NTHL1 biallelic mutations seldom cause colorectal cancer, serrated polyposis or a multi-tumour phenotype, in absence of colorectal adenomas

Isabel Quintana1,2, Sami Belhadj1,2, Pilar Mur1,2,3, Pau M Munoz-Torres1,2, M. Henar Alonso2,4,5,6, Matilde Navarro1,2,3, Mariona Terradas1,2, Virginia Piñol7,8, Joan Brunet1,3,9, Victor Moreno2,4,5,6, Conxi Lázaro1,2,3, Gabriel Capellá1,2,3, Laura Valle1,2,3

1Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Spain. 2Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, Spain. 3Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain. 4Unit of Biomarkers and Susceptibility, Cancer Prevention and Control Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Spain. 5Centro de InvestigaciónBiomédica en Red de Epidemiologia y Salud Pública (CIBERESP), Madrid, Spain. 6Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain. 7Gastroenterology Unit, Hospital Universitario de Girona DrJosepTrueta, Girona, Spain. 8School of Medicine, University of Girona, Girona, Spain. 9Hereditary Cancer Program, Catalan Institute of Oncology, IDIBGi, Girona, Spain



The cancer-predisposing syndrome caused by biallelic mutations in NTHL1 may not be a solely colorectal cancer (CRC) and polyposis syndrome but rather a multi-tumor recessive disease. The presence of ≤10 adenomas in several mutation carriers suggests a possible causal role of NTHL1 in hereditary or early-onset nonpolyposis CRC. The involvement of NTHL1 in serrated/hyperplastic polyposis remains unexplored. The aim of our study is to elucidate the role of NTHL1 in the predisposition to personal or familial history of multiple tumor types, familial/early-onset nonpolyposis CRC, and serrated polyposis.


NTHL1 mutational screening was performed in 312 cancer patients with personal or family history of multiple tumor types, 488 with hereditary nonpolyposis CRC, and 96 with serrated/hyperplastic polyposis. NTHL1 promoter hypermethylation assessment and copy number alteration analysis were also performed in the monoallelic mutation carriers identified.


While no biallelic mutation carriers were identified in patients with personal and/or family history of multiple tumor types or with serrated polyposis, one was identified among the 488nonpolyposis CRC patients. The carrier of c.268C>T (p.Q90*) and 550-1G>A was diagnosed with CRC and meningioma at ages 37 and 45 respectively, being reclassified as attenuated adenomatous polyposis after the cumulative detection of 26 adenomas.


Our findings suggest that the NTHL1-associated syndrome is not a multi-tumor syndrome in absence of adenomatous polyposis, the serrated polyposis syndrome is not caused by NTHL1 mutations, and the presence of biallelicNTHL1 mutation carriers in hereditary CRC patients without polyposis is, if any, extremely rare.