RT Journal
A1 Jager, Myrthe
A1 Blokzijl, Francis
A1 Kuijk, Ewart
A1 Bertl, Johanna
A1 Vougioukalaki, Maria
A1 Janssen, Roel
A1 Besselink, Nicolle
A1 Boymans, Sander
A1 de Ligt, 
Joep
A1 Pedersen, Jakob Skou
A1 Hoeijmakers, Jan
A1 Pothof, Joris
A1 van Boxtel, 
Ruben
A1 Cuppen, Edwin
T1 Deficiency of nucleotide excision repair is associated with mutational signature observed in cancer
JF Genome Research 
JO Genome Research 
YR 2019 
FD July 01 
VO 29 
IS 7 
SP 1067 
OP 1077 
DO 10.1101/gr.246223.118 
UL http://genome.cshlp.org/content/29/7/1067.abstract 
AB 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. Mutational characteristics of NER-deficiency may reveal important diagnostic opportunities, as tumors deficient in NER are more sensitive to certain treatments. Here, we analyzed the genome-wide somatic mutational profiles of adult stem cells (ASCs) from NER-deficient Ercc1−/Δ mice. Our results indicate that NER-deficiency increases the base substitution load twofold in liver but not in small intestinal ASCs, which coincides with the tissue-specific aging pathology observed in these mice. Moreover, NER-deficient ASCs of both tissues show an increased contribution of Signature 8 mutations, which is a mutational pattern with unknown etiology that is recurrently observed in various cancer types. The scattered genomic distribution of the base substitutions indicates that deficiency of global-genome NER (GG-NER) underlies the observed mutational consequences. In line with this, we observe 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 could therefore contribute to a predictor of NER-deficiency based on a patient's mutational profile.