Lab Invest. 2024 Jan 12:100325. doi: 10.1016/j.labinv.2024.100325. Online ahead of print.
Formalin-fixed paraffin-embedded (FFPE) tissues stored in biobanks and pathology archives are a vast but underutilized source for molecular studies on different diseases. Beyond being the gold standard for preservation of diagnostic human tissues, FFPE samples retain similar genetic information as matching blood samples, which could make FFPE samples an ideal resource for genomic analysis. However, research on this resource has been hindered by the perception that DNA extracted from FFPE samples is of poor quality. Here, we show that germline disease-predisposing variants and polygenic risk scores (PRS) can be identified from FFPE normal tissue (FFPE-NT) DNA with high accuracy. We optimized performance of FFPE-NT DNA on a genome-wide array containing 657 675 variants. Via a series of testing and validation phases, we established a protocol for FFPE-NT genotyping with results comparable to blood genotyping. The median call rate of FFPE-NT samples in the validation phase was 99.85% (range 98.26-99.94%) and median concordance with matching blood samples was 99.79% (range 98.85-99.9%). We also demonstrated that a rare pathogenic PALB2 variant predisposing to cancer can be correctly identified in FFPE-NT samples. We further imputed the FFPE-NT genotype data and calculated the FFPE-NT genome-wide PRS in three diseases and four disease risk variables. In all cases, FFPE-NT and matching blood PRS were highly concordant (all Pearson’s r>0.95). The ability to precisely genotype FFPE-NT on a genome-wide array enables translational genomics applications of archived FFPE-NT samples with the possibility to link to corresponding phenotypes and longitudinal health data.