A MUTYH germline mutation is associated with small intestinal neuroendocrine tumors

Abstract

The genetics behind predisposition to small intestinal neuroendocrine tumors (SI-NETs) is largely unknown, but there is growing awareness of a familial form of the disease. We aimed to identify germline mutations involved in the carcinogenesis of SI-NETs. The strategy included next-generation sequencing of exome- and/or whole-genome of blood DNA, and in selected cases, tumor DNA, from 24 patients from 15 families with the history of SI-NETs. We identified seven candidate mutations in six genes that were further studied using 215 sporadic SI-NET patients. The result was compared with the frequency of the candidate mutations in three control cohorts with a total of 35,688 subjects. A heterozygous variant causing an amino acid substitution p.(Gly396Asp) in the MutY DNA glycosylase gene (MUTYH) was significantly enriched in SI-NET patients (minor allele frequencies 0.013 and 0.003 for patients and controls respectively) and resulted in odds ratio of 5.09 (95% confidence interval 1.56–14.74; P value = 0.0038). We also found a statistically significant difference in age at diagnosis between familial and sporadic SI-NETs. MUTYH is involved in the protection of DNA from mutations caused by oxidative stress. The inactivation of this gene leads to specific increase of G:C- > T:A transversions in DNA sequence and has been shown to cause various cancers in humans and experimental animals. Our results suggest that p.(Gly396Asp) in MUTYH, and potentially other mutations in additional members of the same DNA excision-repair pathway (such as the OGG1 gene) might be involved in driving the tumorigenesis leading to familial and sporadic SI-NETs.

Neuroendocrine Neoplasms of the Small Bowel and Pancreas

“…Finally, neurofibromatosis type-1 [35,36] and tuberous sclerosis [37] are very rare inherited disorders that can also be associated with PanNEN. Distinct hereditary forms of SBNEN have also been described and their genetic underpinnings are increasingly being elucidated [38][39][40], such as mutations in MUTYH, which encodes MYH glycosylase, involved in base excision repair of DNA. These tend to present as isolated endocrinopathies, as opposed to constellations as seen in MEN1.…”

Genetic and epigenetic drivers of neuroendocrine tumours (NET)

“…These syndromes include multiple endocrine neoplasia type 1 (MEN1) and von Hippel-Lindau syndrome (VHL), but also the less common neurofibromatosis type 1 (NF1) syndrome (Larsson et al 1988, Wallace et al 1990, Maher et al 1991. Familial small intestinal NET seem to have a wider spectrum of very rare mutations (Sei et al 2015, Dumanski et al 2017, even if no gene mutation has been mechanistically proven to directly cause this disease.…”

“…Recently, a monoallelic amino acid substitution (G396D) in the MutY DNA glycosylase gene (MUTYH) was reported as germline and somatic mutation in SI-NET (Dumanski et al 2017). This protein is involved in oxidative DNA damage repair.…”

Whole exome sequencing reveals a combination of rare high and low penetrance variants that correlates with familial breast cancer relative risk

“…The OGG1 gene has the highest Vareclect score matching with breast cancer disorders (236,97). The variant R46Q has been previously described as a risk allele for the Human clear_cell_carcinoma_of_kidney that impairs the enzymatic activity of the OGG1 DNA glycosylase 41 and recently observed in an affected member by a familial form of small intestinal neuroendocrine tumors (SI-NETs ) and also in a putative clinically healthy carrier member 42 .…”