Institut Jacques Monod Seminar – Prof. Karin Forsberg-Nilsson

Invited by the Ladoux/Mège, Prof. Karin Forsberg-Nilsson (Uppsala University, Sweden) will present an Institut Jacques Monod on the theme:

Leveraging non-coding mutations with evolutionary constraint to discover novel driver genes in solid tumors

Abstract:

Cancer genomics has been biased against non-coding mutations, which account for 98% of all mutations, and driver mutations outside exons remain underrepresented. We hypothesized that evolutionary constraint could be used to identify functional cancer mutations. In our previous work, we successfully identified functionally active non-coding constraint mutations (NCCMs) in glioblastoma. The Zoonomia Consortium has since published single-base (phyloP) constraint scores from whole-genome alignments of 240 mammals. Through comparisons with previous large-scale genome annotations and datasets such as ClinVar, we provide proof of concept that evolutionarily constrained positions are enriched for disease-associated variants, including those implicated in medulloblastoma.

We next examined whether NCCMs and their associated genes exert functional effects across multiple tumor types. To investigate this, we mapped evolutionary constraint annotations to somatic single-nucleotide variants (SNVs) and insertions/deletions across more than 2,500 tumors representing 19 tumor types in the ICGC-PCAWG dataset. This analysis identified 56 pan-cancer and 132 cancer-type-specific putative driver genes enriched for NCCMs. Notably, genes with a high NCCM load rarely harbor protein-coding mutations, suggesting that distinct selective pressures preserve protein integrity while altering gene expression regulation.

Collectively, these findings demonstrate the power of evolutionary constraint to decode non-coding genome function and identify candidate regulatory drivers of cancer.

Biography :

Karin Forsberg-Nilsson is Professor of Stem Cell Research in the Department of Immunology, Genetics and Pathology at Uppsala University, Sweden. Her research brings together stem cell biology and cancer genomics, with a focus on brain tumors and the identification of cancer driver genes. She obtained her PhD at Uppsala University in 1992 and conducted postdoctoral research at the US National Institutes of Health. She served as Head of Department from 2014 to 2020 and Dean of the Faculty of Medicine from 2020 to 2026. In 2015, she was a visiting professor at the Collège de France.