Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

POLE, POLD1, and NTHL1: the last but not the least hereditary cancer-predisposing genes

Oncogene volume 40, pages 5893–5901 (2021)Cite this article

Subjects

Abstract

POLE, POLD1, and NTHL1 are involved in DNA replication and have recently been recognized as hereditary cancer-predisposing genes, because their alterations are associated with colorectal cancer and other tumors. POLE/POLD1-associated syndrome shows an autosomal dominant inheritance, whereas NTHL1-associated syndrome follows an autosomal recessive pattern. Although the prevalence of germline monoallelic POLE/POLD1 and biallelic NTHL1 pathogenic variants is low, they determine different phenotypes with a broad tumor spectrum overlapping that of other hereditary conditions like Lynch Syndrome or Familial Adenomatous Polyposis. Endometrial and breast cancers, and probably ovarian and brain tumors are also associated with POLE/POLD1 alterations, while breast cancer and other unusual tumors are correlated with NTHL1 pathogenic variants. POLE-mutated colorectal and endometrial cancers are associated with better prognosis and may show favorable responses to immunotherapy. Since POLE/POLD1-mutated tumors show a high tumor mutational burden producing an increase in neoantigens, the identification of POLE/POLD1 alterations could help select patients suitable for immunotherapy treatment. In this review, we will investigate the role of POLE, POLD1, and NTHL1 genetic variants in cancer predisposition, discussing the potential future therapeutic applications and assessing the utility of performing a routine genetic testing for these genes, in order to implement prevention and surveillance strategies in mutation carriers.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Role of POLE/POLD1 in DNA replication.
Fig. 2: Germline biallelic NTHL1 mutations and predisposition to the development of a multitumor syndrome.

Similar content being viewed by others

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer J Clin. 2018;68:394–424.

    Google Scholar 

  2. Short E, Thomas LE, Hurley J, Jose S, Sampson JR. Inherited predisposition to colorectal cancer: towards a more complete picture. J Med Genet. 2015;52:791–6.

    Article  CAS  PubMed  Google Scholar 

  3. van Wezel T, de Miranda NFCC, Morreau H, Schubert SA. The missing heritability of familial colorectal cancer. Mutagenesis. 2020;35:221–31.

    Article  PubMed  CAS  Google Scholar 

  4. Stjepanovic N, Moreira L, Carneiro F, Balaguer F, Cervantes A, Balmaña J, et al. Hereditary gastrointestinal cancers: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Ann Oncol. 2019;30:1558–71.

    Article  CAS  PubMed  Google Scholar 

  5. Colas C, Coulet F, Svrcek M, Collura A, Fléjou J-F, Duval A, et al. Lynch or Not Lynch? Is that Always a Quest? 2012;113:121–66.

    CAS  Google Scholar 

  6. Vasen H, Watson P, Mecklin J, Lynch H. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative Group on HNPCC☆. Gastroenterology. 1999;116:1453–6.

    Article  CAS  PubMed  Google Scholar 

  7. Umar A, Boland CR, Terdiman JP, Syngal S, Chapelle ADL, Ruschoff J, et al. Revised bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch Syndrome) and microsatellite instability. JNCI J Natl Cancer Inst. 2004;96:261–8.

    Article  CAS  PubMed  Google Scholar 

  8. Nieuwenhuis MH, Vogt S, Jones N, Nielsen M, Hes FJ, Sampson JR, et al. Evidence for accelerated colorectal adenoma–carcinoma progression inMUTYH-associated polyposis? Gut. 2012;61:734–8.

    Article  CAS  PubMed  Google Scholar 

  9. Urso EDL, Ponz de Leon M, Vitellaro M, Piozzi GN, Bao QR, Martayan A, et al. Definition and management of colorectal polyposis not associated with APC/MUTYH germline pathogenic variants: AIFEG consensus statement. Dig Liver Dis. 2021;53:409–17.

    Article  CAS  PubMed  Google Scholar 

  10. Lindor NM, Rabe K, Petersen GM, Haile R, Casey G, Baron J, et al. Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency. JAMA. 2005;293:1979.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Palles C, Cazier J-B, Howarth KM, Domingo E, Jones AM, Broderick P, et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet. 2012;45:136–44.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Pursell ZF, Isoz I, Lundstrom EB, Johansson E, Kunkel TA. Yeast DNA polymerase participates in leading-strand DNA replication. Science. 2007;317:127–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Mertz TM, Baranovskiy AG, Wang J, Tahirov TH, Shcherbakova PV. Nucleotide selectivity defect and mutator phenotype conferred by a colon cancer-associated DNA polymerase δ mutation in human cells. Oncogene. 2017;36:4427–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Alani E, Thresher R, Griffith JD, Kolodner RD. Characterization of DNA-binding and strand-exchange stimulation properties of y-RPA, a yeast single-strand-DNA-binding protein. J Mol Biol. 1992;227:54–71.

    Article  CAS  PubMed  Google Scholar 

  15. Rayner E, van Gool IC, Palles C, Kearsey SE, Bosse T, Tomlinson I, et al. A panoply of errors: polymerase proofreading domain mutations in cancer. Nat Rev Cancer. 2016;16:71–81.

    Article  CAS  PubMed  Google Scholar 

  16. Briggs S, Tomlinson I. Germline and somatic polymerase ϵ and δ mutations define a new class of hypermutated colorectal and endometrial cancers. J Pathol. 2013;230:148–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bellido F, Pineda M, Aiza G, Valdés-Mas R, Navarro M, Puente DA, et al. POLE and POLD1 mutations in 529 kindred with familial colorectal cancer and/or polyposis: review of reported cases and recommendations for genetic testing and surveillance. Genet Med. 2015;18:325–32.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Belhadj S, Quintana I, Mur P, Munoz-Torres PM, Alonso MH, Navarro M. NTHL1 biallelic mutations seldom cause colorectal cancer, serrated polyposis or a multi-tumor phenotype, in absence of colorectal adenomas. Sci Rep. 2019;9:1–5.

    Article  CAS  Google Scholar 

  19. Limpose KL, Trego KS, Li Z, Leung SW, Sarker AH, Shah JA, et al. Overexpression of the base excision repair NTHL1 glycosylase causes genomic instability and early cellular hallmarks of cancer. Nucleic Acids Res. 2018;46:4515–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Mur P, García-Mulero S, del Valle J, Magraner-Pardo L, Vidal A, Pineda M, et al. Role of POLE and POLD1 in familial cancer. Genet Med. 2020;22:2089–2100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Fang H, Barbour JA, Poulos RC, Katainen R, Aaltonen LA, Wong JWH. Mutational processes of distinct POLE exonuclease domain mutants drive an enrichment of a specific TP53 mutation in colorectal cancer. PLOS Genet. 2020;16:e1008572.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Yao J, Gong Y, Zhao W, Han Z, Guo S, Liu H. et al. Comprehensive analysis of POLE and POLD1 gene variations identifies cancer patients potentially benefit from immunotherapy in Chinese population. Sci Rep. 2019;9:1–14.

    Article  Google Scholar 

  23. Haradhvala NJ, Kim J, Maruvka YE, Polak P, Rosebrock D, Livitz D. et al. Distinct mutational signatures characterize concurrent loss of polymerase proofreading and mismatch repair. Nat Commun. 2018;9:1–9.

    Article  CAS  Google Scholar 

  24. He J, Ouyang W, Zhao W, Shao L, Li B, Liu B, et al. Distinctive genomic characteristics in POLE/POLD1-mutant cancers can potentially predict beneficial clinical outcomes in patients who receive immune checkpoint inhibitor. Ann Transl Med. 2021;9:129–129.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Valle L, Hernández-Illán E, Bellido F, Aiza G, Castillejo A, Castillejo M-I, et al. New insights into POLE and POLD1 germline mutations in familial colorectal cancer and polyposis. Hum Mol Genet. 2014;23:3506–12.

    Article  CAS  PubMed  Google Scholar 

  26. Spier I, Holzapfel S, Altmüller J, Zhao B, Horpaopan S, Vogt S, et al. Frequency and phenotypic spectrum of germline mutations inPOLEand seven other polymerase genes in 266 patients with colorectal adenomas and carcinomas. Int J Cancer. 2015;137:320–31.

    Article  CAS  PubMed  Google Scholar 

  27. Palles C, Martin L, Domingo E, Chegwidden L, McGuire J, Cuthill V, et al. The clinical features of polymerase proof-reading associated polyposis (PPAP) and recommendations for patient management. Familial Cancer. 2021; 1–13.

  28. Chubb D, Broderick P, Dobbins SE, Frampton M, Kinnersley B, Penegar S. Rare disruptive mutations and their contribution to the heritable risk of colorectal cancer. Nat Commun. 2016;7:1–7.

    Article  CAS  Google Scholar 

  29. Dong H, Bai Y, Cao X, Wang Y, Shi L, Li F, et al. Abstract 5137: comprehensive analysis of POLE and POLD1 mutation in 9322 Chinese cancer patients 2019: 5137–5137.

  30. Rosner G, Gluck N, Carmi S, Bercovich D, Fliss-Issakov N, Ben-Yehoyada M, et al. POLD1 and POLE gene mutations in Jewish cohorts of early-onset colorectal cancer and of multiple colorectal adenomas. Dis Colon Rectum. 2018;61:1073–9.

    Article  PubMed  Google Scholar 

  31. Siraj AK, Bu R, Iqbal K, Parvathareddy SK, Masoodi T, Siraj N. et al. POLE and POLD1 germline exonuclease domain pathogenic variants, a rare event in colorectal cancer from the Middle East. Mol Genet Genom Med. 2020;8:1–11.

    Google Scholar 

  32. Djursby M, Madsen MB, Frederiksen JH, Berchtold LA, Therkildsen C, Willemoe GL, et al. New pathogenic germline variants in very early onset and familial colorectal cancer patients. Front Genet. 2020;11:566266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Esteban-Jurado C, Giménez-Zaragoza D, Muñoz J, Franch-Expósito S, Álvarez-Barona M, Ocaña T, et al. POLE and POLD1 screening in 155 patients with multiple polyps and early-onset colorectal cancer. Oncotarget. 2017;8:26732–43.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–23.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Campbell BB, Light N, Fabrizio D, Zatzman M, Fuligni F, de Borja R, et al. Comprehensive analysis of hypermutation in human cancer. Cell. 2017;171:1042–56. e1010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Strickler JH, Hanks BA, Khasraw M. Tumor mutational burden as a predictor of immunotherapy response: is more always better? Clin Cancer Res. 2021;27:1236–41.

    Article  CAS  PubMed  Google Scholar 

  37. Gelsomino F, Barbolini M, Spallanzani A, Pugliese G, Cascinu S. The evolving role of microsatellite instability in colorectal cancer: a review. Cancer Treat Rev. 2016;51:19–26.

    Article  CAS  PubMed  Google Scholar 

  38. Fabrizio DA, George TJ Jr, Dunne RF, Frampton G, Sun J, Gowen K, et al. Beyond microsatellite testing: assessment of tumor mutational burden identifies subsets of colorectal cancer who may respond to immune checkpoint inhibition. J Gastrointest Oncol. 2018;9:610–7.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Zhao P, Li L, Jiang X, Li Q. Mismatch repair deficiency/microsatellite instability-high as a predictor for anti-PD-1/PD-L1 immunotherapy efficacy. J Hematol Oncol. 2019;12:1–14.

    Article  Google Scholar 

  40. Gong J, Wang C, Lee PP, Chu P, Fakih M. Response to PD-1 blockade in microsatellite stable metastatic colorectal cancer harboring aPOLEMutation. J Natl Compr Cancer Netw. 2017;15:142–7.

    Article  Google Scholar 

  41. Jansen AML, van Wezel T, van den Akker BEWM, Ventayol Garcia M, Ruano D, Tops CMJ, et al. Combined mismatch repair and POLE/POLD1 defects explain unresolved suspected Lynch syndrome cancers. Eur J Hum Genet. 2015;24:1089–92.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Domingo E, Freeman-Mills L, Rayner E, Glaire M, Briggs S, Vermeulen L, et al. Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer: a retrospective, pooled biomarker study. Lancet Gastroenterol Hepatol. 2016;1:207–16.

    Article  PubMed  Google Scholar 

  43. Fancello L, Gandini S, Pelicci PG, Mazzarella L. Tumor mutational burden quantification from targeted gene panels: major advancements and challenges. J Immun Ther Cancer. 2019;1–13.

  44. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl J Med. 2015;372:2509–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Silberman R, Steiner DF, Lo AA, Gomez A, Zehnder JL, Chu G. et al. Complete and prolonged response to immune checkpoint blockade in POLE-mutated colorectal cancer. JCO Precision Oncol. 2019;3:1–5.

    Google Scholar 

  46. Wang F, Zhao Q, Wang Y-N, Jin Y, He M-M, Liu Z-X, et al. Evaluation of POLE and POLD1 mutations as biomarkers for immunotherapy outcomes across multiple cancer types. JAMA Oncol. 2019;5:1504.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Forgó E, Gomez AJ, Steiner D, Zehnder J, Longacre TA. Morphological, immunophenotypical and molecular features of hypermutation in colorectal carcinomas with mutations in DNA polymerase ε (POLE). Histopathology. 2019;76:366–74.

    Article  PubMed  Google Scholar 

  48. Bourdais R, Rousseau B, Pujals A, Boussion H, Joly C, Guillemin A, et al. Polymerase proofreading domain mutations: New opportunities for immunotherapy in hypermutated colorectal cancer beyond MMR deficiency. Crit Rev Oncol/Hematol. 2017;113:242–8.

    Article  Google Scholar 

  49. Rousseau B, Foote MB, Maron SB, Diplas BH, Lu S, Argilés G, et al. The spectrum of benefit from checkpoint blockade in hypermutated tumors. N. Engl J Med. 2021;384:1168–70.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Hu H, Cai W, Wu D, Hu W, Dong Wang L, Mao J, et al. Ultra‐mutated colorectal cancer patients with POLE driver mutations exhibit distinct clinical patterns. Cancer Med. 2020;10:135–42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Nijman SMB. Synthetic lethality: general principles, utility and detection using genetic screens in human cells. FEBS Lett. 2011;585:1–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kaelin WG. The concept of synthetic lethality in the context of anticancer therapy. Nat Rev Cancer. 2005;5:689–98.

    Article  CAS  PubMed  Google Scholar 

  53. Hocke S, Guo Y, Job A, Orth M, Ziesch A, Lauber K, et al. A synthetic lethal screen identifies ATR-inhibition as a novel therapeutic approach for POLD1-deficient cancers. Oncotarget. 2016;7:7080–95.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Job A, Tatura M, Schäfer C, Lutz V, Schneider H, Lankat-Buttgereit B. The POLD1R689W variant increases the sensitivity of colorectal cancer cells to ATR and CHK1 inhibitors. Sci Rep. 2020;10:1–12.

    Article  CAS  Google Scholar 

  55. Church DN, Briggs SEW, Palles C, Domingo E, Kearsey SJ, Grimes JM, et al. DNA polymerase ɛ and δ exonuclease domain mutations in endometrial cancer. Hum Mol Genet. 2013;22:2820–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. McConechy MK, Talhouk A, Leung S, Chiu D, Yang W, Senz J, et al. Endometrial carcinomas with POLE exonuclease domain mutations have a favorable prognosis. Clin Cancer Res. 2016;22:2865–73.

    Article  CAS  PubMed  Google Scholar 

  57. León‐Castillo A, Britton H, McConechy MK, McAlpine JN, Nout R, Kommoss S, et al. Interpretation of somatic POLE mutations in endometrial carcinoma. J Pathol. 2020;250:323–35.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Howitt BE, Shukla SA, Sholl LM, Ritterhouse LL, Watkins JC, Rodig S, et al. Association of polymerase e–mutated and microsatellite-instable endometrial cancers with neoantigen load, number of tumor-infiltrating lymphocytes, and expression of PD-1 and PD-L1. JAMA Oncol. 2015;1:1319.

    Article  PubMed  Google Scholar 

  59. Mehnert JM, Panda A, Zhong H, Hirshfield K, Damare S, Lane K, et al. Immune activation and response to pembrolizumab in POLE-mutant endometrial cancer. J Clin Investig. 2016;126:2334–40.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Imboden S, Nastic D, Ghaderi M, Rydberg F, Rau TT, Mueller MD, et al. Phenotype of POLE-mutated endometrial cancer. Plos One. 2019;14:e0214318.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Siraj AK, Parvathareddy SK, Bu R, Iqbal K, Siraj S, Masoodi T. Germline POLE and POLD1 proofreading domain mutations in endometrial carcinoma from Middle Eastern region. Cancer Cell Int. 2019;19:1–9.

    Article  CAS  Google Scholar 

  62. Wong A, Kuick CH, Wong WL, Tham JM, Mansor S, Loh E, et al. Mutation spectrum of POLE and POLD1 mutations in South East Asian women presenting with grade 3 endometrioid endometrial carcinomas. Gynecologic Oncol. 2016;141:113–20.

    Article  CAS  Google Scholar 

  63. He Y, Wang T, Li N, Yang B, Hu Y. Clinicopathological characteristics and prognostic value of POLE mutations in endometrial cancer. Medicine. 2020;99:e19281.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Hansen MF, Johansen J, Bjørnevoll I, Sylvander AE, Steinsbekk KS, Sætrom P, et al. A novel POLE mutation associated with cancers of colon, pancreas, ovaries and small intestine. Fam Cancer. 2015;14:437–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Aoude LG, Heitzer E, Johansson P, Gartside M, Wadt K, Pritchard AL, et al. POLE mutations in families predisposed to cutaneous melanoma. Fam Cancer. 2015;14:621–8.

    Article  CAS  PubMed  Google Scholar 

  66. Siraj AK, Bu R, Arshad M, Iqbal K, Parvathareddy SK, Masoodi T, et al. POLE and POLD1 pathogenic variants in the proofreading domain in papillary thyroid cancer. Endocr Connect. 2020;9:923–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Vande Perre P, Siegfried A, Corsini C, Bonnet D, Toulas C, Hamzaoui N, et al. Germline mutation p.N363K in POLE is associated with an increased risk of colorectal cancer and giant cell glioblastoma. Fam Cancer. 2018;18:173–8.

    Article  CAS  Google Scholar 

  68. Hamzaoui N, Alarcon F, Leulliot N, Guimbaud R, Buecher B, Colas C, et al. Genetic, structural, and functional characterization of POLE polymerase proofreading variants allows cancer risk prediction. Genet Med. 2020;22:1533–41.

    Article  CAS  PubMed  Google Scholar 

  69. Gao S, Zhang X, Song Q, Liu J, Ji X, Wang P. POLD1 deficiency is involved in cognitive function impairment in AD patients and SAMP8 mice. Biomed Pharmacother. 2019;114:108833.

    Article  CAS  PubMed  Google Scholar 

  70. Liu J, Liu Y, Fu J, Liu C, Yang T, Zhang X. Preliminary study on the function of the POLD1 (CDC2) EXON2 c.56G>A mutation. Mol Genet Genom Med. 2020;8:1–6.

    Google Scholar 

  71. Weren RDA, Ligtenberg MJL, Kets CM, de Voer RM, Verwiel ETP, Spruijt L, et al. A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer. Nat Genet. 2015;47:668–71.

    Article  CAS  PubMed  Google Scholar 

  72. Grolleman JE, de Voer RM, Elsayed FA, Nielsen M, Weren RDA, Palles C, et al. Mutational signature analysis reveals NTHL1 deficiency to cause a multi-tumor phenotype. Cancer Cell. 2019;35:256–66. e255

    Article  CAS  PubMed  Google Scholar 

  73. Li N, Zethoven M, McInerny S, Devereux L, Huang Y-K, Thio N. et al. Evaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects. npj Breast Cancer. 2021;7:1–12.

    Article  CAS  Google Scholar 

  74. Groves A, Gleeson M, Spigelman AD. NTHL1-associate polyposis: first Australian case report. Fam Cancer. 2019;18:179–82.

    Article  PubMed  Google Scholar 

  75. Rivera B, Castellsagué E, Bah I, van Kempen LC, Foulkes WD. Biallelic NTHL1 mutations in a woman with multiple primary tumors. N. Engl J Med. 2015;373:1985–6.

    Article  PubMed  Google Scholar 

  76. Weren RDA, Ligtenberg MJL, Geurts van Kessel A, De Voer RM, Hoogerbrugge N, Kuiper RP. NTHL1 and MUTYH polyposis syndromes: two sides of the same coin? J Pathol. 2018;244:135–42.

    Article  PubMed  Google Scholar 

  77. Elsayed FA, Grolleman JE, Ragunathan A, Buchanan DD, van Wezel T, de Voer RM, et al. Monoallelic NTHL1 loss-of-function variants and risk of polyposis and colorectal cancer. Gastroenterology. 2020;159:2241–3. e2246

    Article  CAS  PubMed  Google Scholar 

  78. Das L, Quintana VG, Sweasy JB. NTHL1 in genomic integrity, aging and cancer. DNA Repair. 2020;93:102920.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Drost J, van Boxtel R, Blokzijl F, Mizutani T, Sasaki N, Sasselli V, et al. Use of CRISPR-modified human stem cell organoids to study the origin of mutational signatures in cancer. Science. 2017;358:234–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Pilati C, Shinde J, Alexandrov LB, Assié G, André T, Hélias‐Rodzewicz Z, et al. Mutational signature analysis identifies MUTYH deficiency in colorectal cancers and adrenocortical carcinomas. J Pathol. 2017;242:10–15.

    Article  CAS  PubMed  Google Scholar 

  81. Marie Lewis K. Identifying hereditary cancer: genetic counseling and cancer risk assessment. Curr Probl Cancer. 2014;38:216–25.

    Article  Google Scholar 

  82. Fanale D, Incorvaia L, Filorizzo C, Bono M, Fiorino A, Calò V, et al. Detection of germline mutations in a cohort of 139 patients with bilateral breast cancer by multi-gene panel testing: impact of pathogenic variants in other genes beyond BRCA1/2. Cancers. 2020;12:2415.

    Article  CAS  PubMed Central  Google Scholar 

  83. Hegde M, Ferber M, Mao R, Samowitz W, Ganguly A. ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). Genet Med. 2013;16:101–16.

    Article  PubMed  CAS  Google Scholar 

  84. Dhooge M, Baert-Desurmont S, Corsini C, Caron O, Andrieu N, Berthet P, et al. National recommendations of the French Genetics and Cancer Group - Unicancer on the modalities of multi-genes panel analyses in hereditary predispositions to tumors of the digestive tract. Eur J Med Genet. 2020;63:104080.

    Article  PubMed  Google Scholar 

  85. Mao R, Krautscheid P, Graham RP, Ganguly A, Shankar S, Ferber M et al. Genetic testing for inherited colorectal cancer and polyposis, 2021 revision: a technical standard of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021; 1–11.

Download references

Acknowledgements

The authors thank Dr. Chiara Drago for the English language revision.

Author information

Author notes

  1. These authors contributed equally: Luigi Magrin, Daniele Fanale, Chiara Brando, Antonio Russo, Viviana Bazan.

Authors and Affiliations

  1. Section of Medical Oncology, Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127, Palermo, Italy

    Luigi Magrin, Daniele Fanale, Chiara Brando, Alessia Fiorino, Lidia Rita Corsini, Roberta Sciacchitano, Clarissa Filorizzo, Alessandra Dimino & Antonio Russo

  2. Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, 90127, Palermo, Italy

    Viviana Bazan

Authors
  1. Luigi Magrin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniele Fanale
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chiara Brando
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alessia Fiorino
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lidia Rita Corsini
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Roberta Sciacchitano
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Clarissa Filorizzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Alessandra Dimino
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Antonio Russo
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Viviana Bazan
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

LM, DF, CB, AR, and VB conceived, wrote, and critically revised the manuscript with the contribution of AF, LRC, RS, CF, and AD. Literature data were acquired and analyzed by LM, DF, CB, AF, LRC, RS, CF, and AD. The figures of the manuscript were conceived and designed by AF, CB, and LRC. The tables were conceived and designed by LM, DF, and CB. AF, LRC, RS, CF, and AD participated to the critical revision of the manuscript. All authors have read and approved the final version of the manuscript.

Corresponding author

Correspondence to Antonio Russo.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Magrin, L., Fanale, D., Brando, C. et al. POLE, POLD1, and NTHL1: the last but not the least hereditary cancer-predisposing genes. Oncogene 40, 5893–5901 (2021). https://doi.org/10.1038/s41388-021-01984-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-021-01984-2

This article is cited by

Search

Advanced search

Quick links