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Review
. 2021 Oct;40(40):5893-5901.
doi: 10.1038/s41388-021-01984-2. Epub 2021 Aug 6.

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

Luigi Magrin #  1 , Daniele Fanale #  1 , Chiara Brando #  1 , Alessia Fiorino  1 , Lidia Rita Corsini  1 , Roberta Sciacchitano  1 , Clarissa Filorizzo  1 , Alessandra Dimino  1 , Antonio Russo #  2 , Viviana Bazan #  3
Affiliations
Review

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

Luigi Magrin et al. Oncogene. 2021 Oct.

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.

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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.
    1. 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. - PubMed - DOI
    1. van Wezel T, de Miranda NFCC, Morreau H, Schubert SA. The missing heritability of familial colorectal cancer. Mutagenesis. 2020;35:221–31. - PubMed - DOI
    1. 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. - PubMed - DOI
    1. 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.

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