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Diagnosis & Discussion


NTHL1-associated polyposis.


There are several adenomatous polyposis syndromes described in the literature, including familial adenomatous polyposis (FAP), MUTYH-associated polyposis (MAP), polymerase proofreading-associated polyposis, and NTHL1-associated polyposis (NAP).

MUTYH is a well-known gene responsible for alterations in the base-excision repair (BER) pathway, while nth-like DNA glycosylase 1 (NTHL1) is a newly found gene discovered to result in similar pathologic events. 

The NTHL1 gene is located on chromosome 16p13.3 and encodes DNA N-glycosylase protein that was found to be involved in the BER pathway. The p.Q90* (c.268C>T) pathogenic mutation results in substitution from glycine to a premature stop codon (CAG>TAG) which creates a nonsense change. Among all known variants of NTHL1 mutation, p.Gln90* (c.268C>T) was found to be most frequently present in polyposis syndrome and colorectal cancer in both homozygous and heterozygous states. This was discovered in 2015 by Weren et al, who identified homozygous biallelic mutation in NTHL1.

Data shows that histology of associated colorectal polyps is mainly represented by tubular and tubulovillous adenomas with dysplasia, ranging from low-grade to high-grade. Interestingly, upon colonoscopy these polyps have the appearance of sessile serrated lesions. Duodenal, jejunal, and esophageal polyps have also been reported in several cases.

NTHL1 tumor syndrome (i.e. NTHL1-associated polyposis) is inherited in an autosomal recessive pattern. This syndrome is marked by an increased lifetime risk for colorectal polyposis and hence colorectal cancer. Extracolonic tumors associated with NTHL1 tumor syndrome are broad and include breast, duodenal, endometrial and cervical carcinomas, meningiomas and other brain tumors as well as basal cell skin cancer, urothelial carcinoma, squamous cell cancer of head and neck, and hematologic malignancies. Overall, the exact phenotype and prevalence of NTHL1 syndrome as well as frequency of colorectal cancer in such patients remains to be evaluated.


1. Weren RDA, Ligtenberg MJL, Kets CM, et al. A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer. Nat Genet. 2015;47(6):668-671.

2. Grolleman, J. E. et al. Mutational signature analysis reveals NTHL1 deficiency to cause a multi-tumor phenotype. Cancer Cell. 2019; 35, 256–266 e5.

3. Boulouard F., Kasper E. et al. Further delineation of the NTHL1 associated syndrome: A report from the French Oncogenetic Consortium. Clin Genet. 2021 May;99(5):662-672.

4. Kuiper RP, et al. NTHL1 tumor syndrome. Gene reviews 2020; 32: 239-880

5. Belhadj S, Mur P, Navarro M, et al. Delineating the phenotypic Spectrum of the NTHL1-associated polyposis. Clin Gastroenterol Hepatol. 2017;15(3):461-462.

6. Altaraihi M, Gerdes A-M, 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(1):46.

7. 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(20):1985-1986.

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