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Cited by 16Cancer Genomics and DiagnosticsGenetic factors in colorectal cancerCancer Immunotherapy and Biomarkers

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Exploring Co-occurring POLE Exonuclease and Non-exonuclease Domain Mutations and Their Impact on Tumor Mutagenicity

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Shah, Shreya M., Demidova, Elena V., Ringenbach, Salena, Faezov, Bulat, Andrake, Mark, Gandhi, Arjun, Mur, Pilar, Viana-Errasti, Julen, Xiu, Joanne, Swensen, Jeffrey, Valle, Laura, Dunbrack, Roland L., Hall, Michael J., Arora, Sanjeevani·2024·Cancer Research Communications
DOI 10.1158/2767-9764.crc-23-0312PMC PMC10812383

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Abstract

POLE driver mutations in the exonuclease domain (ExoD driver) are prevalent in several cancers, including colorectal cancer and endometrial cancer, leading to dramatically ultra-high tumor mutation burden (TMB). To understand whether POLE mutations that are not classified as drivers (POLE Variant) contribute to mutagenesis, we assessed TMB in 447 POLE-mutated colorectal cancers, endometrial cancers, and ovarian cancers classified as TMB-high ≥10 mutations/Mb (mut/Mb) or TMB-low <10 mut/Mb. TMB was significantly highest in tumors with “POLE ExoD driver plus POLE Variant” (colorectal cancer and endometrial cancer, P < 0.001; ovarian cancer, P < 0.05). TMB increased with additional POLE variants (P < 0.001), but plateaued at 2, suggesting an association between the presence of these variants and TMB. Integrated analysis of AlphaFold2 POLE models and quantitative stability estimates predicted the impact of multiple POLE variants on POLE functionality. The prevalence of immunogenic neoepitopes was notably higher in the “POLE ExoD driver plus POLE Variant” tumors. Overall, this study reveals a novel correlation between POLE variants in POLE ExoD-driven tumors, and ultra-high TMB. Currently, only select pathogenic ExoD mutations with a reliable association with ultra-high TMB inform clinical practice. Thus, these findings are hypothesis-generating, require functional validation, and could potentially inform tumor classification, treatment responses, and clinical outcomes. Significance: Somatic POLE ExoD driver mutations cause proofreading deficiency that induces high TMB. This study suggests a novel modifier role for POLE variants in POLE ExoD-driven tumors, associated with ultra-high TMB. These data, in addition to future functional studies, may inform tumor classification, therapeutic response, and patient outcomes.

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Research works printed but not linked: 60

  1. Nicolas, 2016, POLD1: central mediator of DNA replication and repair, and implication in cancer and other pathologies, Gene, 590, 128, 10.1016/j.gene.2016.06.031 · DOI
  2. Vande Perre, 2019, Germline mutation p.N363K in POLE is associated with an increased risk of colorectal cancer and giant cell glioblastoma, Fam Cancer, 18, 173, 10.1007/s10689-018-0102-6 · DOI
  3. Mur, 2020, Role of POLE and POLD1 in familial cancer, Genet Med, 22, 2089, 10.1038/s41436-020-0922-2 · DOI
  4. Palles, 2013, Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas, Nat Genet, 45, 136, 10.1038/ng.2503 · DOI
  5. Valle, 2014, New insights into POLE and POLD1 germline mutations in familial colorectal cancer and polyposis, Hum Mol Genet, 23, 3506, 10.1093/hmg/ddu058 · DOI
  6. Djursby, 2020, New pathogenic germline variants in very early onset and familial colorectal cancer patients, Front Genet, 11, 566266, 10.3389/fgene.2020.566266 · DOI
  7. 2013, Germline DNA polymerase mutations increase cancer susceptibility, Cancer Discov, 3, 136, 10.1158/2159-8290.CD-RW2013-006 · DOI
  8. Ahn, 2016, The somatic POLE P286R mutation defines a unique subclass of colorectal cancer featuring hypermutation, representing a potential genomic biomarker for immunotherapy, Oncotarget, 7, 68638, 10.18632/oncotarget.11862 · DOI
  9. León-Castillo, 2020, Interpretation of somatic POLE mutations in endometrial carcinoma, J Pathol, 250, 323, 10.1002/path.5372 · DOI
  10. Campbell, 2017, Comprehensive analysis of hypermutation in human cancer, Cell, 171, 1042, 10.1016/j.cell.2017.09.048 · DOI
  11. Rousseau, 2022, PD-1 blockade in solid tumors with defects in polymerase epsilon, Cancer Discov, 12, 1435, 10.1158/2159-8290.CD-21-0521 · DOI
  12. Garmezy, 2022, Clinical and molecular characterization of pole mutations as predictive biomarkers of response to immune checkpoint inhibitors in advanced cancers, JCO Precis Oncol, 6, e2100267, 10.1200/PO.21.00267 · DOI
  13. Das, 2022, Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency, Nat Med, 28, 125, 10.1038/s41591-021-01581-6 · DOI
  14. Chung, 2021, DNA polymerase and mismatch repair exert distinct microsatellite instability signatures in normal and malignant human cells, Cancer Discov, 11, 1176, 10.1158/2159-8290.CD-20-0790 · DOI
  15. Rahn, 2019, POLE score: a comprehensive profiling of programmed death 1 ligand 1 expression in pancreatic ductal adenocarcinoma, Oncotarget, 10, 1572, 10.18632/oncotarget.26705 · DOI
  16. Haruma, 2018, Clinical impact of endometrial cancer stratified by genetic mutational profiles, POLE mutation, and microsatellite instability, PLoS One, 13, e0195655, 10.1371/journal.pone.0195655 · DOI
  17. Merino, 2020, Establishing guidelines to harmonize tumor mutational burden (TMB): in silico assessment of variation in TMB quantification across diagnostic platforms: phase I of the Friends of Cancer Research TMB Harmonization Project, J Immunother Cancer, 8, e000147, 10.1136/jitc-2019-000147 · DOI
  18. Marabelle, 2020, Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study, Lancet Oncol, 21, 1353, 10.1016/S1470-2045(20)30445-9 · DOI · Paper page
  19. Bartley, 2022, Mismatch repair and microsatellite instability testing for immune checkpoint inhibitor therapy: guideline from the College of American Pathologists in collaboration with the association for molecular pathology and fight colorectal cancer, Arch Pathol Lab Med, 146, 1194, 10.5858/arpa.2021-0632-CP · DOI
  20. Fortuno, 2021, Specifications of the ACMG/AMP variant interpretation guidelines for germline TP53 variants, Hum Mutat, 42, 223, 10.1002/humu.24152 · DOI
  21. Skidmore, 2016, GenVisR: Genomic Visualizations in R, Bioinformatics, 32, 3012, 10.1093/bioinformatics/btw325 · DOI
  22. Cerami, 2012, The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data, Cancer Discov, 2, 401, 10.1158/2159-8290.CD-12-0095 · DOI · Paper page
  23. Gao, 2013, Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal, Sci Signal, 6, pl1, 10.1126/scisignal.2004088 · DOI · Paper page
  24. Díaz-Gay, 2018, Mutational signatures in cancer (MuSiCa): a web application to implement mutational signatures analysis in cancer samples, BMC Bioinformatics, 19, 224, 10.1186/s12859-018-2234-y · DOI
  25. Demidova, 2023, Candidate variants in DNA replication and repair genes in early-onset renal cell carcinoma patients referred for germline testing, BMC Genomics, 24
  26. Hogg, 2014, Structural basis for processive DNA synthesis by yeast DNA polymerase ɛ, Nat Struct Mol Biol, 21, 49, 10.1038/nsmb.2712 · DOI
  27. Yuan, 2020, Structure of the polymerase ε holoenzyme and atomic model of the leading strand replisome, Nat Commun, 11, 3156, 10.1038/s41467-020-16910-5 · DOI
  28. Khatib, 2011, Algorithm discovery by protein folding game players, Proc Natl Acad Sci U S A, 108, 18949, 10.1073/pnas.1115898108 · DOI
  29. Maguire, 2021, Perturbing the energy landscape for improved packing during computational protein design, Proteins, 89, 436, 10.1002/prot.26030 · DOI · Paper page
  30. Krivov, 2009, Improved prediction of protein side-chain conformations with SCWRL4, Proteins, 77, 778, 10.1002/prot.22488 · DOI
  31. Shapovalov, 2011, A smoothed backbone-dependent rotamer library for proteins derived from adaptive kernel density estimates and regressions, Structure, 19, 844, 10.1016/j.str.2011.03.019 · DOI · Paper page
  32. Pettersen, 2004, UCSF Chimera–a visualization system for exploratory research and analysis, J Comput Chem, 25, 1605, 10.1002/jcc.20084 · DOI
  33. Leaver-Fay, 2013, Scientific benchmarks for guiding macromolecular energy function improvement, Methods Enzymol, 523, 109, 10.1016/B978-0-12-394292-0.00006-0 · DOI
  34. Shah, 2022, Co-occurring mutations in the POLE exonuclease and non-exonuclease domains define a unique subset of highly mutagenic tumors, bioRxiv
  35. Alexandrov, 2020, The repertoire of mutational signatures in human cancer, Nature, 578, 94, 10.1038/s41586-020-1943-3 · DOI · Paper page
  36. Hodel, 2020, POLE mutation spectra are shaped by the mutant allele identity, its abundance, and mismatch repair status, Mol Cell, 78, 1166, 10.1016/j.molcel.2020.05.012 · DOI
  37. Park, 2022, Mouse model and human patient data reveal critical roles for Pten and p53 in suppressing POLE mutant tumor development, NAR Cancer, 4, zcac004, 10.1093/narcan/zcac004 · DOI
  38. Robinson, 2021, Increased somatic mutation burdens in normal human cells due to defective DNA polymerases, Nat Genet, 53, 1434, 10.1038/s41588-021-00930-y · DOI · Paper page
  39. Kim, 2023, DeepNeo: a webserver for predicting immunogenic neoantigens, Nucleic Acids Res, 51, W134, 10.1093/nar/gkad275 · DOI
  40. Wu, 2023, Neodb: a comprehensive neoantigen database and discovery platform for cancer immunotherapy, Database, 2023, baad041, 10.1093/database/baad041 · DOI
  41. Parra-Herran, 2017, Molecular-based classification algorithm for endometrial carcinoma categorizes ovarian endometrioid carcinoma into prognostically significant groups, Mod Pathol, 30, 1748, 10.1038/modpathol.2017.81 · DOI
  42. van 't Erve, 2021, KRAS A146 mutations are associated with distinct clinical behavior in patients with colorectal liver metastases, JCO Precis Oncol, 5, PO.21.00223
  43. Kim, 2020, PTEN protein loss and loss-of-function mutations in gastric cancers: the relationship with microsatellite instability, EBV, HER2, and PD-L1 expression, Cancers, 12, 1724, 10.3390/cancers12071724 · DOI
  44. Post, 2020, Multi-model functionalization of disease-associated PTEN missense mutations identifies multiple molecular mechanisms underlying protein dysfunction, Nat Commun, 11, 2073, 10.1038/s41467-020-15943-0 · DOI
  45. Xu, 2014, Combined PTEN mutation and protein expression associate with overall and disease-free survival of glioblastoma patients, Transl Oncol, 7, 196, 10.1016/j.tranon.2014.02.004 · DOI
  46. Serebriiskii, 2022, Comprehensive characterization of PTEN mutational profile in a series of 34,129 colorectal cancers, Nat Commun, 13, 1618, 10.1038/s41467-022-29227-2 · DOI · Paper page
  47. Rudd, 2011, A unique spectrum of somatic PIK3CA (p110alpha) mutations within primary endometrial carcinomas, Clin Cancer Res, 17, 1331, 10.1158/1078-0432.CCR-10-0540 · DOI
  48. Dahl, 2022, Probing the mechanisms of two exonuclease domain mutators of DNA polymerase ϵ, Nucleic Acids Res, 50, 962, 10.1093/nar/gkab1255 · DOI
  49. Park, 2019, POLE proofreading defects: Contributions to mutagenesis and cancer, DNA Repair, 76, 50, 10.1016/j.dnarep.2019.02.007 · DOI
  50. Príncipe, 2021, LRP1B: a giant lost in cancer translation, Pharmaceuticals, 14, 836, 10.3390/ph14090836 · DOI
  51. Lu, 2021, Pan-cancer analysis of SETD2 mutation and its association with the efficacy of immunotherapy, NPJ Precis Oncol, 5, 51, 10.1038/s41698-021-00193-0 · DOI
  52. Okamura, 2020, ARID1A alterations function as a biomarker for longer progression-free survival after anti-PD-1/PD-L1 immunotherapy, J Immunother Cancer, 8, e000438, 10.1136/jitc-2019-000438 · DOI
  53. Chen, 2023, Pan-cancer analysis of histone methyltransferase KMT2D with potential implications for prognosis and immunotherapy in human cancer, Comb Chem High Throughput Screen, 26, 83, 10.2174/1386207325666220221092318 · DOI
  54. Scott, 2004, Germline missense changes in the APC gene and their relationship to disease, Hered Cancer Clin Pract, 2, 81, 10.1186/1897-4287-2-2-81 · DOI
  55. Zhang, 2017, Multiple roles of APC and its therapeutic implications in colorectal cancer, J Natl Cancer Inst, 109, djw332, 10.1093/jnci/djw332 · DOI
  56. Lüchtenborg, 2004, APC mutations in sporadic colorectal carcinomas from The Netherlands Cohort Study, Carcinogenesis, 25, 1219, 10.1093/carcin/bgh117 · DOI
  57. De Mattos-Arruda, 2020, Neoantigen prediction and computational perspectives towards clinical benefit: recommendations from the ESMO Precision Medicine Working Group, Ann Oncol, 31, 978, 10.1016/j.annonc.2020.05.008 · DOI
  58. Parkash, 2019, Structural consequence of the most frequently recurring cancer-associated substitution in DNA polymerase ε, Nat Commun, 10, 373, 10.1038/s41467-018-08114-9 · DOI
  59. Cao, 2019, DeepDDG: predicting the stability change of protein point mutations using neural networks, J Chem Inf Model, 59, 1508, 10.1021/acs.jcim.8b00697 · DOI
  60. Xing, 2019, A recurrent cancer-associated substitution in DNA polymerase ε produces a hyperactive enzyme, Nat Commun, 10, 374, 10.1038/s41467-018-08145-2 · DOI

Metadata

Authors
Shah, S. M., Demidova, E. V., Ringenbach, S., Faezov, B., Andrake, M., Gandhi, A., Mur, P., Viana-Errasti, J., Xiu, J., Swensen, J., Valle, L., Dunbrack, R. L., Hall, M. J., & Arora, S.
Affiliations
  • Fox Chase Cancer Center (US)
  • University College Dublin (IE)
  • Institut d'Investigació Biomédica de Bellvitge (ES)
  • Caris Life Sciences (United States) (US)
Corresponding author
Arora, Sanjeevani
ORCID
Venue
Cancer Research Communications
Publisher
American Association for Cancer Research (AACR)
Published
2024-01-26
Volume
4
Issue
1
Pages
213-225
ISSN
2767-9764 (ISSN-L)
DOI
10.1158/2767-9764.crc-23-0312
PMC
PMC10812383
OpenAlex
W4390733351
Cited by
16
References
3
Citations by year
2026: 5 · 2025: 10 · 2024: 1
FWCI
3.21
Type
journal article
Language
en
Update notices
correction (2024-05-31)
Open access
Licence
Locations
  • Cancer Research Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • TUScholarShare (Temple University) (submittedVersion, cc-by)
  • Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, cc-by)
Funders
  • HHS | National Institutes of Health (P30 CA006927, R35 GM122517, UH2CA271230-01, CEP Award (Yale Head and Neck Cancer NIH SPORE))
  • American Cancer Society
  • U.S. Department of Defense (W81XWH-18-1-0148)
  • Spanish Ministry of Science and Innovation (PID2020-112595RB-I00 and predoctoral fellowship to JV-E)
  • MEC | Instituto de Salud Carlos III (CIBERONC CB16/12/00234)
  • Generalitat de Catalunya (AGAUR 2017SGR1282,CERCA Program)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords
POLE mutation, exonuclease domain, tumor mutational burden, mutagenesis, colorectal cancer, endometrial cancer, ovarian cancer, neoantigens, protein stability

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