcomes measures were standardised for overall sensitivity and specificity estimates.Results7941 men (45%) and women (55%), mean age 60 years, enrolled. Results from 53 CRC cases and from 1457 subjects without CRC yielded a standardised sensitivity of 48.2% (95% CI 32.4% to 63.6%; crude rate 50.9%); for CRC stages I–IV, values were 35.0%, 63.0%, 46.0% and 77.4%, respectively. Specificity was 91.5% (95% CI 89.7% to 93.1%; crude rate 91.4%). Sensitivity for advanced adenomas was low (11.2%).ConclusionsOur study using the blood based mSEPT9 test showed that CRC signal in blood can be detected in asymptomatic average risk individuals undergoing screening. However, the utility of the test for population screening for CRC will require improved sensitivity for detection of early cancers and advanced adenomas.Clinical Trial Registration Number:NCT00855348

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The observation that mutations in tumor suppressor genes can have haploinsufficient, as well as gain of function and dominant negative, phenotypes has caused a reevaluation of the 'two-hit' model of tumor suppressor inactivation. Here we examine the history of haploinsufficiency and tumor suppressors in order to understand the origin of the 'two-hit' dogma. The two-hit model of tumor suppressor gene inactivation was derived from mathematical modeling of cancer incidence. Subsequent interpretations implied that tumor suppressors were recessive, requiring mutations in both alleles. This model has provided a useful conceptual framework for three decades of research on the genetics and biology of tumor suppressor genes. Recently it has become clear that mutations in tumor suppressor genes are not always completely recessive. Haploinsufficiency occurs when one allele is insufficient to confer the full functionality produced from two wild-type alleles. Haploinsufficiency, however, is not an absolute property. It can be partial or complete and can vary depending on tissue type, other epistatic interactions, and environmental factors. In addition to simple quantitative differences (one allele versus two alleles), gene mutations can have qualitative differences, creating gain of function or dominant negative effects that can be difficult to distinguish from dosage-dependence. Like mutations in many other genes, tumor suppressor gene mutations can be haploinsufficient, dominant negative or gain of function in addition to recessive. Thus, under certain circumstances, one hit may be sufficient for inactivation. In addition, the phenotypic penetrance of these mutations can vary depending on the nature of the mutation itself, the genetic background, the tissue type, environmental factors and other variables. Incorporating these new findings into existing models of the clonal evolution will be a challenge for the future.