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NTHL1 Tumor Syndrome

Synonym: NTHL1-Associated Polyposis

, PhD, , MD, PhD, , PhD, and , MD, PhD.

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Estimated reading time: 18 minutes

Summary

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, cervical 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 on 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: Due to the limited number of affected individuals reported, surveillance recommendations are likely to evolve. They currently include: colonoscopy with polypectomy every two years beginning at age 18-20 years; breast MRI examination annually between ages 30 and 60 years; mammography annually between ages 40 and 50 years, then every two years between ages 50 and 75 years; transvaginal ultrasound examination and endometrial biopsy to screen for endometrial cancer every two years between ages 40 and 60 years; upper endoscopy and side-viewing duodenoscopy every five years beginning at age 25 years.

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. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants in the family have been identified.

Diagnosis

Formal diagnostic criteria for NTHL1 tumor syndrome have not been established.

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 including breast, colon, or urothelial cell cancer, brain tumors, 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 of multiple cancers (especially when including 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) consistent with autosomal recessive inheritance

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

Establishing the Diagnosis

The diagnosis of NTHL1 tumor syndrome is established in a proband with biallelic germline NTHL1 pathogenic variants identified on molecular genetic testing [Weren et al 2015] (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel, single-gene testing) and comprehensive genomic testing (exome sequencing, genome sequencing).

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of NTHL1 tumor syndrome is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of NTHL1 tumor syndrome has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

When phenotypic findings suggest the diagnosis of NTHL1 tumor syndrome, molecular genetic testing approaches can include use of a multigene panel or single-gene testing:

  • A CRC and polyposis multigene panel that includes NTHL1, APC, MUTYH, and other genes of interest (see Differential Diagnosis) is most likely to identify NTHL1 tumor syndrome at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Of note, given the rarity of NTHL1 tumor syndrome, some cancer-predisposition multigene panels may not include NTHL1. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • Single-gene testing. Sequence analysis of NTHL1 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants. Sequence analysis of all six exons of NTHL1 is recommended. No large exon or whole-gene deletions or duplications in NTHL1 have yet been reported, but their contribution to NTHL1 tumor syndrome cannot be excluded. Therefore, copy number analysis is recommended, particularly when only one germline NTHL1 pathogenic variant has been identified in an individual with findings suggestive of NTHL1 tumor syndrome.

Option 2

When the diagnosis of NTHL1 tumor syndrome is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.

If exome sequencing is not diagnostic, an exome array (when clinically available) may be considered to detect the known pathogenic variants as well as (multi)exon deletions or duplications. Thus far, NTHL1 copy number aberrations have not been described in individuals with NTHL1 tumor syndrome.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in NTHL1 Tumor Syndrome

Gene 1MethodProportion of Pathogenic Variants 2 Detectable by Method
NTHL1Sequence analysis 323/23 4
Gene-targeted deletion/duplication analysis 5None reported 6
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.
5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole.

6.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

Clinical Characteristics

Clinical Description

NTHL1 tumor syndrome has been described in 20 families including 33 affected individuals [Rivera et al 2015, Weren et al 2015, Belhadj et al 2017, Broderick et al 2017, Fostira et al 2018, Altaraihi et al 2019, Belhadj et al 2019, Grolleman et al 2019, Groves et al 2019]. The following description of the phenotypic features associated with this condition is based on these reports.

Colon polyps. The 24 individuals reported by Grolleman et al [2019] who had been evaluated by colonoscopy were all found to have adenomatous polyps (range 1-100). Seven of these individuals had hyperplastic/sessile serrated polyps.

Colorectal cancer (CRC). Nineteen of 33 individuals reported to date developed CRC. The median age of onset was 61 years (range 33-73 years). Nine individuals were diagnosed with CRC before age 50 years [Fostira et al 2018, Belhadj et al 2019, Grolleman et al 2019]. 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]. Metachronous or synchronous tumors were identified in six individuals [Grolleman et al 2019]. 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 was observed in nine of 15 women with NTHL1 tumor syndrome with a median age of onset of 49 years (range 38-63 years) [Grolleman et al 2019]. Three women had bilateral breast cancer. The reported subtypes included ductal, lobular, and mixed ductal/papillary. Hormone receptor status (triple negative) was reported in one individual.

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. Another individual developed duodenal cancer at age 52 years [Weren et al 2015].

Other cancers. Endometrial cancer has been diagnosed in five of the 17 women with NTHL1 tumor syndrome reported thus far, with a median age of diagnosis of 57 years (range 47-74 years). Additional cancers reported in individuals with NTHL1 tumor syndrome include cervical cancer, urothelial carcinoma of the bladder, meningiomas, 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]. 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 as yet unclear.

NTHL1 heterozygotes. The risk of developing CRC or other malignancy in individuals with a heterozygous germline NTHL1 pathogenic variant is unclear. In the eleven families reported by Grolleman et al [2019], three confirmed heterozygotes developed cancer. A previously reported individual with breast cancer was found to have a germline heterozygous NTHL1 variant (p.Gln287Ter) and loss of heterozygosity in tumor tissue [Nik-Zainal et al 2016, Drost et al 2017].

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Nomenclature

This condition has been referred to as NTHL1 polyposis and familial adenomatous polyposis 3 (OMIM 616415), terms which emphasize 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].

Differential Diagnosis

Table 2.

Genes to Consider in the Differential Diagnosis of NTHL1 Tumor Syndrome

MOIGene(s) 1DisorderClinical Features of Differential Disorder
Overlapping w/NTHL1 tumor syndromeDistinguishing from NTHL1 tumor syndrome
ARMSH3Familial adenomatous polyposis 4
(OMIM 617100)
  • ↑ CRC risk
  • 10-100 adenomas
  • Duodenal adenomas
No other cancer risk reported
MUTYHMUTYH polyposis
  • ↑ CRC risk
  • Usually 10-100 adenomas
  • Serrated polyps also observed
  • Duodenal adenomas
ADAPCAttenuated familial adenomatous polyposis
  • ↑ CRC risk
  • Usually 10-100 adenomas
  • Duodenal adenomas
Extracolonic manifestations (e.g., desmoid tumors, fundic gland polyps, congenital hypertrophy of retinal pigmented epithelium, dental abnormalities, fibromas, lipomas, & osteomas)
BMPR1A
SMAD4
Juvenile polyposis syndrome↑ CRC risk
  • GI hamartomatous (juvenile) polyps
  • ↑ risk of cancers of upper GI tract & pancreas
  • Hereditary hemorrhagic telangiectasia (SMAD4-related)
EPCAM
MLH1
MSH2
MSH6
PMS2
Lynch syndrome
  • ↑ CRC risk
  • Endometrial cancer
  • Usually <10 adenomas
  • ↑ risk for ovarian cancer
  • Sebaceous skin tumors
  • Mismatch repair deficient tumors
Duplication upstream of GREM1Hereditary mixed polyposis syndrome
(OMIM 601228)
  • Adenomatous polyps
  • ↑ CRC risk
Mixed polyposis (hyperplastic, atypical juvenile & adenomatous polyps)
POLD1CRC, susceptibility to, 10
(OMIM 612591)
  • 10-100 adenomas
  • ↑ CRC & endometrial cancer risk
Astrocytoma risk
POLECRC, susceptibility to, 12
(OMIM 615083)
  • 10-100 adenomas
  • ↑ CRC, ureter, & endometrial cancer
↑ risk for ovarian, gastric cancer, & astrocytoma
PTENPTEN hamartoma tumor syndrome↑ CRC, breast, & endometrial cancer risk
  • Multiple hamartomatous & mixed polyps in GI tract
  • Macrocephaly, lipomas of the skin & multinodular goiter
  • ↑ risks for melanoma, thyroid, & renal cancers
STK11Peutz-Jeghers syndrome↑ CRC & breast cancer risk
  • GI hamartomatous polyps, most often in small bowel
  • Typical mucocutaneous pigmentation
  • ↑ risk for lung, gastric, pancreas, & sex organ cancers
TP53Li-Fraumeni syndrome↑ CRC & breast cancer risk↑ risk for sarcoma, lung cancer, adrenocortical carcinoma, choroid plexus carcinoma, & additional cancers

AD = autosomal dominant; AR = autosomal recessive; GI = gastrointestinal; MOI = mode of inheritance; CRC = colorectal cancer

1.

Listed by mode of inheritance, then alphabetically by gene

Management

Evaluations Following Initial Diagnosis

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

Due to the lifelong increased cancer risk and the diversity of tumors associated with NTHL1 tumor syndrome, evaluations for cancer in individuals with NTHL1 tumor syndrome need to be ongoing and comprehensive (see Surveillance). Individuals with NTHL1 tumor syndrome should seek a cancer genetics consultation to review the diagnosis and medical management recommendations.

Treatment of Manifestations

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).

Colon polyps and colon cancer. Colonoscopy is effective surveillance for colon cancer; 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 [Lipton & Tomlinson 2006, Sampson & Jones 2009].

Breast cancer, endometrial cancer, and other cancers. The treatment for these cancers in individuals with NTHL1 tumor syndrome is the same as for that of the general population.

Duodenal polyps. Management of polyps is similar to that in individuals with FAP. In particular, large polyps or those polyps showing dysplasia or villous changes should be excised during endoscopy.

Surveillance

Table 3.

Recommended Surveillance for Individuals with NTHL1 Tumor Syndrome

ConcernEvaluationFrequency
Colon cancerColonoscopyEvery 2 yrs starting at age 18-20 yrs
Breast cancerBreast MRIAnnually between ages 30 & 60 yrs; MRI sensitivity is greater than that of mammography.
Mammography
  • Annually between ages 40 & 50 yrs
  • Every 2 yrs between ages 50 & 75 yrs
Endometrial
cancer
Transvaginal ultrasound examination & endometrial biopsyEvery 2 yrs between ages 40 & 60 yrs
Duodenal
polyps/cancer
Upper endoscopyStarting at age 25 yrs; frequency per Spigelman criteria (at least every 5 yrs) [Spigelman et al 1989]

Individuals heterozygous for a germline NTHL1 pathogenic variant. To date, there is no evidence that NTHL1 heterozygotes are at increased risk for cancer and 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 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 who has biallelic germline NTHL1 pathogenic variants in order to identify as early as possible those 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, or two to five years earlier than the earliest diagnosis in the family [NCCN 2016]. Therefore, a history of early cancers in the family may warrant testing prior to age 18.

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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

NTHL1 tumor syndrome is inherited in an autosomal recessive manner.

Parents of a proband

Sibs of a proband

  • If each parent is 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 not being a carrier.
  • The risk of cancer in individuals with a heterozygous germline NTHL1 pathogenic variant is unclear; however, available data do not suggest that heterozygous individuals have an increased risk for colorectal cancer or breast cancer (see Management, Surveillance).

Offspring of a proband. Provided the reproductive partner of the proband is not a carrier of an NTHL1 pathogenic variant, the offspring of an individual with NTHL1 tumor syndrome are 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 (Heterozygote) Detection

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

Note: If consanguinity is a factor, the reproductive partner of an individual with one or two NTHL1 pathogenic variants can be offered NTHL1 sequence analysis to clarify the risk for NTHL1 tumor syndrome in their offspring.

Related Genetic Counseling Issues

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

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal 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.

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).

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

  • Predictive testing for at-risk relatives is possible once the NTHL1 pathogenic variants have been identified in an affected family member.
  • Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals age <18 years)

  • In general, 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. In asymptomatic individuals with biallelic NTHL1 pathogenic variants, screening is recommended beginning at age 18 years, or two to five years prior to the earliest diagnosis in the family [NCCN 2016]. Therefore, a history of early cancers in the family may warrant testing prior to age 18.
  • For more information, see the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

If the reproductive partner of a proband (or carrier) is also known to have one or two NTHL1 pathogenic variants, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Cancer Society (ACS)
    250 Williams Street Northwest
    Atlanta GA 30303
    Phone: 800-227-2345 (toll-free 24/7); 866-228-4327 (toll-free 24/7 TTY)
  • C3: Colorectal Cancer Coalition
    1414 Prince Street
    Suite 204
    Alexandria VA 22314
    Phone: 877-427-2111 (toll-free); 703-548-1225
    Fax: 202-315-3871
    Email: info@fightcolorectalcancer.org
  • Collaborative Group of the Americas on Inherited Gastrointestinal Cancer (CGA-IGC)
  • Colon Cancer Alliance (CCA)
    1200 G Street Northwest
    Suite 800
    Washington DC 20005
    Phone: 877-422-2030 (Toll-free Helpline); 202-434-8980
    Fax: 866-304-9075 (toll-free)
  • Hereditary Colon Cancer Takes Guts
  • International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
  • National Cancer Institute (NCI)
    6116 Executive Boulevard
    Suite 300
    Bethesda MD 20892-8322
    Phone: 800-422-6237 (toll-free)
    Email: cancergovstaff@mail.nih.gov
  • United Ostomy Associations of America, Inc. (UOAA)
    PO Box 66
    Fairview TN 37062-0066
    Phone: 800-826-0826 (toll-free)
    Email: info@uoaa.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

NTHL1 Tumor Syndrome: Genes and Databases

GeneChromosome LocusProteinHGMDClinVar
NTHL116p13​.3Endonuclease III-like protein 1NTHL1NTHL1

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for NTHL1 Tumor Syndrome (View All in OMIM)

602656ENDONUCLEASE III-LIKE 1; NTHL1
616415FAMILIAL ADENOMATOUS POLYPOSIS 3; FAP3

Molecular Pathogenesis

The protein encoded by 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].

NTHL1 tumor syndrome is an autosomal recessive condition caused by biallelic NTHL1 pathogenic variants. Thus far, all nine identified variants are either stop-gain, frameshift-, or splice site variants, likely resulting in disruption 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.

Mechanism of disease causation. Currently, the nine different NTHL1 pathogenic variants identified in NTHL1 tumor syndrome lead to premature stop codons (see Table 4).

Individuals with biallelic NTHL1 loss-of-function pathogenic variants develop tumors that have somatic pathogenic variants strongly biased towards 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 [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.

Table 4.

Notable NTHL1 Pathogenic Variants

Reference SequencesDNA Nucleotide ChangePredicted Protein ChangeComment [Reference]
NM_002528​.6
NP​_002519
c.268C>Tp.Gln90TerFounder/recurrent variant 1 [Weren et al 2018, Grolleman et al 2019]
c.235_236insGp.Ala79GlyfsTer2
c.390>Ap.Tyr130Ter
c.545G>Ap.Trp182Ter
c.550-1G>ALoss splice donor site
c.709+1G>Ap.Gly201_Ile236del
c.733dupp.Ile245AsnfsTer28
c.806G>Ap.Trp269Ter
c.859C>Tp.Gln287Ter

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

This variant is common in the Dutch population, but has also been observed in affected individuals from different ethnic groups, suggesting that there may be multiple independent founders. Fifteen reported families have been homozygous for this variant [Chubb et al 2016, Belhadj et al 2017, Fostira et al 2018, Altaraihi et al 2019, Grolleman et al 2019, Groves et al 2019]

References

Literature Cited

  • 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]
  • 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]
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Revision History

  • 2 April 2020 (sw) Review posted live
  • 17 June 2019 (nh/rk) Original submission
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