Deficiency of nucleotide excision repair explains mutational signature observed in cancer

Abstract

Nucleotide excision repair (NER) is one of the main DNA repair pathways that protect cells against genomic damage. Disruption of this pathway can contribute to the development of cancer and accelerate aging. Tumors deficient in NER are more sensitive to cisplatin treatment. Characterization of the mutational consequences of NER-deficiency may therefore provide important diagnostic opportunities. Here, we analyzed the somatic mutational profiles of adult stem cells (ASCs) from NER-deficient Ercc1-/Δ mice, using whole-genome sequencing analysis of clonally derived organoid cultures. Our results indicate that NER-deficiency increases the base substitution load in liver, but not in small intestinal ASCs, which coincides with a tissue-specific aging-pathology observed in these mice. The mutational landscape changes as a result of NER-deficiency in ASCs of both tissues and shows an increased contribution of Signature 8 mutations, which is a pattern with unknown etiology that is recurrently observed in various cancer types. The scattered genomic distribution of the acquired base substitutions indicates that deficiency of global-genome NER (GG-NER) is responsible for the altered mutational landscape. In line with this, we observed increased Signature 8 mutations in a GG-NER-deficient human organoid culture in which XPC was deleted using CRISPR-Cas9 gene-editing. Furthermore, genomes of NER-deficient breast tumors show an increased contribution of Signature 8 mutations compared with NER-proficient tumors. Elevated levels of Signature 8 mutations may therefore serve as a biomarker for NER-deficiency and could improve personalized cancer treatment strategies.

A computational and structural analysis of germline and somatic variants affecting the DDR mechanism, and their impact on human diseases

“…Our analysis of germline and somatic variants in the different pathways where DDRs are involved showed that the Homology Recombination, Fanconi Anemia, and Mismatch Repair pathways are the most affected by both types of mutations, whereas the Nucleotide Excision Repair pathway appears to be more affected by somatic variants in primary tumours than by germline pathogenic variants. The latter finding is in agreement with the results of other authors in that it shows an increased contribution of a somatic mutational pattern 25 .…”

“…2, panel d). Therefore, our analyses of accumulation of somatic variants in the NER pathway coincide with the results by other authors in that this pathway shows an increased contribution of a somatic mutational pattern (COSMIC mutational signature 8) recurrently observed in various cancer types 25 . So, the disruption of this pathway could potentially drive carcinogenesis and accelerate aging.…”

Pancreatic cancer organoids recapitulate disease and allow personalized drug screening

“…Cluster 4 (purple) is dominated by mutation patterns (SBS3 and deletions with microhomology) highly characteristic for homologous recombination deficiency (23). The final cluster (orange) is predominantly characterized by the aging signatures (SBS1, SBS5, and SBS40), although some samples also show APOBEC activity (20,24,25).…”

Network-based approaches elucidate differences within APOBEC and clock-like signatures in breast cancer

“…NER pathway is involved in neutralizing oxidative DNA damage [38] and Signature 5 has been also associated with smoking [39], which itself is associated with oxidative damage. Indeed Signature 5 was linked to the NER pathway in a recent study [40].…”