Accurate genome-wide genotyping from archival tissue to explore the contribution of common genetic variants to pre-cancer outcomes

PurposeThe contribution of common genetic variants to pre-cancer progression is understudied due to long follow-up time, rarity of poor outcomes and lack of available germline DNA collection. Alternatively, DNA from diagnostic archival tissue is available, but its somatic nature, limited quantity and suboptimal quality would require an accurate cost-effective genome-wide germline genotyping methodology.Experimental designBlood and tissue DNA from 10 individuals were used to benchmark the accuracy of Single Nucleotide Polymorphisms (SNP) genotypes, Polygenic Risk Scores (PRS) or HLA haplotypes using low-coverage whole-genome sequencing (lc-WGS) and genotype imputation. Tissue-derived PRS were further evaluated for 36 breast cancer patients (11.7 years median follow-up time) diagnosed with DCIS and used to model the risk of Breast Cancer Subsequent Events (BCSE).ResultsTissue-derived germline DNA profiling resulted in accurate genotypes at common SNPs (blood correlation r(2)>0.94) and across 22 disease-related polygenic risk scores (PRS, mean correlation r=0.93). Imputed Class I and II HLA haplotypes were 96.7% and 82.5% concordant with clinical-grade blood HLA haplotypes, respectively. In DCIS patients, tissue-derived PRS was significantly associated with BCSE (HR=2, 95% CI 1.2-3.8). The top and bottom decile patients had an estimated 28% and 5% chance of BCSE at 10 years, respectively.ConclusionsArchival tissue DNA germline profiling using lc-WGS and imputation, represents a cost and resource-effective alternative in the retrospective design of long-term disease genetic studies. Initial results in breast cancer suggest that common risk variants contribute to pre-cancer progression.

Automated summary

This study demonstrates that germline DNA profiling from archival tissue using low-coverage whole-genome sequencing and genotype imputation can accurately determine genotypes at common SNPs and evaluate disease-related polygenic risk scores. Tissue-derived PRS in DCIS patients is significantly associated with BCSE. Breast cancer patients have a 5% to 28% chance of BCSE within 10 years.