Single genome analysis of normal cells identifies the early steps of kidney cancer.

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.

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Cite

BibTeX RIS

BibTeX

@misc{margaria2026single,
  title = {{Single genome analysis of normal cells identifies the early steps of kidney cancer.}},
  author = {J. P. Margaria and G. B. Pipitone and A. Larcher and S. Faienza and I. Rowe and F. Corea and V. Piatti and N. Sala and J. M. Garcia Manteiga and J. Ge and D. Mas-Ponte and G. Distefano and S. Vanharanta and U. Capitanio and F. Supek and P. Carrera and A. Salonia and A. Boletta and I. Franco},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.03.749153},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.03.749153v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - Single genome analysis of normal cells identifies the early steps of kidney cancer.
AU  - J. P. Margaria
AU  - G. B. Pipitone
AU  - A. Larcher
AU  - S. Faienza
AU  - I. Rowe
AU  - F. Corea
AU  - V. Piatti
AU  - N. Sala
AU  - J. M. Garcia Manteiga
AU  - J. Ge
AU  - D. Mas-Ponte
AU  - G. Distefano
AU  - S. Vanharanta
AU  - U. Capitanio
AU  - F. Supek
AU  - P. Carrera
AU  - A. Salonia
AU  - A. Boletta
AU  - I. Franco
PY  - 2026
DA  - 2026/09/03
PB  - bioRxiv
DO  - 10.64898/2026.09.03.749153
UR  - https://www.biorxiv.org/content/10.64898/2026.09.03.749153v1
AB  - 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.
ER  -

Abstract

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