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• W3080988723 abstract "The endonuclease III-like protein 1, encoded by NTHL1, is a bifunctional glycosylase involved in base-excision repair (BER) that recognizes and removes oxidized pyrimidines.1Krokan H.E. Bjørås M. Cold Spring Harb Perspect Biol. 2013; 5: a012583Crossref PubMed Scopus (525) Google Scholar Similar to biallelic loss-of-function (LoF) variants in MUTYH,2Al-Tassan N. et al.Nat Genet. 2002; 30: 227-232Crossref PubMed Scopus (1001) Google Scholar biallelic LoF variants in NTHL1 predispose to colorectal polyps and colorectal cancer (CRC).3Weren R.D. et al.Nat Genet. 2015; 47: 668-671Crossref PubMed Scopus (208) Google Scholar Recently, a multitumor phenotype was observed in individuals diagnosed with NTHL1 deficiency.4Grolleman J.E. de Voer R.M. Elsayed F.A. et al.Cancer Cell. 2019; 35: 256-266Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Carriers of monoallelic pathogenic variants in MUTYH have an increased, albeit small, risk of CRC.5Win A.K. et al.Int J Cancer. 2011; 129: 2256-2262Crossref PubMed Scopus (59) Google Scholar Thus far, it is unknown if monoallelic NTHL1 LoF variants also increase the risk of polyposis and/or CRC. This information is especially important for carriers of the most common LoF variant in NTHL1 (p.(Gln90∗); NM_002528.5), which is heterozygous in approximately 0.28% of the general population.6Karczewski K.J. et al.Nature. 2020; 581: 434-443Crossref PubMed Scopus (0) Google Scholar Identification of monoallelic NTHL1 LoF variants currently presents a clinical conundrum regarding how best to counsel carriers with respect to their cancer risk because of the lack of published evidence. Here, we show that monoallelic LoF variants in NTHL1 are not enriched in individuals with polyposis and/or CRC compared to the general population. Furthermore, 13 colorectal tumors from NTHL1 LoF carriers did not show a somatic second hit, and we did not find evidence of a main contribution of mutational signature SBS30, the signature associated with NTHL1 deficiency, suggesting that monoallelic loss of NTHL1 does not substantially contribute to colorectal tumor development. A total of 5,942 individuals with unexplained polyposis, familial CRC, or sporadic CRC at young age or suspected of having Lynch syndrome with CRC or multiple adenomas were included in this study and defined as case patients (individual studies and their ascertainment are described in Supplementary Methods and Supplementary Table 1). Three independent data sets were used as controls, including (1) the non-Finnish European subpopulation of the genome aggregation database (gnomAD: n = 64,328),6Karczewski K.J. et al.Nature. 2020; 581: 434-443Crossref PubMed Scopus (0) Google Scholar (2) a Dutch cohort of individuals without a suspicion of hereditary cancer who underwent whole-exome sequencing (WES) (Dutch WES; n = 2,329),7de Voer R.M. Hahn M.M. Mensenkamp A.R. et al.Sci Rep. 2015; 5: 14060Crossref PubMed Google Scholar and (3) a population-based and cancer-unaffected cohort from the Colon Cancer Family Registry Cohort (CCFRC; n = 1,207) (Supplementary Methods and Supplementary Table 1). Pathogenic NTHL1 LoF variants were identified in case patients by sequencing the exonic regions of NTHL1 (n = 3,439) or by genotyping of 2 LoF variants in NTHL1 (c.268C>T, p.(Gln90∗); n = 2503 and c.806G>A, p.(Trp269∗); n = 261) (Supplementary Table 1). For control individuals, all pathogenic LoF variants were retrieved from gnomAD and the Dutch WES-cohort,6Karczewski K.J. et al.Nature. 2020; 581: 434-443Crossref PubMed Scopus (0) Google Scholar,7de Voer R.M. Hahn M.M. Mensenkamp A.R. et al.Sci Rep. 2015; 5: 14060Crossref PubMed Google Scholar and for the CCFRC control individuals, the exonic regions of NTHL1 were sequenced (Supplementary Table 1). Odds ratios between case patients and control groups were calculated and a Fisher exact test was performed to assess the significance of difference in carrier rates. Cosegregation analysis was performed by using Sanger sequencing. Two adenomas and 11 primary CRCs from NTHL1 LoF variant carriers were subjected to WES, and subsequently, mutational signature analysis was performed (Supplementary Methods and Supplementary Table 2). For signature analysis comparison, we included 3 CRCs from individuals with a biallelic NTHL1 LoF variant. Monoallelic NTHL1 LoF variants were identified in 11 of 3,439 case patients (0.32%) and in 5 of 1,207 (0.41%) of CCFRC control individuals, indicating no significant difference (P = .784) (Figure 1A, Supplementary Table 1). Genotyping of the NTHL1 p.(Gln90∗) variant in another 2,503 case patients identified 7 additional carriers (0.28%). The overall frequency of NTHL1 p.(Gln90∗) in case patients was not different from the frequency in the gnomAD (17/5,942 vs 250/64,328; P = .914), CCFRC (17/5,942 vs 3/1,207; P = .556) or Dutch WES control individuals (17/5,942; vs 17/2,329; P = .998) (Figure 1A and Supplementary Table 1). Via cosegregation analysis, we identified 3 additional NTHL1 p.(Gln90∗) carriers. The phenotype of all carriers identified in this study is described in Supplementary Table 2. Thirteen colorectal tumors from NTHL1 LoF carriers underwent WES (details in Supplementary Table 2). The NTHL1 wild-type allele was unaffected by somatic mutations or loss of heterozygosity in all tumors tested. In contrast to NTHL1-deficient tumors, in none of the tumors of the carriers was mutational signature SBS30 the main signature, because it was only present in 1 tumor, where it had a minor contribution (Figure 1B and Supplementary Table 2).4Grolleman J.E. de Voer R.M. Elsayed F.A. et al.Cancer Cell. 2019; 35: 256-266Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar These observations indicate that biallelic inactivation of NTHL1 through a somatic second hit was not evident and that monoallelic inactivation of NTHL1 was insufficient to result in the accumulation of somatic mutations that are characteristic of an NTHL1-deficiency phenotype. In this study, the largest investigating monoallelic LoF variants in NTHL1 to date to our knowledge, we observed no evidence of an association between carriers and the risk of polyposis and/or CRC. In our case patients, the prevalence of pathogenic NTHL1 LoF variant alleles is comparable to that of the general population. However, we cannot rule out that a small risk for CRC, similar to what is observed for MUTYH carriers, still exists. Colorectal tumors from monoallelic NTHL1 LoF variant carriers did not show evidence of a somatic second hit in NTHL1 nor of defective base-excision repair, which is typically associated with biallelic NTHL1 inactivation. Only 1 tumor showed a minor SBS30 contribution to the mutation profile, but this contribution was far less significant compared to NTHL1-deficient CRC and is likely the result of multiple testing correction. Our data suggest that inactivation of the NTHL1 wild-type allele is a rare event in colorectal tumors, which is in agreement with the observation that loss of heterozygosity of chromosome arm 16p is not frequently observed in CRC.8Cerami E. et al.Cancer Discov. 2012; 2: 401-404Crossref PubMed Scopus (7132) Google Scholar We were unable to discriminate between individuals with polyposis or CRC due to the historical nature of the case collections. Therefore, differences in the frequencies of monoallelic NTHL1 LoF variants between control individuals and these 2 phenotypes were not made separately. However, because we identified NTHL1 LoF variants in individuals with polyposis or CRC, we do not consider a major difference between these 2 phenotypes. Because NTHL1 deficiency may also predispose to extracolonic tumors, the risk for these tumor types in monoallelic NTHL1 carriers still needs further assessment. In conclusion, the evidence to date does not support an increased risk of polyposis and/or CRC for carriers of monoallelic NTHL1 LoF variants, and consequently, no additional surveillance is currently warranted beyond population screening for CRC, unless family history characteristics point to a reason for colonoscopy. The authors thank all study participants, the CCFRC and staff, and the Dutch Parelsnoer Institute Biobank Hereditary Colorectal Cancer for their contributions to this project. Furthermore, we would like to thank Robbert Weren, Eveline Kamping, M. Elisa Vink-Börger, Riki Willems, Christian Gillissen, Peggy Manders, Dina Ruano, Ruud van der Breggen, Marina Ventayol, Sanne ten Broeke, Allyson Templeton, Maggie Angelakos, members of the Colorectal Oncogenomics Group, Sharelle Joseland, Susan Preston, Julia Como, Thomas Green, Magda Kloc, and Chris Cotsopoulos for their contributions to this project. The author(s) would further like to acknowledge networking support by the Cooperation in Science and Technology Action CA17118, supported by the European Cooperation in Science and Technology . NTHL1 study group: Arnoud Boot, Marija Staninova Stojovska, Khalid Mahmood, Mark Clendenning, Noel de Miranda, Dagmara Dymerska, Demi van Egmond, Steven Gallinger, Peter Georgeson, Nicoline Hoogerbrugge, John L. Hopper, Erik A.M. Jansen, Mark A. Jenkins, Jihoon E. Joo, Roland P. Kuiper, Marjolijn J.L. Ligtenberg, Jan Lubinski, Finlay A. Macrae, Hans Morreau, Polly Newcomb, Maartje Nielsen, Claire Palles, Daniel J. Park, Bernard J. Pope, Christophe Rosty, Clara Ruiz Ponte, Hans K. Schackert, Rolf H. Sijmons, Ian P. Tomlinson, Carli M. J. Tops, Lilian Vreede, Romy Walker, Aung K. Win, Colon Cancer Family Registry Cohort Investigators, Aleksandar J. Dimovski, and Ingrid M. Winship. Fadwa A. Elsayed, MSc (Data curation: Equal; Formal analysis: Equal; Writing – original draft: Equal); Judith E. Grolleman, MSc (Data curation: Equal; Formal analysis: Equal; Visualization: Equal; Writing – original draft: Equal); Abiram Ragunathan, MBBS (Data curation: Equal; Formal analysis: Equal; Visualization: Equal; Writing – original draft: Equal); Daniel D. Buchanan, PhD (Conceptualization: Equal; Formal analysis: Equal; Funding acquisition: Equal; Supervision: Equal; Writing – original draft: Equal; Writing – review & editing: Equal); Tom van Wezel, PhD (Conceptualization: Equal; Formal analysis: Equal; Funding acquisition: Equal; Supervision: Equal; Writing – review & editing: Equal); Richarda M. de Voer, PhD (Conceptualization: Equal; Formal analysis: Equal; Funding acquisition: Equal; Supervision: Equal; Writing – original draft: Equal; Writing – review & editing: Equal). We included 5,942 patients with unexplained polyposis, familial CRC, or sporadic CRC at a young age or suspected of having Lynch syndrome with CRC or multiple adenomas (Supplementary Table 1) from the Netherlands (n = 3,158); United Kingdom (n = 275); Poland (n = 144); Germany (n = 104); Spain (n = 35); North Macedonia (n = 273); and North America, Canada, and Australia (CCFRC; n = 1,953).1Grolleman J.E. de Voer R.M. Elsayed F.A. et al.Mutational signature analysis reveals NTHL1 deficiency to cause a multi-tumor phenotype.Cancer Cell. 2019; 35: 256-266Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar, 2Jenkins M.A. Win A.K. Templeton A.S. et al.Cohort Profile: The Colon Cancer Family Registry Cohort (CCFRC).Int J Epidemiol. 2018; 47: 387-388iCrossref PubMed Scopus (19) Google Scholar, 3Newcomb P.A. Baron J. Cotterchio M. et al.Colon Cancer Family Registry: an international resource for studies of the genetic epidemiology of colon cancer.Cancer Epidemiol Biomarkers Prev. 2007; 16: 2331-2343Crossref PubMed Scopus (274) Google Scholar All participants provided written informed consent. Local medical ethical committees approved this study (Radboudumc [Commissie mensgebonden onderzoek (CMO)-light, 2015/2172 and 2015/1748], Leiden University Medical Center (LUMC) [P01-019], and Ontario Cancer Research Ethics Board, University of Melbourne Human Research Ethics Committee, and Fred Hutchinson Cancer Research Center institutional review board). A total of 1,207 cancer-unaffected control individuals were available from the population-based recruitment arms of the CCFRC.2Al-Tassan N. et al.Nat Genet. 2002; 30: 227-232Crossref PubMed Scopus (1001) Google Scholar,3Weren R.D. et al.Nat Genet. 2015; 47: 668-671Crossref PubMed Scopus (208) Google Scholar From the Netherlands, 2,329 WES control individuals with a >90-fold median coverage without a suspicion of hereditary cancer were available.4de Voer R.M. Hahn M.M. Mensenkamp A.R. et al.Deleterious germline BLM mutations and the risk for early-onset colorectal cancer.Sci Rep. 2015; 5: 14060Crossref PubMed Scopus (46) Google Scholar The European non-Finnish population of gnomAD was used to determine overall frequencies of LoF variants.5Karczewski K.J. Francioli L.C. Tiao G. et al.The mutational constraint spectrum quantified from variation in 141,456 humans.Nature. 2020; 581: 434-443Crossref PubMed Scopus (1240) Google Scholar Leukocyte DNA from 1,953 CRC-affected case patients and 1,207 control individuals was used to screen the coding regions of NTHL1 by using multiplex polymerase chain reaction (PCR)–based targeted sequencing and variant calling approach (HiPlex2 and Hiplexpipe, hiplex.org, github.com/khalidm/hiplexpipe).6Hammet F. Mahmood K. Green T.R. et al.Hi-Plex2: a simple and robust approach to targeted sequencing-based genetic screening.Biotechniques. 2019; 67: 118-122Crossref PubMed Scopus (5) Google Scholar Germline variants in NTHL1 (NM_002528.5) were prioritized according to quality—the sequence depth of >30 reads and variant frequency of >30%. Leukocyte DNA from 1,486 polyposis and/or CRC cases was screened for all coding regions and intron–exon boundaries of NTHL1 (NM_002528.5) by using molecular inversion probe MIPsequencing, combined with a panel of base excision repair genes, as described previously.1Grolleman J.E. de Voer R.M. Elsayed F.A. et al.Mutational signature analysis reveals NTHL1 deficiency to cause a multi-tumor phenotype.Cancer Cell. 2019; 35: 256-266Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar Reads were mapped with Burrows-Wheeler Aligner (BWA), and variant calling was performed with UnifiedGenotyper.7DePristo M.A. Banks E. Poplin R. et al.A framework for variation discovery and genotyping using next-generation DNA sequencing data.Nat Genet. 2011; 43: 491-498Crossref PubMed Scopus (6094) Google Scholar Somatic variants in NTHL1 were prioritized according to quality: sequence depth of >40 reads, >20 variant reads, variant frequency of >25%, and quality by depth scores >8,000. Variants from HiPlex and MIP screenings were further selected based on predicted LoF of NTHL1. We selected all nonsense, frameshift canonical splice sites and included only coding and noncoding splice site region variants with a predicted change of >20%, based on Alamut (Interactive Biosoftware, Rouen, France) (MaxEnt, NNSplice, and Human Splicesite Finder [HSF]). Leukocyte DNA (n = 1,260) or germline DNA extracted from formalin-fixed, paraffin embedded (FFPE) surgical specimens (n = 982) was genotyped for NTHL1 p.(Gln90∗) by using KBioscience Competitive Allele-Specific PCR (KASPar) assay.1Grolleman J.E. de Voer R.M. Elsayed F.A. et al.Mutational signature analysis reveals NTHL1 deficiency to cause a multi-tumor phenotype.Cancer Cell. 2019; 35: 256-266Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar Leukocyte DNA from 261 individuals with sporadic or familial CRC was subjected to an allele-specific PCR (AS-PCR) specific for NTHL1 p.(Gln90∗) and p.(Trp269∗); primers are available upon request. Sanger sequencing was used for variant validation and to sequence the entire open reading frame of NTHL1 in confirmed heterozygous cases. In addition, when available, family members were sequenced by using Sanger sequencing for cosegregation purposes. A 1-sided Fisher exact test was performed to determine differences in the frequency of monoallelic NTHL1 germline LoF variants in carriers with polyposis and/or CRC compared to control individuals. We calculated the P value, odds ratio, and the 95% confidence interval using R (R Foundation for Statistical Computing, Vienna, Austria; http://www.R-project.org). Three control data sets were used in this comparison. First, we retrieved all LoF variants (nonsense, frameshift canonical splice sites, and coding or noncoding splice site regions with >20% splice site change) in canonical transcripts of NTHL1 listed in the non-Finnish European subpopulation of the genome aggregation database (gnomAD).5Karczewski K.J. Francioli L.C. Tiao G. et al.The mutational constraint spectrum quantified from variation in 141,456 humans.Nature. 2020; 581: 434-443Crossref PubMed Scopus (1240) Google Scholar All variants were checked manually in gnomAD for their quality. Second, LoF variants in NTHL1 identified in the Dutch WES cohort (n = 2,329 individuals without a suspicion of hereditary cancer) were extracted in a similar way as described earlier.4de Voer R.M. Hahn M.M. Mensenkamp A.R. et al.Deleterious germline BLM mutations and the risk for early-onset colorectal cancer.Sci Rep. 2015; 5: 14060Crossref PubMed Scopus (46) Google Scholar Third, LoF variants in NTHL1 identified in the CCFRC control group of 1,207 individuals, sequenced in this study, were used. Exome captures (Supplementary Table 2) were performed according to the manufacturer by using either Agilent Clinical Research Exome (CRE) V2 (Agilent, Santa Clara, CA) in combination with sequencing on a NovaSeq 6000 (Illumina, San Diego, CA), Agilent SureSelect XTHS Human All Exon V6 enrichment kit in combination with sequencing on a NextSeq 500, or xGEN Exome Research Panel (Integrated DNA Technology [IDT], Coralville, IA) in combination with sequencing on a NovaSeq 6000. Novaseq 6000 sequencing reads were trimmed by using Trimmomaticv0.36 and aligned to hs37d5 by using BWA-MEM, followed by merging and PCR duplicate removal with Sambamba (version 0.5.8).8Cerami E. et al.Cancer Discov. 2012; 2: 401-404Crossref PubMed Scopus (7132) Google Scholar,1Grolleman J.E. de Voer R.M. Elsayed F.A. et al.Mutational signature analysis reveals NTHL1 deficiency to cause a multi-tumor phenotype.Cancer Cell. 2019; 35: 256-266Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar Variant calling was performed bt using Strelka (version 2.017) and Freebayes for paired samples; only variants called by both callers were reported.2Jenkins M.A. Win A.K. Templeton A.S. et al.Cohort Profile: The Colon Cancer Family Registry Cohort (CCFRC).Int J Epidemiol. 2018; 47: 387-388iCrossref PubMed Scopus (19) Google Scholar,3Newcomb P.A. Baron J. Cotterchio M. et al.Colon Cancer Family Registry: an international resource for studies of the genetic epidemiology of colon cancer.Cancer Epidemiol Biomarkers Prev. 2007; 16: 2331-2343Crossref PubMed Scopus (274) Google Scholar For LUMC2745, no paired sample was available, and variant calling was performed with Mutect2 (GATK version 4.1.0.0; GATK, Broadinstitute, Cambridge, MA). Trimmed NextSeq 500 sequencing reads were aligned to GRCh37 by using BWA-MEM, and duplicates were flagged by using Picard Tools, version 1.90. Variants were called with Mutect2 (GATK version 4.1.0.0), with or without matched germline samples; variant filtering was performed as described,1Grolleman J.E. de Voer R.M. Elsayed F.A. et al.Mutational signature analysis reveals NTHL1 deficiency to cause a multi-tumor phenotype.Cancer Cell. 2019; 35: 256-266Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar with minor modifications. Variants in dbSNPv132 (minus catalogue of somatic mutations in cancer [COSMIC]), microsatellites, homopolymers, simple repeats, and variants called outside of the respective exome capture target were removed. Somatic variants with a variant allele frequency of <10%, <20× coverage in both normal and tumor, and fewer than 4 reads supporting the variant were removed. For tumor-only analysis, variants shared by more than 1 individual and variants with a variant allele frequency of >80% were removed to reduce germline leakage. Mutation spectra were generated by using In-depth characterization and analysis of mutational signatures (ICAMS), version 2.1.2 (github.com/steverozen/ICAMS), and mutational signature analysis was performed by using mSigAct v2.0.0.9018.12Ng A.W.T. Poon S.L. Huang M.N. et al.Aristolochic acids and their derivatives are widely implicated in liver cancers in Taiwan and throughout Asia.Sci Transl Med. 2017; 9eaan6446Crossref PubMed Scopus (158) Google Scholar Tissue-specific CRC signature universes were inferred from the Pan-cancer analysis of whole genomes (PCAWG) signature assignments.13Alexandrov L.B. Kim J. Haradhvala N.J. et al.The repertoire of mutational signatures in human cancer.Nature. 2020; 578: 94-101Crossref PubMed Scopus (461) Google Scholar The signature universe was extended with SBS30 and potential artefact signatures SBS45, SBS51, SBS52, SBS54, and SBS58, which were present in a subset of the samples of this cohort. Signatures were normalized to the trinucleotide abundance of the respective exome capture panel used. Per mutation spectrum, mutational signature assignment was performed by using mSigAct::SparseAssignActivity, with P = .5 to reduce sparsity. The presence of SBS30 was then determined using mSigAct::SignaturePresenceTest using the signatures determined by mSigAct::SparseAssignActivity plus SBS30 as well as the aging-associated signatures SBS1, SBS5, and SBS40 (Supplementary Table 2). Multiple testing correction was done according to Benjamini-Hochberg. NA, not applicable; ParelBED, The Dutch Parelsnoer Institute Biobank Hereditary Colorectal Cancer.14Vos JR Manders P. de Voer R.M. et al.Parelsnoer Institute Biobank Hereditary Colorectal Cancer: a joint infrastructure for patient data and biomaterial on hereditary colorectal cancer in the Netherlands.Open J Bioresources. 2019; 6 (Doi: http://doi.org/10.5334/ojb.54): 1Crossref Scopus (1) Google Scholar A, colorectal adenomatous polyps; BCC, basal cell carcinoma; EC, endometrial cancer; HP, hyperplastic polyps; ID, identifier; LC, lung cancer; LiC, liver cancer; OvC, ovarian cancer; PC, prostate cancer; SCC, squamous cell carcinoma; UC, uterine cancer; unk, age unknown; —, not applicable." @default.
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• W3080988723 title "Monoallelic NTHL1 Loss-of-Function Variants and Risk of Polyposis and Colorectal Cancer" @default.
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