Whole-genome DNA sequencing of human renal proximal tubule epithelial cells
Clear cell renal cell carcinoma (ccRCC) is initiated by loss of chromosome 3p, yet chromosome losses impose a severe fitness burden on normal cells. How renal epithelial cells tolerate this deleterious aneuploidy and evolve toward malignancy is poorly understood. Genomic characterization of 949 ccRCC tumors revealed two major classes of chromosome 3p alterations: simple arm-level deletions and localized complex rearrangements surrounding a terminal breakpoint – a pattern we term breakpoint-confined chromothripsis. To model these initiating events, we introduced a single DNA double-strand break on chromosome 3p in non-transformed human renal proximal tubule epithelial cells. Despite imposing an initial fitness disadvantage, longitudinal clonal tracking revealed that 3p loss drives adaptive genomic evolution that recapitulates recurrent ccRCC-associated aneuploidies, including chromosome 5q gain and 14q loss. These secondary alterations alleviate the fitness costs of 3p loss and promote metabolic reprogramming, clonal expansion, and malignant transformation in vivo, producing tumors with histological and molecular features of renal cell carcinoma. We further propose a breakage-fusion-bridge mechanism that explains the origin of breakpoint-confined chromothripsis in cancer genomes. Together, our findings demonstrate that a single chromosome break can initiate the evolutionary trajectory of ccRCC by generating chromosome 3p alterations that fuel tumorigenesis through aneuploidy-driven adaptation.
Clear cell renal cell carcinoma (ccRCC) is initiated by loss of chromosome 3p, yet chromosome losses impose a severe fitness burden on normal cells. How renal epithelial cells tolerate this deleterious aneuploidy and evolve toward malignancy is poorly understood. Genomic characterization of 949 ccRCC tumors revealed two major classes of chromosome 3p alterations: simple arm-level deletions and localized complex rearrangements surrounding a terminal breakpoint – a pattern we term breakpoint-confined chromothripsis. To model these initiating events, we introduced a single DNA double-strand break on chromosome 3p in non-transformed human renal proximal tubule epithelial cells. Despite imposing an initial fitness disadvantage, longitudinal clonal tracking revealed that 3p loss drives adaptive genomic evolution that recapitulates recurrent ccRCC-associated aneuploidies, including chromosome 5q gain and 14q loss. These secondary alterations alleviate the fitness costs of 3p loss and promote metabolic reprogramming, clonal expansion, and malignant transformation in vivo, producing tumors with histological and molecular features of renal cell carcinoma. We further propose a breakage-fusion-bridge mechanism that explains the origin of breakpoint-confined chromothripsis in cancer genomes. Together, our findings demonstrate that a single chromosome break can initiate the evolutionary trajectory of ccRCC by generating chromosome 3p alterations that fuel tumorigenesis through aneuploidy-driven adaptation.