Clinical characteristics.

NTHL1 tumor syndrome is characterized by an increased lifetime risk for colorectal cancer (CRC), breast cancer, and colorectal polyposis. Colorectal polyps can be adenomatous, hyperplastic, and/or sessile serrated. Duodenal polyposis has also been reported. Additional cancers reported in individuals with NTHL1 tumor syndrome include endometrial cancer, urothelial carcinoma of the bladder, meningiomas, unspecified brain tumors, basal cell carcinomas, head and neck squamous cell carcinomas, and hematologic malignancies. The cumulative lifetime risk of developing extracolonic cancer by age 60 years has been estimated at 35% to 78%.

Diagnosis/testing.

The diagnosis is established in a proband by identification of germline biallelic pathogenic variants in NTHL1 by molecular genetic testing.

Management.

Treatment of manifestations: Colorectal polyps should be removed (polypectomy) until polypectomy alone cannot manage the large size and density of the polyps. At that point, either subtotal colectomy or proctocolectomy is performed based on polyp features and location. Large duodenal polyps or those polyps showing dysplasia or villous changes should be excised during endoscopy.

Surveillance: Colonoscopy every two years beginning at age 18-20 years; breast MRI examination annually in females between ages 30 and 60 years; mammography annually in females between ages 40 and 50 years, then every two years between ages 50 and 75 years; transvaginal ultrasound and endometrial biopsy every two years in females between ages 40 and 60 years may be considered depending on local guidelines for endometrial cancer surveillance; esophagogastroduodenoscopy at least every five years beginning at age 25 years; brain MRI for meningioma at diagnosis with follow-up imaging in those with signs and/or symptoms of meningioma.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an individual who has germline biallelic NTHL1 pathogenic variants in order to identify as early as possible those who would benefit from appropriate surveillance, early diagnosis, and treatment of NTHL1-associated tumors.

Genetic counseling.

NTHL1 tumor syndrome is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an NTHL1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the NTHL1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk family members and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

NTHL1 tumor syndrome should be suspected in an individual with the following clinical findings, family history, and/or molecular genetic findings on tumor tissue.

Clinical findings

• Presence of multiple primary cancers before age 50 years, especially breast, colon, or urothelial cell cancer, meningiomas, head and neck squamous cell carcinoma, hematologic malignancies, endometrial malignancies and premalignancies, and/or basal cell carcinoma
• Colorectal cancer (CRC) diagnosed before age 40 years
• One or more colorectal adenomas in an individual age ≤40 years
• A personal cumulative lifetime history of ten or more colorectal adenomas in an individual age ≤60 years
• A personal cumulative lifetime history of any combination of 20 or more colorectal adenomas, hyperplastic polyps, and/or sessile serrated polyps in an individual of any age

Family history is consistent with autosomal recessive inheritance of multiple cancers (especially breast, colorectal, or urothelial cell cancer, brain tumors, head and neck squamous cell carcinoma, hematologic malignancies, endometrial malignancies and premalignancies, and/or basal cell carcinoma).

Molecular genetic findings on tumor tissue. A specific mutational signature due to a high percentage of somatic C>T transversions (e.g., COSMIC Signature 30) is identified on tumor tissue testing [Grolleman et al 2019].

Establishing the Diagnosis

The diagnosis of NTHL1 tumor syndrome is established in a proband with biallelic germline pathogenic (or likely pathogenic) variants in NTHL1 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic NTHL1 variants of uncertain significance (or of one known NTHL1 pathogenic variant and one NTHL1 variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

NTHL1 tumor syndrome has been described in 50 families with 72 affected individuals [Rivera et al 2015, Weren et al 2015, Chubb et al 2016, Belhadj et al 2017, Broderick et al 2017, Buchanan et al 2017, Fostira et al 2018, Altaraihi et al 2019, Belhadj et al 2019, Grolleman et al 2019, Groves et al 2019, Heald et al 2019, Terradas et al 2019, Boulouard et al 2021, Liu et al 2021, Opalič et al 2021, Esnakula et al 2022, Wakeling et al 2022, Pinto et al 2023, Weatherill et al 2023, Terlouw et al 2024]. The following description of the phenotypic features associated with this condition is based on these reports.

Colon polyps. Of the 40 individuals reported by Beck et al [2022] who had been evaluated by colonoscopy, all but two were found to have adenomatous polyps (range: 2-150). In addition, several individuals were reported to have had hyperplastic/sessile serrated polyps [Grolleman et al 2019].

Colorectal cancer (CRC). Thirty-seven of 72 individuals reported to date developed CRC. The median age of onset was 51 years (range: 31-73 years). Nineteen individuals were diagnosed with CRC before age 50 years [Rivera et al 2015, Weren et al 2015, Chubb et al 2016, Fostira et al 2018, Belhadj et al 2019, Grolleman et al 2019, Boulouard et al 2021, Beck et al 2022, Esnakula et al 2022, Wakeling et al 2022, Pinto et al 2023, Weatherill et al 2023, Terlouw et al 2024]. CRC in individuals with NTHL1 tumor syndrome was mostly right-sided, but has been observed throughout the colon, from the rectum to the appendix [Rivera et al 2015, Weren et al 2015, Belhadj et al 2017, Grolleman et al 2019, Terlouw et al 2024]. Metachronous or synchronous tumors were identified in at least nine individuals [Fostira et al 2018, Grolleman et al 2019, Wakeling et al 2022, Weatherill et al 2023, Terlouw et al 2024]. The limited number of families and the presence of a selection bias in the individuals reported to date hamper accurate cancer risk analysis. In the absence of timely surveillance, the lifetime risk for CRC in individuals with NTHL1 tumor syndrome is likely to be high.

Breast cancer has been observed in 12 of 22 females with NTHL1 tumor syndrome with a median age of onset of 49 years (range: 36-63 years) [Beck et al 2022]. At least three had bilateral breast cancer. The reported subtypes included ductal, lobular, and mixed ductal/papillary. Hormone receptor status (triple negative) was reported in one individual. One male was reported with breast cancer [Esnakula et al 2022].

Endometrial cancer has been diagnosed in five of 22 females with NTHL1 tumor syndrome, with a median age of diagnosis of 57 years (range: 47-74 years) [Grolleman et al 2019, Beck et al 2022].

Duodenal polyps and cancer. Multiple duodenal polyps were reported in two individuals with NTHL1 tumor syndrome [Weren et al 2015, Fostira et al 2018]. One individual also developed esophageal polyps. Two individuals developed duodenal cancer [Weren et al 2015, Boulouard et al 2021]. However, one individual with duodenal cancer also presented with a heterozygous germline pathogenic variant in MSH2 [Boulouard et al 2021, Beck et al 2022].

Meningiomas. To date, 11 meningiomas have been reported in individuals with NTHL1 tumor syndrome (10 females, 1 male) with a median age of onset of 46 years (range: 37-64 years) [Rivera et al 2015, Weren et al 2015, Fostira et al 2018, Belhadj et al 2019, Grolleman et al 2019, Boulouard et al 2021, Liu et al 2021, Esnakula et al 2022, Weatherill et al 2023].

Other cancers. Additional cancers reported in individuals with NTHL1 tumor syndrome include urothelial carcinoma of the bladder, unspecified brain tumors, basal cell carcinomas, head and neck squamous cell carcinomas, and hematologic malignancies [Rivera et al 2015, Weren et al 2015, Belhadj et al 2017, Grolleman et al 2019, Beck et al 2022]. Grolleman et al [2019] reported the presence of multiple primary tumors in 16 of 29 individuals (55%). Based on these findings, the cumulative lifetime risk of developing extracolonic cancer by age 60 years was estimated at 35% to 78% (95% CI) [Grolleman et al 2019].

Benign extraintestinal manifestations reported in some individuals include skin hemangiomas, seborrheic keratosis, and intradermal nevi; ovarian and hepatic cysts; and breast papillomas. To date, the number of individuals reported with these features is low and an association with NTHL1 tumor syndrome is unclear.

NTHL1 heterozygotes. To date, there is no evidence that NTHL1 heterozygotes are at increased risk for colorectal cancer [Elsayed et al 2020, Beck et al 2022]. A low-to-moderate increased risk for breast cancer has been reported [Li et al 2021, Nurmi et al 2023]. A previously reported individual with breast cancer had a germline heterozygous NTHL1 variant (NM_002528.6:c.859C>T [p.Gln287Ter]) and loss of heterozygosity in tumor tissue [Nik-Zainal et al 2016, Drost et al 2017].

Genotype-Phenotype Correlations

No clinically relevant genotype-phenotype correlations have been identified.

Nomenclature

This condition has been referred to as NTHL1 polyposis and familial adenomatous polyposis 3 (OMIM 616415), a term that emphasizes the similarity with MUTYH polyposis [Belhadj et al 2017, Groves et al 2019, Valle et al 2019]. Considering the broad tumor spectrum reported in individuals with biallelic NTHL1 pathogenic variants and the fact that the diagnosis has been identified in individuals without CRC and/or (suspected) polyposis, the term NTHL1 tumor syndrome is preferred.

Prevalence

The prevalence of NTHL1 tumor syndrome is unknown. Based on the prevalence of NTHL1 pathogenic variants in the population, it has been estimated that in Europeans, NTHL1 tumor syndrome would occur with a frequency approximately one fifth (1:114,770) that of MUTYH polyposis (1:19,079) [Weren et al 2018].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with NTHL1 tumor syndrome, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 4). In general, the treatment regarding gastrointestinal tumors is similar to that of familial adenomatous polyposis (FAP) and attenuated familial adenomatous polyposis (AFAP) (see APC-Associated Polyposis Conditions).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.

Individuals heterozygous for a germline NTHL1 pathogenic variant. To date, there is no evidence that NTHL1 heterozygotes are at increased risk for colorectal cancer [Elsayed et al 2020, Beck et al 2022]. A small increased risk for breast cancer has been reported [Li et al 2021, Nurmi et al 2023]. There are no specific screening recommendations for heterozygous relatives of individuals with NTHL1 tumor syndrome. NTHL1 heterozygotes are advised to participate in population screening measures for colorectal cancer (CRC) and breast cancer or could be offered screening based on their family history (e.g., incidence of CRC and/or breast cancer in family members who do not have biallelic NTHL1 pathogenic variants).

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an individual with NTHL1 tumor syndrome in order to identify as early as possible sibs with biallelic NTHL1 pathogenic variants who would benefit from appropriate surveillance (beginning at age 18 years), early diagnosis, and treatment of NTHL1-associated tumors.

In general, molecular genetic testing for NTHL1 tumor syndrome is not recommended for at-risk individuals younger than age 18 years. However, predictive testing should be considered if there is a history of early-onset cancer in the family. For unaffected individuals with biallelic NTHL1 pathogenic variants, screening should begin by age 18 years. A history of early cancers in the family may warrant testing prior to age 18 [NCCN 2024].

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

NTHL1 tumor syndrome is inherited in an autosomal recessive manner.

Parents of a proband

• The parents of an affected individual are presumed to be heterozygous for an NTHL1 pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an NTHL1 pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• To date, there is no evidence that NTHL1 heterozygotes are at increased risk for colorectal cancer [Elsayed et al 2020, Beck et al 2022]. A small increased risk for breast cancer has been reported [Li et al 2021, Nurmi et al 2023] (see Surveillance, Individuals heterozygous for a germline NTHL1 pathogenic variant).

Sibs of a proband

• If both parents are known to be heterozygous for an NTHL1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither of the familial pathogenic variants.
• To date, there is no evidence that NTHL1 heterozygotes are at increased risk for colorectal cancer [Elsayed et al 2020, Beck et al 2022]. A small increased risk for breast cancer has been reported [Li et al 2021, Nurmi et al 2023] (see Surveillance, Individuals heterozygous for a germline NTHL1 pathogenic variant).

Offspring of a proband

• Unless an affected individual's reproductive partner also has NTHL1 tumor syndrome or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in NTHL1.
• Given the very low carrier frequency of NTHL1 pathogenic variants (see Prevalence), it is unlikely that the reproductive partner of the proband is a carrier of an NTHL1 pathogenic variant unless consanguinity is a factor.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a NTHL1 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the NTHL1 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk sibs for the purpose of appropriate surveillance, early diagnosis, and treatment of NTHL1-associated tumors.

Predictive testing for at-risk asymptomatic sibs requires prior identification of the germline NTHL1 pathogenic variants in the family.

Genetic cancer risk assessment and counseling. For a comprehensive description of the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without molecular genetic testing, see Cancer Genetics Risk Assessment and Counseling – Health Professional Version (part of PDQ^®, National Cancer Institute).

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of individuals known to have NTHL1 pathogenic variant(s), particularly if consanguinity is likely and/or if both partners are of the same ancestry.

Prenatal Testing and Preimplantation Genetic Testing

Once the NTHL1 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

The protein encoded by NTHL1, endonuclease III-like protein 1 (NTHL1), is a DNA glycosylase of the base excision repair pathway that removes endogenously damaged nucleotides in DNA [Robertson et al 2009]. Various DNA glycosylases target different types of damage caused by oxidation, deamination, or alkylation. NTHL1 specifically targets oxidized pyrimidine residues in DNA and has apurinic/apyrimidinic lyase activity [Wallace et al 2012]. Subsequently, the repair process completes with the incorporation of the correct nucleotide or elongation of multiple nucleotides by a DNA polymerase and sealing of the remaining nick by a DNA ligase [Svilar et al 2011, Wallace et al 2012, Krokan et al 2014].

To date, all identified NTHL1 pathogenic variants are stop-gain, frameshift, or splice site variants, likely resulting in loss of function of both alleles. Therefore, in affected individuals every cell is NTHL1 deficient, resulting in slow but progressive accumulation of somatic pathogenic variants, thereby increasing the risk of cancer in tissues that are most vulnerable to this type of damage.

Individuals with loss of NTHL1 function develop tumors that have somatic pathogenic variants strongly biased toward C>T transitions, predominantly at non-CpG sites [Weren et al 2015]. Analysis of the somatic mutational patterns in NTHL1-deficient colon organoid clones and in multiple tumors of persons with biallelic germline NTHL1 pathogenic variants revealed that loss of NTHL1 function elicits a specific mutational signature [Drost et al 2017, Grolleman et al 2019]. The resulting mutational process is most prominent in tissues with higher proliferation rates and/or higher rates of oxidative damage and increases the chance that cancer-driver genes are hit by a pathogenic variant. Establishing the mutational pattern in tumor tissue can be of help in proving the pathogenicity of (novel) NTHL1 variants [Pinto et al 2023]. Performing mutational signature analysis can assist in determining if NTHL1 deficiency was the main mutational driver in colorectal adenomas or colorectal cancer [Terlouw et al 2024, Walker et al 2025].

Mechanism of disease causation. Loss of function

Author Notes

The authors are actively involved in clinical research regarding individuals with NTHL1 tumor syndrome. They would be happy to communicate with persons who have any questions regarding diagnosis of NTHL1 tumor syndrome or other considerations.

Collaborative Group of the Americas on Inherited Gastrointestinal Cancer (CGA-IGC)
cgaigc.com

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
insight-group.org

Revision History

• 20 March 2025 (sw) Comprehensive updated posted live
• 2 April 2020 (sw) Review posted live
• 17 June 2019 (nh/rk) Original submission

Literature Cited

• Aelvoet AS, Hoekman DR, Redeker BJW, Weegenaar J, Dekker E, van Noesel CJM, Duijkers FAM. A large family with MSH3-related polyposis. Fam Cancer. 2023;22:49-54. [PMC free article: PMC9829574] [PubMed: 35675019]
• Altaraihi M, Gerdes AM, Wadt K. A new family with a homozygous nonsense variant in NTHL1 further delineated the clinical phenotype of NTHL1-associated polyposis. Hum Genome Var. 2019;6:46. [PMC free article: PMC6804823] [PubMed: 31645984]
• Beck SH, Jelsig AM, Yassin HM, Lindberg LJ, Wadt KAW, Karstensen JG. Intestinal and extraintestinal neoplasms in patients with NTHL1 tumor syndrome: a systematic review. Fam Cancer. 2022;21:453-62. [PubMed: 35292903]
• Belhadj S, Mur P, Navarro M, González S, Moreno V, Capellá G, Valle L. Delineating the phenotypic spectrum of the NTHL1-associated polyposis. Clin Gastroenterol Hepatol. 2017;15:461-2. [PubMed: 27720914]
• Belhadj S, Quintana I, Mur P, Munoz-Torres PM, Alonso MH, Navarro M, Terradas M, Piñol V, Brunet J, Moreno V, Lázaro C, Capellá G, Valle L. NTHL1 biallelic mutations seldom cause colorectal cancer, serrated polyposis or a multi-tumor phenotype, in absence of colorectal adenomas. Sci Rep. 2019;9:9020. [PMC free article: PMC6588610] [PubMed: 31227763]
• Boulouard,Fl, Kasper E, Buisine MP, Lienard G, Vasseur S, Manase S, Bahuau M, Barouk Simonet E, Bubien V, Coulet F, Cusin V, Dhooge M, Golmard L, Goussot V, Hamzaoui N, Lacaze E, Lejeune S, Mauillon J, Beaumont MP, Pinson S, Tlemsani C, Toulas C, Rey JM, Uhrhammer N, Bougeard G, Frebourg T, Houdayer C, Baert-Desurmont S. Further delineation of the NTHL1 associated syndrome: a report from the French Oncogenetic Consortium. Clin Genet. 2021;99:662-72. [PubMed: 33454955]
• Broderick P, Dobbins SE, Chubb D, Kinnersley B, Dunlop MG, Tomlinson I, Houlston RS. Validation of recently proposed colorectal cancer susceptibility gene variants in an analysis of families and patients-a systematic review. Gastroenterology. 2017;152:75-7.e4. [PMC free article: PMC5860724] [PubMed: 27713038]
• Buchanan D, Clendenning M, Rosty C, et al. Germline predisposition to serrated polyposis syndrome including evidence for RNF43 as a susceptibility gene. Conference Abstract. Fam Cancer. 2017;16(1 Suppl 1):S51.
• Chubb D, Broderick P, Dobbins SE, Frampton M, Kinnersley B, Penegar S, Price A, Ma YP, Sherborne AL, Palles C, Timofeeva MN, Bishop DT, Dunlop MG, Tomlinson I, Houlston RS. Rare disruptive mutations and their contribution to the heritable risk of colorectal cancer. Nat Commun. 2016;7:11883. [PMC free article: PMC4917884] [PubMed: 27329137]
• Drost J, van Boxtel R, Blokzijl F, Mizutani T, Sasaki N, Sasselli V, de Ligt J, Behjati S, Grolleman JE, van Wezel T, Nik-Zainal S, Kuiper RP, Cuppen E, Clevers H. Use of CRIPSR-modified human stem cell organoids to study the origin of mutational signatures in cancer. Science. 2017;358:234-8. [PMC free article: PMC6038908] [PubMed: 28912133]
• Elsayed FA, Grolleman JE, Ragunathan A, group Ns, Buchanan DD, van Wezel T, de Voer RM. Monoallelic NTHL1 loss-of-function variants and risk of polyposis and colorectal cancer. Gastroenterology. 2020;159:2241-2243.e6. [PMC free article: PMC7899696] [PubMed: 32860789]
• Esnakula A, Hampel H, Shane K, Pearlman R, Stanich P, Shenoy A, Frankel W. NTHL1-associated tumor syndrome: expanding the neoplastic spectrum of a rare tumor predisposition syndrome [Abstract]. Gastrointestinal Pathology. 2022. Presented at USCAP 111th Annual Meeting, March 19-24, 2022, Los Angeles, CA. Available online (accessed 3-11-25).
• Fostira F, Kontopodis E, Apostolou P, Fragkaki M, Androulakis N, Yannoukakos D, Konstantopoulou I, Saloustros E. Extending the clinical phenotype associated with biallelic NTHL1 germline mutations. Clin Genet. 2018;94:588-9. [PubMed: 30248171]
• Grolleman JE, de Voer RM, Elsayed FA, Nielsen M, Weren RDA, Palles C, Ligtenberg MJL, Vos JR, Ten Broeke SW, de Miranda NFCC, et al. Mutational signature analysis reveals NTHL1 deficiency to cause a multi-tumor phenotype. Cancer Cell. 2019;35:256-266.e5. [PubMed: 30753826]
• Groves A, Gleeson M, Spigelman AD. NTHL1-associate polyposis: first Australian case report. Fam Cancer. 2019;18:179-82. [PubMed: 30859360]
• Heald B, Keel E, Marquard J, et al. Pathogenic variants in new colorectal cancer/ polyposis genes rarely identified among patients with colorectal, breast, prostate, and pancreatic cancer. Conference Abstract. Fam Cancer. 2019;18(Suppl 1):S23-S24.
• Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, et al. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519-22. [PubMed: 28959963]
• Krokan HE, Saetrom P, Aas PA, Pettersen HS, Kavli B, Slupphaug G. Error-free versus mutagenic processing of genomic uracil - relevance to cancer. DNA Repair. 2014;19:38-47. [PubMed: 24746924]
• Li N, Zethoven M, McInerny S, Devereux L, Huang YK, Thio N, Cheasley D, Gutierrez-Enriquez S, Moles-Fernandez A, Diez O, Nguyen-Dumont T, Southey MC, Hopper JL, Simard J, Dumont M, Soucy P, Meindl A, Schmutzler R, Schmidt MK, Adank MA, Andrulis IL, Hahnen E, Engel C, Lesueur F, Girard E, Neuhausen SL, Ziv E, Allen J, Easton DF, Scott RJ, Gorringe KL, James PA, Campbell IG. 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;7:52. [PMC free article: PMC8115524] [PubMed: 33980861]
• Lipton L, Tomlinson I. The genetics of FAP and FAP-like syndromes. Fam Cancer. 2006;5:221-6. [PubMed: 16998667]
• Liu K, Kupfer SS, Jain R. A case of multiple adenomatous colon polyps and meningiomas. Gastroenterology. 2021;161:811-3. [PubMed: 33417938]
• NCCN. NCCN Guidelines Version 2.2024 Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric. 2024. Available online (purchase or subscription required).
• Nik-Zainal S, Davies H, Staaf J, Ramakrishna M, Glodzik D, Zou X, Martincorena I, Alexandrov LB, Martin S, Wedge DC, et al. Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature. 2016;534:47-54. [PMC free article: PMC4910866] [PubMed: 27135926]
• Nurmi AK, Pelttari LM, Kiiski JI, Khan S, Nurmikolu M, Suvanto M, Aho N, Tasmuth T, Kalso E, Schleutker J, Kallioniemi A, Heikkila P, FinnGen, Aittomaki K, Blomqvist C, Nevanlinna H. NTHL1 is a recessive cancer susceptibility gene. Sci Rep. 2023;13:21127. [PMC free article: PMC10689455] [PubMed: 38036545]
• Opalič I, Strojnik K, Krajc M, Banjac M, Stegel V, Škerl P, Šetrajčič Dragoš V, Klančar G, Novaković S, Blatnik A. NTHL1-tumor syndrome in Slovenian patients with adenomatous polyposis. 2021. European Human Genetics Conference (ESHG) 2021 – Virtual Conference, August 28-31, 2021. Available online (accessed 3-11-25).
• Pinto C, Guerra J, Pinheiro M, Escudeiro C, Santos C, Pinto P, Porto M, Bartosch C, Silva J, Peixoto A, Teixeira MR. Combined germline and tumor mutation signature testing identifies new families with NTHL1 tumor syndrome. Front Genet. 2023;14:1254908. [PMC free article: PMC10505957] [PubMed: 37727376]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee. 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;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]
• 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. [PubMed: 26559593]
• Robertson AB, Klungland A, Rognes T, Leiros I. DNA repair in mammalian cells: base excision repair: the long and short of it. Cell Mol Life Sci. 2009;66:981-93. [PMC free article: PMC11131461] [PubMed: 19153658]
• Sampson JR, Jones N. MUTYH-associated polyposis. Best Pract Res Clin Gastroenterol. 2009;23:209-18. [PubMed: 19414147]
• Spigelman AD, Williams CB, Talbot IC, Domizio P, Phillips RK. Upper gastrointestinal cancer in patients with familial adenomatous polyposis. Lancet. 1989;2:783–5. [PubMed: 2571019]
• Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197-207.. [PMC free article: PMC7497289] [PubMed: 32596782]
• Svilar D, Goellner EM, Almeida KH, Sobol RW. Base excision repair and lesion-dependent subpathways for repair of oxidative DNA damage. Antioxid Redox Signal. 2011;14:2491-507. [PMC free article: PMC3096496] [PubMed: 20649466]
• Terlouw D, Boot A, Ducarmon QR, Nooij S, Jessurun MA, van Leerdam ME, Tops CM, Langers AMJ, Morreau H, van Wezel T, Nielsen M. Colibactin mutational signatures in NTHL1 tumor syndrome and MUTYH associated polyposis patients. Genes Chromosomes Cancer. 2024;63:e23208. [PubMed: 37795928]
• Terradas M, Munoz-Torres PM, Belhadj S, Aiza G, Navarro M, Brunet J, Capellá G, Valle L. Contribution to colonic polyposis of recently proposed predisposing genes and assessment of the prevalence of NTHL1- and MSH3-associated polyposes. Hum Mutat. 2019;40:1910-23. [PubMed: 31243857]
• Valle L, de Voer RM, Goldberg Y, Sjursen W, Försti A, Ruiz-Ponte C, Caldés T, Garré P, Olsen MF, Nordling M, Castellvi-Bel S, Hemminki K. Update on genetic predisposition to colorectal cancer and polyposis. Mol Aspects Med. 2019;69:10-26. [PubMed: 30862463]
• Wakeling AM, Blanco AM, Singh A. NTHL1-associated polyposis: a diagnostic dilemma solved by repeated multi-gene panel testing. Fam Cancer. 2022;21:612-21.
• Walker R, Joo JE, Mahmood K, Clendenning M, Como J, Preston SG, Joseland S, Pope BJ, Medeiros ABD, Murillo BV, Pachter N, Sweet K, Spigelman AD, Groves A, Gleeson M, Bernatowicz K, Poplawski N, Andrews L, Healey E, Gallinger S, Grant RC, Win AK, Hopper JL, Jenkins MA, Torrezan GT, Rosty C, Macrae FA, Winship IM, Buchanan DD, Georgeson P. Adenomas from individuals with pathogenic biallelic variants in the MUTYH and NTHL1 genes demonstrate base excision repair tumour mutational signature profiles similar to colorectal cancers, expanding potential diagnostic and variant classification applications. Transl Oncol. 2025;52:102266. [PMC free article: PMC11774829] [PubMed: 39793275]
• Wallace SS, Murphy DL, Sweasy JB. Base excision repair and cancer. Cancer Lett. 2012;327:73-89. [PMC free article: PMC3361536] [PubMed: 22252118]
• Weatherill CB, Burke SA, Haskins CG, Berry DK, Homer JP, Demeure MJ, Darabi S. Six case reports of NTHL1-associated tumor syndrome further support it as a multi-tumor predisposition syndrome. Clin Genet. 2023;103:231-5. [PubMed: 36196035]
• Weren RDA, Ligtenberg MJL, Kets CM, de Voer RM, Verwiel ET, Spruijt L, van Zelst-Stams WA, Jongmans MC, Gilissen C, Hehir-Kwa JY, 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. [PubMed: 25938944]
• Weren RD, Ligtenberg MJ, 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. [PubMed: 29105096]