Year: 2026
Type: preprint
Abstract: Whole genome analyses have shown that every cell of the body accumulates thousands of genetic changes during a lifetime, with implications for cancer initiation. We have analyzed normal kidney cells from both healthy individuals and patients with the Von Hippel Lindau (VHL) syndrome, which predisposes to kidney cancer. Using a clonal-expansion method that enables the collection of high confidence genetic and gene expression data from the same cell, we define a new mutational signature that marks a specific subset of damage-activated proximal tubule cells, as well as 96% of clear cell renal cell carcinomas. The underlying mutational process is specifically active in highly transcribed DNA and impacts the occurrence of cancer driver variants in the VHL gene. Our data from normal cells, supported by in vitro experiments, point to perturbations of oxygen availability as a causative factor. These findings link hypoxia, a frequent endogenous stress in the normal renal tissue, to excessive mutation and cancer initiation.
Authors: Jean Piero Margaria, Giovanni Battista Pipitone, Alessandro Larcher, Sipontina Faienza, Isaline Rowe, Francesca Corea, Valentina Piatti, Nicola Sala, Jose Manuel Garcia Manteiga, Jianfeng Ge, David Mas-Ponte, Gianfranco Distefano, Sakari Vanharanta, Umberto Capitanio, Fran Supek, Paola Carrera, Andrea Salonia, Alessandra Boletta, Irene Franco
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
Awards: G1228939035, G6235985580
OpenAlex ID: W7211895651