Mutational signature analysis identifies MUTYH deficiency in colorectal cancers and adrenocortical carcinomas
Open accessAbstract
Germline alterations in DNA repair genes are implicated in cancer predisposition and can result in characteristic mutational signatures. However, specific mutational signatures associated with base excision repair ( BER ) defects remain to be characterized. Here, by analysing a series of colorectal cancers ( CRCs ) using exome sequencing, we identified a particular spectrum of somatic mutations characterized by an enrichment of C > A transversions in NpCpA or NpCpT contexts in three tumours from a MUTYH ‐associated polyposis ( MAP ) patient and in two cases harbouring pathogenic germline MUTYH mutations. In two series of adrenocortical carcinomas ( ACCs ), we identified four tumours with a similar signature also presenting germline MUTYH mutations. Taken together, these findings demonstrate that MUTYH inactivation results in a particular mutational signature, which may serve as a useful marker of BER ‐related genomic instability in new cancer types. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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In COAD and PAAD, SBS18 was strongly associated with G12C mutations.
“in COAD and PAAD, SBS18 (navy blue bars), likely caused by damage from reactive oxygen species29,30, was strongly associated with G12C mutations”
From The origins and genetic interactions of KRAS mutations are allele- and tissue-specific (2021) · cites this paper as [30]
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“Notably, two genome-wide studies of pancreatic neuroendocrine [13] and adrenocortical [14] cancers (neither previously associated with MUTYH deficiency) found that tumors with a mutational spectrum dominated by G:C to T:A mutations were from heterozygous carriers of MAP variants, and further analysis confirmed a somat…”
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MUTYH-associated tumor syndrome: The other face of MAP
Magrin, L., Fanale, D., Brando, C., Corsini, L. R., Randazzo, U., Piazza, M. D., Gurrera, V., Pedone, E., Russo, T. D. B., Vieni, S., et al. (2022) · Oncogene · doi:10.1038/s41388-022-02304-y · Cited by 36 · see citing works
Helderman, N. C., ten Broeke, S. W., Morreau, H. M., Suerink, M., Terlouw, D., Lam, A.-S. V. D. W.-’. T., van Wezel, T., & Nielsen, M. (2021) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2021.103338 · Cited by 33 · see citing works
Thibodeau, M. L., Stutheit-Zhao, E. Y., Reisle, C., Ch’ng, C., Wong, H., Shen, Y., Jones, M. R., Lim, H. J., Young, S. S., Cremin, C., et al. (2019) · Molecular Case Studies · doi:10.1101/mcs.a003681 · Cited by 33 · see citing works
“…ranked the transversion signatures previously associated with germline or combined germline/somatic MUTYH impairment (COSMIC Signature 18 [Pilati et al. 2017; Scarpa et al. 2017], SigProfiler SBS36 [Alexandrov et al. 2018], and SignatureAnalyzer SBS36 [Alexandrov et al. 2018]) at the top…”
InfluentialJouinot, A., & Bertherat, J. Y. (2019) · Experientia supplementum · doi:10.1007/978-3-030-25905-1_9 · Cited by 32 · see citing works
Self-citationGeorgeson, P., Harrison, T. A., Pope, B. J., Zaidi, S. H. E., Qu, C., Steinfelder, R. S., Lin, Y., Joo, J. E., Mahmood, K., Clendenning, M., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-30916-1 · Cited by 32 · see citing works
Monoallelic deleterious MUTYH germline variants as a driver for tumorigenesis
Barreiro, R., Sabbaga, J., Rossi, B. M., Achatz, M. I., Bettoni, F., Camargo, A. A., Asprino, P. F., & Galante, P. A. F. (2021) · The Journal of Pathology · doi:10.1002/path.5829 · Cited by 31 · see citing works
“This signature, characteristic ofMUTYH deficiency [34,35], was over-represented only in the set of monoallelic MUTYH carriers with LOH and expression of the pathogenic variant, whereas monoallelic carriers alone had a mutational signature similar to that of non-carriers in TCGA cohort (Figure 4A).”
ResultBrandsma, A. M., Bertrums, E. J. M., van Roosmalen, M. J., Hofman, D. A., Oka, R., Verheul, M., Manders, F., Ubels, J., Belderbos, M. E., & van Boxtel, R. (2021) · Blood Cancer Discovery · doi:10.1158/2643-3230.bcd-21-0010 · Cited by 31 · see citing works
“In conclusion, the increased somatic mutation load of pAML is caused by a higher number of SBS1 and SBS18 mutations, indicating more replication-and oxidative stress–related mutagenesis.”
InfluentialImpact of Helicobacter pylori Infection and Its Major Virulence Factor CagA on DNA Damage Repair
Kontizas, E., Tastsoglou, S., Karamitros, T., Karayiannis, Y., Κollia, P., Hatzigeorgiou, A. G., & Sgouras, D. N. (2020) · Microorganisms · doi:10.3390/microorganisms8122007 · Cited by 29 · see citing works
Defects in 8-oxo-guanine repair pathway cause high frequency of C > A substitutions in neuroblastoma
van den Boogaard, M. L., Oka, R., Hakkert, A., Schild, L. G., Ebus, M. E., van Gerven, M. R., Zwijnenburg, D. A., Molenaar, P., Hoyng, L., Dolman, M. E. M., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2007898118 · Cited by 29 · see citing works
“Signature 36 was discovered in tumors of patients with MUTYH-associated polyposis but has not been described in neuroblastoma tumors (9, 27).”
BackgroundInfluentialQuantification of somatic mutation flow across individual cell division events by lineage sequencingPreprint
Brody, Y., Kimmerling, R. J., Maruvka, Y. E., Benjamin, D. I., Elacqua, J. J., Haradhvala, N. J., Kim, J., Mouw, K. W., Frangaj, K., Koren, A., et al. (2018) · Genome Research · doi:10.1101/gr.238543.118 · Cited by 23 · see citing works
“S6) fromthe RPE1 data set that has previously been associated with in vitro culture and only rarely contributes many mutations under physiological conditions (Costello et al. 2013; Rouhani et al. 2016; Pilati et al. 2017; Zou et al. 2018).”
Direct detection of 8-oxo-dG using nanopore sequencing
Pagès-Gallego, M., van Soest, D. M. K., Besselink, N. J. M., Straver, R., Keijer, J. P., Vermeulen, C., Marcozzi, A., van Roosmalen, M. J., van Boxtel, R., Burgering, B. M. T., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-60391-3 · Cited by 27 · see citing works
“The mutational process behind C>A mutations in COSMIC signatures 18 and 36 has been long attributed to oxidative stress and unrepaired 8-oxo-dG 17 – 19 .”
Unraveling the genomic landscape of colorectal cancer through mutational signatures
Díaz‐Gay, M., & Alexandrov, L. B. (2021) · Advances in cancer research · doi:10.1016/bs.acr.2021.03.003 · Cited by 25 · see citing works
Self-citationTomasini, P. P., Guecheva, T. N., Leguisamo, N. M., Péricart, S., Brunac, A., Hoffmann, J., & Saffi, J. (2021) · Cancers · doi:10.3390/cancers13133130 · Cited by 24 · see citing works
Olivier, M., Bouaoun, L., Villar, S., Robitaille, A., Cahais, V., Heguy, A., Byrnes, G. B., Calvez‐Kelm, F. L., Torres-Mejı́a, G., Alvarado‐Cabrero, I., et al. (2019) · PLoS ONE · doi:10.1371/journal.pone.0210372 · Cited by 20 · see citing works
Genetics, genomics and clinical features of adenomatous polyposis
Joo, J. E., Viana-Errasti, J., Buchanan, D. D., & Valle, L. (2025) · Familial Cancer · doi:10.1007/s10689-025-00460-0 · Cited by 19 · see citing works
“MUTYH - deficient adenomas and cancers developed in the context of MAP are characterised by COSMIC mutational signatures SBS18 and SBS36, related to an abundance C>A nucleotide transversions [103, 108–111].”
DNA Glycosylases Define the Outcome of Endogenous Base Modifications
Lirussi, L., & Nilsen, H. L. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241210307 · Cited by 20 · see citing works
“Oxidative damage (8-oxoG formation) produces a G > T/C > A pattern, similar to the one identified in adrenocortical cancers and neuroblastomas (SBS18) and qualitatively analogous to the mutational signature of inactivating of germline mutations in MUTYH1 (SBS36) [18,21].”
ResultAdvances in adrenal tumors 2018
Crona, J., Beuschlein, F., Pacák, K., & Skogseid, B. M. (2018) · Endocrine Related Cancer · doi:10.1530/erc-18-0138 · Cited by 19 · see citing works
Conlon, S. G., Khuu, C., Trasviña‐Arenas, C. H., Xia, T., Hamm, M. L., Raetz, A. G., & David, S. S. (2024) · ACS Central Science · doi:10.1021/acscentsci.3c00784 · Cited by 18 · see citing works
Ahn, E., & Lee, S. H. T. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20010199 · Cited by 17 · see citing works
“, the mutation appears at the second position of each trinucleotide) and enables classifying observed substitutions into 96 categories (4 bases × 6 substitutions × 4 bases) [13,14].”
Establishment and Characterization of a Brca1−/−, p53−/− Mouse Mammary Tumor Cell Line
Hámori, L., Kudlik, G., Szebényi, K., Kucsma, N., Szeder, B., Póti, Á., Uher, F., Várady, G., Szüts, D., Tóvári, J., et al. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21041185 · Cited by 17 · see citing works
“t ti f t s ectr i t S I utati l sig at res deri e fr ca c r se t t t r s f t ti si t a 8 associate it eficiency [64], as ll i t , i i i iff t r t i l i st c c r, in association ith oxidative a a e [65] (Fi re 3 ).”
BackgroundMethodLi, Y. R., Kandyba, E. E., Halliwill, K. D., Delrosario, R., Tran, Q., Bayani, N., Wu, D., Mirzoeva, O. K., Reeves, M. Q., Islam, S. M. A., et al. (2025) · Cancer Discovery · doi:10.1158/2159-8290.cd-24-1379 · Cited by 16 · see citing works
“26, 27).”
Self-citationPaske, I. T., Ligtenberg, M. J. L., Hoogerbrugge, N., & de Voer, R. M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21228757 · Cited by 16 · see citing works
“MUTYH deficiency, causing 8-OxoG BER pathway redundancy, is now linked to mutational signatures 18 and 36 [87,88].”
BackgroundGermline mutation contribution to chromosomal instability
Chan, S. H., & Ngeow, J. Y. Y. (2017) · Endocrine Related Cancer · doi:10.1530/erc-17-0062 · Cited by 15 · see citing works
Sherwood, K., Ward, J. C., Soriano, I., Martin, L. M., Campbell, A. I., Rahbari, R., Kafetzopoulos, I., Sproul, D., Green, A., Sampson, J. R., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-39248-0 · Cited by 14 · see citing works
“2c) 35 .”
Sholler, G. L. S., Bergendahl, G., Lewis, E. C., Kraveka, J. M., Ferguson, W. S., Nagulapally, A. B., Dykema, K. J., Brown, V. I., Isakoff, M. S., Junewick, J. J., et al. (2024) · Genome Medicine · doi:10.1186/s13073-024-01297-5 · Cited by 14 · see citing works
“The etiology of this signature has been previ‑ ously shown to be related to damage by reactive oxygen species [48], which is a long‑known biological stimulus in NB [49].”
BackgroundSomatic mutational signatures in polyposis and colorectal cancer
Grolleman, J. E., Díaz‐Gay, M., Franch‐Expósito, S., Castellvı́-Bel, S., & de Voer, R. M. (2019) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2019.05.002 · Cited by 14 · see citing works
“Thereafter, others associated MUTYH deficiency in CRCs and CRC stem cells with signature 36 (Viel et al., 2017).”
BackgroundInfluentialGO System, a DNA Repair Pathway to Cope with Oxidative Damage
Endutkin, A. V., & Zharkov, D. O. (2021) · Molecular Biology · doi:10.1134/s0026893321020072 · Cited by 13 · see citing works
Brosda, S., Aoude, L. G., Bonazzi, V., Patel, K., Lonie, J. M., Belle, C. J., Newell, F., Koufariotis, L. T., Addala, V., Naeini, M. M., et al. (2024) · Genome Medicine · doi:10.1186/s13073-024-01362-z · Cited by 13 · see citing works
Unravelling the instability of mutational signatures extraction via archetypal analysis
Pancotti, C., Rollo, C., Birolo, G., Benevenuta, S., Fariselli, P., & Sanavia, T. (2023) · Frontiers in Genetics · doi:10.3389/fgene.2022.1049501 · Cited by 12 · see citing works
Sasani, T. A., Quinlan, A. R., & Harris, K. (2023) · eLife · doi:10.7554/elife.89096 · Cited by 12 · see citing works
“The online version of this article includes the following figure supplement(s) for figure 1: C>A mutations ( David et al., 2007 ; Viel et al., 2017 ; Pilati et al., 2017 ).”
BackgroundGame of clones: Battles in the field of carcinogenesis
Rahal, Z., Sinjab, A. F., Wistuba, I. I., & Kadara, H. N. (2022) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2022.108251 · Cited by 13 · see citing works
Crumbaker, M., Chan, E. K. F., Gong, T., Corcoran, N. M., Jaratlerdsiri, W., Lyons, R. J., Haynes, A., Kulidjian, A., Kalsbeek, A. M. F., Petersen, D. C., et al. (2020) · Cancers · doi:10.3390/cancers12051178 · Cited by 12 · see citing works
Huang, X., Qiao, Y., Brady, S. W., Factor, R. E., Downs-Kelly, E. P., Farrell, A., McQuerry, J. A., Shrestha, G., Jenkins, D. F., Johnson, W. E., et al. (2021) · Genome Medicine · doi:10.1186/s13073-021-00989-6 · Cited by 12 · see citing works
Pei, G., Hu, R., Dai, Y., Zhao, Z., & Jia, P. (2020) · Oncogene · doi:10.1038/s41388-020-1343-z · Cited by 11 · see citing works
Ge, Z., Feng, Y., Sheh, A., Muthupalani, S., Gong, G., Chawanthayatham, S., Essigmann, J. M., & Fox, J. G. (2019) · International Journal of Cancer · doi:10.1002/ijc.32332 · Cited by 11 · see citing works
Hölzl‐Armstrong, L., Moody, S., Kucab, J. E., Zwart, E., Bellamri, M., Luijten, M., Turesky, R. J., Stratton, M. R., Arlt, V. M., & Phillips, D. H. (2020) · Food and Chemical Toxicology · doi:10.1016/j.fct.2020.111855 · Cited by 10 · see citing works
Lasabová, Z., Kalman, M., Holubeková, V., Grendár, M., Kašubová, I., Jašek, K., Meršaková, S., Malicherová, B., Baranenko, D., Adamek, M., et al. (2019) · Clinical and Experimental Medicine · doi:10.1007/s10238-019-00558-7 · Cited by 9 · see citing works
CaMuS: simultaneous fitting and de novo imputation of cancer mutational signature
Cartolano, M., Abedpour, N., Achter, V., Yang, T.-P., Ackermann, S., Fischer, M., & Peifer, M. (2020) · Scientific Reports · doi:10.1038/s41598-020-75753-8 · Cited by 9 · see citing works
Tumor Signature Analysis Implicates Hereditary Cancer Genes in Endometrial Cancer Development
Kondrashova, O., Shamsani, J., O’Mara, T. A., Newell, F., Reed, A. E. M., Lakhani, S. R., Kirk, J., Pearson, J. V., Waddell, N., & Spurdle, A. B. (2021) · Cancers · doi:10.3390/cancers13081762 · Cited by 9 · see citing works
“we attributed 41% of all somatic single nucleotide variants to Signature 18 (Figure 3B), previously associated with inactivation of MUTYH in a series of familial colorectal cancer and adrenocortical carcinomas [49], indicating that the germline variant was driving the pattern of somatic mutations, and underlay develop…”
BackgroundThe APOBEC3A deaminase drives episodic mutagenesis in cancer cellsPreprint
Petljak, M., Chu, K., Dananberg, A., Bergstrom, E. N., von Morgen, P., Alexandrov, L. B., Stratton, M. R., & Maciejowski, J. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.02.14.431145 · Cited by 9 · see citing works
Self-citationOhno, M., Takano, N., Hidaka, K., Sasaki, F., Yamauchi, K., Aoki, Y., Nohmi, T., Nakabeppu, Y., Nakatsu, Y., & Tsuzuki, T. (2024) · Genome Research · doi:10.1101/gr.278326.123 · Cited by 9 · see citing works
“The lists of somatic mutations in the human MAP tumor were adapted from Pilati et al. (2017).”
Patterson, A., Elbasir, A., Tian, B., & Auslander, N. (2023) · Cancers · doi:10.3390/cancers15071958 · Cited by 8 · see citing works
“For example, germline mutations in the base excision-repair gene MUTYH left distinct mutation signatures corresponding to COSMIC signature 18 (Box 1) in colorectal cancers and adrenocortical carcinomas [50].”
BackgroundA maternal germline mutator phenotype in a family affected by heritable colorectal cancer
Young, C. L., Beichman, A., Ponte, D. M., Hemker, S. L., Zhu, L., Kitzman, J., Shirts, B., & Harris, K. (2024) · Genetics · doi:10.1093/genetics/iyae166 · Cited by 7 · see citing works
“Due to MUTYH’s role in this repair pathway, defects in this enzyme can cause excess accumulation of C > A mutations in tissues that are experiencing ROS damage (Pilati et al .”
Treviño, V. (2019) · Molecular Genetics & Genomic Medicine · doi:10.1002/mgg3.810 · Cited by 8 · see citing works
“Yet, new signatures are being discovered (Alsøe et al., 2017; Inman et al., 2018; Pilati et al., 2017) and systematically determined in vitro (Kucab et al., 2019).”
BackgroundClick-code-seq reveals strand biases of DNA oxidation and depurination in human genome
Takhaveev, V., Püllen, N. J. L., Singh, N. K., Lefevre, L., Aghajani, E. A., Huber, S. M., Schauer, S., Gahlon, H. L., Poetsch, A. R., & Sturla, S. J. (2026) · Nature Chemical Biology · doi:10.1038/s41589-025-02052-6 · Cited by 10 · see citing works
Molecular testing in colorectal cancer
Thomas, J. S., & Shi, C. (2023) · Elsevier eBooks · doi:10.1016/b978-0-12-822824-1.00018-3 · Cited by 7 · see citing works
Multiple neoplasia in a patient with Gitelman syndrome harboring germline monoallelic MUTYH mutation
Chan, J. Y., Toh, M. R., Chong, S. T., Ishak, N. D. B., Kolinjivadi, A. M., Chan, S. H., Lee, E., Boot, A., Li, S.-T., Chew, M., et al. (2020) · npj Genomic Medicine · doi:10.1038/s41525-020-00146-9 · Cited by 7 · see citing works
Cohen, R., Sroussi, M., Pilati, C., Houry, S., Laurent‐Puig, P., & André, T. (2018) · Journal of Gastrointestinal Oncology · doi:10.21037/jgo.2018.05.10 · Cited by 7 · see citing works
Self-citationBonjoch, L., Mur, P., Arnau‐Collell, C., Vargas‐Parra, G., Shamloo, B., Franch‐Expósito, S., Pineda, M., Capellá, G., Erman, B., & Castellvı́-Bel, S. (2019) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2019.03.004 · Cited by 7 · see citing works
Burns, M. B., Montassier, E., Abrahante, J., Priya, S., Niccum, D. E., Khoruts, A., Starr, T. K., Knights, D., & Blekhman, R. (2016) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/090795 · Cited by 7 · see citing works
- Authors
- Pilati, C., Shinde, J., Alexandrov, L. B., Assié, G., André, T., Hélias‐Rodzewicz, Z., Ducoudray, R., Le Corre, D., Zucman‐Rossi, J., Emile, J., Bertherat, J., Letouzé, E., & Laurent‐Puig, P.
- Affiliations
- Inserm (FR)
- Los Alamos National Laboratory (US)
- Centre National de la Recherche Scientifique (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Université de Versailles Saint-Quentin-en-Yvelines (FR)
- INSERM UMR‐S1147, Personalized Medicine, Pharmacogenomics, Therapeutic Optimization Université Paris Descartes Paris France
- INSERM U1016, CNRS UMR 8104 Paris Descartes University Institut Cochin, Paris France
- INSERM Unité Mixte de Recherche (UMR) 1162 Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue contre le Cancer Paris France
- Corresponding author
- Laurent‐Puig, Pierre
- ORCID
- Venue
- The Journal of Pathology
- Publisher
- Wiley
- Published
- 2017-03-29
- Volume
- 242
- Issue
- 1
- Pages
- 10-15
- ISSN
- 0022-3417 (ISSN-L)
- 1096-9896
- OpenAlex
- W2581568937
- Cited by
- 150
- References
- 22
- Citations by year
- 2026: 11 · 2025: 11 · 2024: 12 · 2023: 15 · 2022: 13 · 2021: 27 · 2020: 16 · 2019: 22 · 2018: 16 · 2017: 6 · 2016: 1
- FWCI
- 12.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.osti.gov
- Licence
- Locations
- The Journal of Pathology (publishedVersion)
- PubMed (publishedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- Los Alamos National Laboratory
- Centre National de la Recherche Scientifique
- Institut National de la Santé et de la Recherche Médicale
- Agence Nationale de la Recherche (ANR‐10‐NANO‐0002‐09)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- MUTYH, mutational signatures, base excision repair, colorectal cancer, adrenocortical carcinoma, MUTYH-associated polyposis, genomic instability, DNA repair genes, cancer susceptibility
- MeSH terms
- Adrenal Cortex Neoplasms, Animals, DNA Mutational Analysis, DNA, Neoplasm, Humans, Mutation, Colorectal Neoplasms, Germ-Line Mutation, Adrenocortical Carcinoma, Mice, Knockout, Genetic Predisposition to Disease, DNA Glycosylases, Transcriptome
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