Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-tumor Phenotype

Grolleman, Judith E.; Voer, Richarda M. de; Elsayed, Fadwa A.; Nielsen, Maartje; Weren, Robbert D.A.; Palles, Claire; Ligtenberg, Marjolijn J. L.; Vos, Janet R.; Broeke, Sanne W. ten; Miranda, Noel F C C de; Kuiper, Renske A.; Kamping, Eveline J.; Jansen, Erik A. M.; Vink-Börger, M. Elisa; Popp, I; Lang, Alois; Spier, Isabel; Hüneburg, Robert; James, Paul; Li, Na; Staninova, Marija; Lindsay, Helen; Cockburn, David; Spasić-Bošković, Olivera; Clendenning, Mark; Sweet, Kevin; Capellà, Gabriel; Sjursen, Wenche; Høberg-Vetti, Hildegunn; Jongmans, Marjolijn C.J.; Neveling, Kornelia; Kessel, Ad Geurts van; Morreau, Hans; Hes, Frederik J.; Sijmons, Rolf H.; Schackert, Hans K.; Ruíz-Ponte, Clara; Dymerska, Dagmara; Lubiński, Jan; Rivera, Bárbara; Foulkes, William D.; Tomlinson, Ian; Valle, Laura; Buchanan, Daniel D.; Kenwrick, Sue; Adlard, Julian; Dimovski, Aleksandar; Campbell, Ian G.; Aretz, Stefan; Schindler, Detlev; Wezel, Tom van; Hoogerbrugge, Nicoline; Kuiper, Roland P.

doi:10.1016/j.ccell.2018.12.011

Cited by 135 publications

(138 citation statements)

References 34 publications

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“…Other genes, such as PPM1D, ERCC3, BAP1, and NTHL1 have been reported in BC/OC families [117,[261][262][263][264][265][266], but further studies are needed to confirm these associations.…”

Section: Other Emerging Genesmentioning

confidence: 97%

Genetic Predisposition to Breast and Ovarian Cancers: How Many and Which Genes to Test?

Angeli

Salvi

Tedaldi

2020

IJMS

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Breast and ovarian cancers are some of the most common tumors in females, and the genetic predisposition is emerging as one of the key risk factors in the development of these two malignancies. BRCA1 and BRCA2 are the best-known genes associated with hereditary breast and ovarian cancer. However, recent advances in molecular techniques, Next-Generation Sequencing in particular, have led to the identification of many new genes involved in the predisposition to breast and/or ovarian cancer, with different penetrance estimates. TP53, PTEN, STK11, and CDH1 have been identified as high penetrance genes for the risk of breast/ovarian cancers. Besides them, PALB2, BRIP1, ATM, CHEK2, BARD1, NBN, NF1, RAD51C, RAD51D and mismatch repair genes have been recognized as moderate and low penetrance genes, along with other genes encoding proteins involved in the same pathways, possibly associated with breast/ovarian cancer risk. In this review, we summarize the past and more recent findings in the field of cancer predisposition genes, with insights into the role of the encoded proteins and the associated genetic disorders. Furthermore, we discuss the possible clinical utility of genetic testing in terms of prevention protocols and therapeutic approaches. the recruitment of the recombinase RAD51 to the DNA double-strand breaks (DSBs) through the formation of a BRCA1-PALB2-BRCA2 complex. The BRCA2 protein contains a helical domain, three oligonucleotide binding domains, and a tower domain, which allow BRCA2 binding to both single-stranded DNA and double-stranded DNA [39,48,49].Germline PV/LPVs in the BRCA2 gene are associated with a 45-55% and 11-18% risk of developing BC and OC by the age of 70, respectively [20][21][22]. BRCA2 PV/LPVs have also been associated with an increased risk of BC in males, which is estimated at 6.8% by the age of 70 [43]. In addition, BRCA2 PV/LPVs have been associated with an increased risk of prostate cancer [50], pancreatic cancer [47,51], and uveal melanoma [52,53].According to the National Comprehensive Cancer Network (NCCN) guidelines, women with BRCA1/2 PV/LPVs should undergo a surveillance protocol, including clinical breast examination every 6-12 months and annual breast magnetic resonance imaging (MRI), starting at the age of 25, annual mammography with consideration of tomosynthesis, starting at the age of 30, and annual transvaginal ultrasound and serum CA-125 concentration, although of uncertain benefit, beginning at age 30-35 years [54]. Moreover, they should evaluate the opportunity of a bilateral risk-reducing mastectomy (RRM) and of a bilateral risk-reducing salpingo-oophorectomy (RRSO), typically at between 35 and 40 years and upon completion of childbearing [54]. Men with BRCA1/2 PV/LPVs should undergo clinical breast examination every 6-12 months, starting at the age of 35, and annual prostate cancer screening, starting at the age of 40 (in particular in BRCA2 PV/LPV carriers) [55]. In both sexes, screening for melanoma and pancreatic cancer should be evaluated on the basis of family...

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“…Other genes, such as PPM1D, ERCC3, BAP1, and NTHL1 have been reported in BC/OC families [117,[261][262][263][264][265][266], but further studies are needed to confirm these associations.…”

Section: Other Emerging Genesmentioning

confidence: 97%

Genetic Predisposition to Breast and Ovarian Cancers: How Many and Which Genes to Test?

Angeli

Salvi

Tedaldi

2020

IJMS

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“…NTHL1 (Nth‐Like DNA Glycosylase 1) encodes a glycosylase involved in the DNA base excision repair (BER) pathway. Biallelic inactivation of this gene has been associated with the predisposition to attenuated adenomatous polyposis, CRC and other tumor types, being the presence of multiple primary tumors characteristic of the associated syndrome (Belhadj et al, ; Broderick et al, ; Grolleman et al, ; Groves, Gleeson, & Spigelman, ; Rivera, Castellsagué, Bah, van Kempen, & Foulkes, ; Weren, Ligtenberg, et al, ). To date, a total of 33 NTHL1 biallelic carriers belonging to 21 unrelated families have been reported (Table S3).…”

Section: The Prevalence Of Biallelic Nthl1 Mutations Among Unexplainementioning

confidence: 99%

“…biallelic carriers belonging to 21 unrelated families have been reported (Table S3) (48.5%) exhibited multiple primary tumors either in the colorectum or extracolonic. All biallelic carriers that underwent colonoscopy screening (n = 28) were diagnosed with adenomatous polyps (range: 1-200) and five of them (18%) were additionally diagnosed with more than four hyperplastic polyps (range: 4 to >30) (Belhadj et al, 2017;Broderick et al, 2017;Fostira et al, 2018;Grolleman et al, 2019;Rivera et al, 2015;Weren, Ligtenberg, et al, 2015; Table S3).…”

Section: The Prevalence Of Biallelic Nthl1 Mutations Among Unexplaimentioning

confidence: 99%

“…However, the evidence gathered supporting their implication in the predisposition to polyposis remains inconclusive, such being the case for MCM9 , FOCAD , and POLQ (Goldberg et al, ; Raskin et al, ; Weren, Venkatachalam, et al, ). Although known to be rare, some of the newly described polyposis genes, such as MSH3 (Adam et al, ), lack of reported data on their actual frequency among polyposis cases without mutations in the classically associated polyposis genes (i.e., APC and MUTYH ), or as NTHL1 , this information is scarce in the literature (Grolleman et al, ). On the contrary, five of the 13 reported carriers of RNF43 mutations, in addition to the serrated/hyperplastic polyps, had developed several adenomas, suggesting a potential implication of RNF43 in the predisposition to adenomatous polyposis and/or polyposis of multiple polyp types (reviewed by Quintana et al, ).…”

Section: Introductionmentioning

confidence: 99%

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Contribution to colonic polyposis of recently proposed predisposing genes and assessment of the prevalence of NTHL1 ‐ and MSH3 ‐associated polyposes

et al. 2019

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Technological advances have allowed the identification of new adenomatous and serrated polyposis genes, and of several candidate genes that require additional supporting evidence of causality. Through an exhaustive literature review and mutational screening of 177 unrelated polyposis patients, we assessed the involvement of MCM9, FOCAD, POLQ, and RNF43 in the predisposition to (nonserrated) colonic polyposis, as well as the prevalence of NTHL1 and MSH3 mutations among genetically unexplained polyposis patients. Our results, together with previously reported data and mutation frequency in controls, indicate that: MCM9 and POLQ mutations are not associated with polyposis; germline RNF43 mutations, with a prevalence of 1.5–2.5% among serrated polyposis patients, do not cause nonserrated polyposis; MSH3 biallelic mutations are highly infrequent among European polyposis patients, and the prevalence of NTHL1 biallelic mutations among unexplained polyposes is ~2%. Although nonsignificant, FOCAD predicted deleterious variants are overrepresented in polyposis patients compared to controls, warranting larger studies to provide definite evidence in favor or against their causal association with polyposis predisposition.

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“…Therefore, NTHL1 deficiency could lead to severe mutagenesis. Indeed, it has been reported that NTHL1 deficiency is highly mutagenic and promotes adenomatous polyposis and colorectal cancer (22).…”

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confidence: 99%

Topologically Dependent Abundance of Spontaneous DNA Damage in Single Human Cells

Zhu

Niu

Gundry

et al. 2019

Preprint

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In the studies of single-cell genomics, the large endeavor has been focused on the detection of the permanent changes in the genome. On the other hand, spontaneous DNA damage frequently occurs and results in transient single-stranded changes to the genome until they are repaired. So far, successful profiling of these dynamic changes has not been demonstrated by single-cell wholegenome amplification methods. Here we reported a novel single-cell WGA method: Linearly Produced Semiamplicon based Split Amplification Reaction (LPSSAR), which allows, for the first time, the genome-wide detection of the DNA damage associated single nucleotide variants (dSNVs) in single human cells. The sequence-based detection of dSNVs allows the direct characterization of the major damage signature that occurred in human cells. In the analysis of the abundance of dSNVs along the genome, we observed two modules of dSNV abundance, instead of a homogeneous abundance of dSNVs. Interestingly, we found that the two modules are associated with the A/B topological compartments of the genome. This result suggests that the genome topology directly influences genome stability. Furthermore, with the detection of a large number of dSNVs in single cells, we showed that only under a stringent filtering condition, can we distinguish the de novo mutations from the dSNVs and achieve a reliable estimation of the total level of de novo mutations in a single cell.

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Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-tumor Phenotype

Cited by 135 publications

References 34 publications

Genetic Predisposition to Breast and Ovarian Cancers: How Many and Which Genes to Test?

Genetic Predisposition to Breast and Ovarian Cancers: How Many and Which Genes to Test?

Contribution to colonic polyposis of recently proposed predisposing genes and assessment of the prevalence of NTHL1 ‐ and MSH3 ‐associated polyposes

Topologically Dependent Abundance of Spontaneous DNA Damage in Single Human Cells

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