Why there are TP53 mutation in non-cancer samples? Really feel surprising??
http://www.ncbi.nlm.nih.gov/pubmed/27377626
Identification of Circulating Tumor DNA for the Early Detection of Small-cell Lung Cancer.
Circulating tumor DNA (ctDNA) is emerging as a key potential biomarker for post-diagnosis surveillance but it may also play a crucial role in the detection of pre-clinical cancer. Small-cell lung cancer (SCLC) is an excellent candidate for early detection given there are no successful therapeutic options for late-stage disease, and it displays almost universal inactivation of TP53. We assessed the presence of TP53 mutations in the cell-free DNA (cfDNA) extracted from the plasma of 51 SCLC cases and 123 non-cancer controls. We identified mutations using a pipeline specifically designed to accurately detect variants at very low fractions. We detected TP53 mutations in the cfDNA of 49% SCLC patients and 11.4% of non-cancer controls. When stratifying the 51 initial SCLC cases by stage, TP53 mutations were detected in the cfDNA of 35.7% early-stage and 54.1% late-stage SCLC patients. The results in the controls were further replicated in 10.8% of an independent series of 102 non-cancer controls. The detection of TP53 mutations in 11% of the 225 non-cancer controls suggests that somatic mutations in cfDNA among individuals without any cancer diagnosis is a common occurrence, and poses serious challenges for the development of ctDNA screening tests.
because the pipeline is designed to be very sensitive it is expected to have a high false positive rate
I don't think so. our previous major assumption is that circulating-mutated fragments would be absent (or very rare) in individuals without cancer because that any ctDNA detection marker owning a specificity close to 100% would be of fundamental importance for large-scale utility in an asymptomatic population
I think maybe we need thought about this question again.
Probably germline variants (1) ? But the frequency is too high for this.
Or maybe they are "first hit" variants waiting for second event to develop full blown cancer ?
Seems much more likely that the authors are developing a biomarker (not a diagnostic test for TP53 mutations) for a horrific fast-moving disease, and will gladly tolerate some false positives, even if it means some individuals who don't have SCLC will have an uncomfortable period before finding out they are all clear.
I didn't mean to sound like my original statement was criticising the pipeline that was chosen.
And it doesn't look like they validated those variants.
Could you share some details of your pipeline for detecting variants at very low fractions. I am currently researching on this and like to have a optimized pipeline set up. Really appreciate :)