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Deficiency of nucleotide excision repair explains mutational signature observed in cancer

By Myrthe Jager, Francis Blokzijl, Ewart Kuijk, Johanna Bertl, Maria Vougioukalaki, Roel Janssen, Nicolle Besselink, Sander Boymans, Joep de Ligt, Jakob Skou Pedersen, Jan Hoeijmakers, Joris Pothof, Ruben van Boxtel, Edwin Cuppen

Posted 17 Nov 2017
bioRxiv DOI: 10.1101/221168

Nucleotide excision repair (NER) is one of the main DNA repair pathways that protect cells against genomic damage. Deficiency in this pathway can contribute to the development of cancer and accelerate aging. In addition, NER-deficiency is an important determinant for cancer treatment outcome, as NER-deficient tumors are sensitive to cisplatin treatment. Non-silent mutations in the NER-gene ERCC2 were previously associated with a specific mutational footprint (Signature 5), potentially providing a functional readout for NER-deficiency. However, not all NER-deficient tumors are characterized by a high Signature 5 contribution, illustrating the importance to further characterize the mutational consequences of NER-deficiency. Here, we analyzed the somatic mutational profiles of adult stem cells (ASCs) from NER-deficient progeroid Ercc1-/Δ mice, using whole-genome sequencing analysis of clonally derived organoids. Our results indicate that NER-deficiency increases the point mutation load in liver, but not in small intestinal ASCs, which coincides with a tissue-specific aging-pathology observed in these mice. More specifically, this increase can be largely explained by Signature 8, a mutational footprint observed in human cancer with as yet unknown etiology. The genomic distribution of the acquired point mutations indicates that deficiency of global-genome NER (GG-NER), rather than transcription-coupled NER (TC-NER), is responsible for the accumulated mutations. We independently confirmed the link between Signature 8 and GG-NER-deficiency through mutational analysis of a human organoid culture that was deleted for XPC using CRISPR-Cas9 gene-editing. Elevated levels of Signature 8 may, therefore, serve as a novel biomarker for GG-NER-deficient tumors and could improve personalized cancer treatment strategies.

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