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

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

doi:10.1038/s41388-021-01984-2

Cited by 39 publications

(25 citation statements)

References 86 publications

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“…The relatively high percentage of MMR-w.t. patients identified only based on personal and familial history of LS-associated tumors (Amsterdam criteria II), in addition to the lower sensitivity of the selection strategy, may probably be due to the presence of uninvestigated germline mutations in other CRC susceptibility genes such as MUTYH, POLE, POLD1, PTEN, STK11, TP53, SMAD4, BMPR1A (56)(57)(58).…”

Section: Discussionmentioning

confidence: 99%

Impact of Different Selection Approaches for Identifying Lynch Syndrome-Related Colorectal Cancer Patients: Unity Is Strength

et al. 2022

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Lynch syndrome (LS) is an inherited genetic condition associated with increased predisposition to colorectal cancer (CRC) and other tumors and is caused by germline mutations in Mismatch Repair (MMR) or EPCAM genes. The identification of LS carriers is currently based on germline testing of subjects with MMR-deficient (dMMR) tumors or fulfilling clinical criteria, but the most efficient strategies to select patients who should be offered genetic testing are yet not well defined. In order to assess the most suitable selection mode to identify LS-related CRC patients, we retrospectively collected and analyzed all clinical and molecular information of 854 CRC patients, recruited from 2013 to 2021 at the University Hospital Policlinico “P. Giaccone” of Palermo (Italy), 100 of which were selected based on revised Bethesda guidelines, Amsterdam criteria II, or tissue MMR deficiency, and genetically tested for germline variants in LS-susceptibility genes. Our study showed that 32 out of 100 CRC patients harbored germline likely pathogenic/pathogenic variants in MMR genes. The analysis of tissue microsatellite instability (MSI) status according to the revised Bethesda guidelines has been to be the best selection approach. However, using different selection approaches as complementary strategies is useful to identify LS carriers, reducing underdiagnosis of this syndrome.

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Section: Discussionmentioning

confidence: 99%

Impact of Different Selection Approaches for Identifying Lynch Syndrome-Related Colorectal Cancer Patients: Unity Is Strength

et al. 2022

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“…Germline mutations in the exonuclease domain of POLD1 and POLE affect the proofreading abilities of these polymerases, predispose to multiple colorectal carcinomas and adenomas, and generate polymerase proofreading-associated polyposis (PPAP) [70]. PPAP represents 0.1-0.4% of familial cancer cases [71]. Moreover, other extracolonic tumors were described, including brain, endometrial, ovarian, breast, skin tumors [72].…”

Section: Pold1/polementioning

confidence: 99%

Landscape of Immunotherapy Options for Colorectal Cancer: Current Knowledge and Future Perspectives beyond Immune Checkpoint Blockade

Gorzo

Galos

Lungulescu

et al. 2022

Life

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Colorectal cancer is the third most prevalent malignancy in Western countries and a major cause of death despite recent improvements in screening programs and early detection methods. In the last decade, a growing effort has been put into better understanding how the immune system interacts with cancer cells. Even if treatments with immune checkpoint inhibitors (anti-PD1, anti-PD-L1, anti-CTLA4) were proven effective for several cancer types, the benefit for colorectal cancer patients is still limited. However, a subset of patients with deficient mismatch repair (dMMR)/microsatellite-instability-high (MSI-H) metastatic colorectal cancer has been observed to have a prolonged benefit to immune checkpoint inhibitors. As a result, pembrolizumab and nivolumab +/− ipilimumab recently obtained the Food and Drug Administration approval. This review aims to highlight the body of knowledge on immunotherapy in the colorectal cancer setting, discussing the potential mechanisms of resistance and future strategies to extend its use.

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“…Moreover, germline or somatic mutations in the exonuclease domain of POLE were found to increase the mutation rate and risk of cancer development in the colon and endometrium [ 179 ]. Although somatic POLD exonuclease domain mutations are less frequent, they were observed in colon, endometrium, and melanoma cancers [ 180 , 181 ] ( Table 1 ). Patients with these mutations have an excellent prognosis and respond well to immunotherapy because the high mutation rate increases the probability of neoantigens, which are recognized by the immune system [ 179 , 181 ].…”

Section: Exonucleases and Cancermentioning

confidence: 99%

Exonucleases: Degrading DNA to Deal with Genome Damage, Cell Death, Inflammation and Cancer

Manils

Marruecos

Soler

2022

Cells

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Although DNA degradation might seem an unwanted event, it is essential in many cellular processes that are key to maintaining genomic stability and cell and organism homeostasis. The capacity to cut out nucleotides one at a time from the end of a DNA chain is present in enzymes called exonucleases. Exonuclease activity might come from enzymes with multiple other functions or specialized enzymes only dedicated to this function. Exonucleases are involved in central pathways of cell biology such as DNA replication, repair, and death, as well as tuning the immune response. Of note, malfunctioning of these enzymes is associated with immune disorders and cancer. In this review, we will dissect the impact of DNA degradation on the DNA damage response and its links with inflammation and cancer.

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

Cited by 39 publications

References 86 publications

Impact of Different Selection Approaches for Identifying Lynch Syndrome-Related Colorectal Cancer Patients: Unity Is Strength

Impact of Different Selection Approaches for Identifying Lynch Syndrome-Related Colorectal Cancer Patients: Unity Is Strength

Landscape of Immunotherapy Options for Colorectal Cancer: Current Knowledge and Future Perspectives beyond Immune Checkpoint Blockade

Exonucleases: Degrading DNA to Deal with Genome Damage, Cell Death, Inflammation and Cancer

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