Our findings suggest that biallelic mutations in NTHL1 rarely cause CRC, a personal/familial multi-tumor history, or serrated polyposis, in absence of adenomas.
Biallelic germline mutations affecting NTHL1 predispose carriers to adenomatous polyposis and colorectal cancer, but the complete phenotype is unknown.
We provide an overview of newly described genes and syndromes associated with predisposition to CRC and polyposis, including: polymerase proofreading-associated polyposis, NTHL1-associated polyposis, mismatch repair gene biallelic inactivation-related adenomatous polyposis (including MSH3- and MLH3-associated polyposes), GREM1-associated mixed polyposis, RNF43-associated serrated polyposis, and RPS20 mutations as a rare cause of hereditary nonpolyposis CRC.
Some patients with an inherited predisposition to CRC will be diagnosed with a "genetic polyposis syndrome" such as familial adenomatous polyposis (FAP), MUTYH-associated polyposis (MAP), polymerase proofreading associated polyposis (PPAP), NTHL1-associated polyposis, MSH3-associated polyposis or a hamartomatous polyposis syndrome.
In addition to the well-established role of the DNA glycosylase gene MUTYH, biallelic mutations in which predispose to MUTYH-associated polyposis, a second DNA glycosylase gene, NTHL1, has recently been associated with adenomatous polyposis and a high colorectal cancer risk.
We therefore found published evidence to support the association between variants in NTHL1 and RPS20 with CRC, but not of other recently reported CRC susceptibility variants.
Most of the approximately 13 high-penetrance genes that predispose to CRC primarily predispose to colorectal polyps, and each gene is associated with a specific type of polyp, whether conventional adenomas (APC, MUTYH, POLE, POLD1, NTHL1), juvenile polyps (SMAD4, BMPR1A), Peutz-Jeghers hamartomas (LKB1/STK11) and mixed polyps of serrated and juvenile types (GREM1).
We conclude that a homozygous loss-of-function germline mutation in the NTHL1 gene predisposes to a new subtype of BER-associated adenomatous polyposis and CRC.
To evaluate whether sequence variants of NTHL1, NEIL1, NEIL2, MPG, TDG, UNG and SMUG1 genes might act as CRC susceptibility alleles, we screened the coding sequence and intron-exon boundaries of these genes in 94 familial CRC cases in which involvement of known genes had been excluded.
Biallelic germline mutations affecting NTHL1 predispose carriers to adenomatous polyposis and colorectal cancer, but the complete phenotype is unknown.
Some patients with an inherited predisposition to CRC will be diagnosed with a "genetic polyposis syndrome" such as familial adenomatous polyposis (FAP), MUTYH-associated polyposis (MAP), polymerase proofreading associated polyposis (PPAP), NTHL1-associated polyposis, MSH3-associated polyposis or a hamartomatous polyposis syndrome.
In addition to the well-established role of the DNA glycosylase gene MUTYH, biallelic mutations in which predispose to MUTYH-associated polyposis, a second DNA glycosylase gene, NTHL1, has recently been associated with adenomatous polyposis and a high colorectal cancer risk.
Chromoendoscopy improved the diagnostic yield of anomas in MAP and FAP 3-fold, and in both MAP and FAP this resulted in a clinically significant upstaging in Spigelman score.
We conclude that a homozygous loss-of-function germline mutation in the NTHL1 gene predisposes to a new subtype of BER-associated adenomatous polyposis and CRC.
We conclude that a homozygous loss-of-function germline mutation in the NTHL1 gene predisposes to a new subtype of BER-associated adenomatous polyposis and CRC.