NTHL1 and MUTYH polyposis syndromes: two sides of the same coin?

It is now well established that germline genomic aberrations can underlie high-penetrant familial polyposis and colorectal cancer syndromes, but a genetic cause has not yet been found for the major proportion of patients with polyposis. Since next-generation sequencing has become widely accessible, several novel, but rare, high-penetrant risk factors for adenomatous polyposis have been identified, all operating in pathways responsible for genomic maintenance and DNA repair. One of these is the base excision repair pathway. 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. Both recessive polyposis syndromes are associated with increased risks for several other cancer types as well, but the spectrum of benign and malignant tumours in individuals with biallelic NTHL1 mutations was shown to be broader; hence the name NTHL1-associated tumour syndrome. Colorectal tumours encountered in patients with these syndromes show unique, clearly distinct mutational signatures that may facilitate the identification of these syndromes. On the basis of the prevalence of pathogenic MUTYH and NTHL1 variants in the normal population, we estimate that the frequency of the novel NTHL1-associated tumour syndrome is five times lower than that of MUTYH-associated polyposis. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Germline MUTYH gene mutations are not frequently found in unselected patients with papillary breast carcinoma.

MUTYH-associated polyposis (MAP) is an autosomal recessive disease, which predisposes to polyposis and colorectal cancer. There is a trend towards an increased risk of breast cancer in MAP patients, with a remarkable proportion of papillary breast cancers. To determine whether MUTYH mutations are associated with this specific and rare type of breast cancer, 53 unselected patients with papillary breast cancer were analyzed for founder mutations in the MUTYH gene. No germline mutations were identified, indicating that biallelic MUTYH mutations are not a frequent underlying cause for the development of papillary carcinomas of the breast.

Mismatch repair deficiency in early-onset duodenal, ampullary, and pancreatic carcinomas is a strong indicator for a hereditary defect.

Mismatch repair deficiency (dMMR) is a hallmark of Lynch syndrome (LS), but its prevalence in early-onset (diagnosed under the age of 50 years) duodenal, ampullary, and pancreatic carcinomas (DC, AC, and PC, respectively) is largely unknown. We explored the prevalence of dMMR and the underlying molecular mechanisms in a retrospectively collected cohort of 90 early-onset carcinomas of duodenal, ampullary, and pancreatic origin. dMMR was most prevalent in early-onset DCs (47.8%); more than half of those were associated with hereditary cancer syndromes (LS or constitutional mismatch repair deficiency syndrome). All dMMR AC and PC were due to LS. Concordance of dMMR with underlying hereditary condition warrants ubiquitous dMMR testing in all early-onset DC, AC, and PC.

Integration of next-generation sequencing in clinical diagnostic molecular pathology laboratories for analysis of solid tumours; an expert opinion on behalf of IQN Path ASBL.

The clinical demand for mutation detection within multiple genes from a single tumour sample requires molecular diagnostic laboratories to develop rapid, high-throughput, highly sensitive, accurate and parallel testing within tight budget constraints. To meet this demand, many laboratories employ next-generation sequencing (NGS) based on small amplicons. Building on existing publications and general guidance for the clinical use of NGS and learnings from germline testing, the following guidelines establish consensus standards for somatic diagnostic testing, specifically for identifying and reporting mutations in solid tumours. These guidelines cover the testing strategy, implementation of testing within clinical service, sample requirements, data analysis and reporting of results. In conjunction with appropriate staff training and international standards for laboratory testing, these consensus standards for the use of NGS in molecular pathology of solid tumours will assist laboratories in implementing NGS in clinical services.

Candidate colorectal cancer predisposing gene variants in Chinese early-onset and familial cases.

AIM: To investigate whether whole-exome sequencing may serve as an efficient method to identify known or novel colorectal cancer (CRC) predisposing genes in early-onset or familial CRC cases. METHODS: We performed whole-exome sequencing in 23 Chinese patients from 21 families with non-polyposis CRC diagnosed at ≤ 40 years of age, or from multiple affected CRC families with at least 1 first-degree relative diagnosed with CRC at ≤ 55 years of age. Genomic DNA from blood was enriched for exome sequences using the SureSelect Human All Exon Kit, version 2 (Agilent Technologies) and sequencing was performed on an Illumina HiSeq 2000 platform. Data were processed through an analytical pipeline to search for rare germline variants in known or novel CRC predisposing genes. RESULTS: In total, 32 germline variants in 23 genes were identified and confirmed by Sanger sequencing. In 6 of the 21 families (29%), we identified 7 mutations in 3 known CRC predisposing genes including MLH1 (5 patients), MSH2 (1 patient), and MUTYH (biallelic, 1 patient), five of which were reported as pathogenic. In the remaining 15 families, we identified 20 rare and novel potentially deleterious variants in 19 genes, six of which were truncating mutations. One previously unreported variant identified in a conserved region of EIF2AK4 (p.Glu738_Asp739insArgArg) was found to represent a local Chinese variant, which was significantly enriched in our early-onset CRC patient cohort compared to a control cohort of 100 healthy Chinese individuals scored negative by colonoscopy (33.3% vs 7%, P < 0.001). CONCLUSION: Whole-exome sequencing of early-onset or familial CRC cases serves as an efficient method to identify known and potential pathogenic variants in established and novel candidate CRC predisposing genes.

Familial gastric cancer: detection of a hereditary cause helps to understand its etiology.

Worldwide, gastric cancer is one of the most common forms of cancer, with a high morbidity and mortality. Several environmental factors predispose to the development of gastric cancer, such as Helicobacter pylori infection, diet and smoking. Familial clustering of gastric cancer is seen in 10% of cases, and approximately 3% of gastric cancer cases arise in the setting of hereditary diffuse gastric cancer (HDGC). In families with HDGC, gastric cancer presents at relatively young age. Germline mutations in the CDH1 gene are the major cause of HDGC and are identified in approximately 25-50% of families which fulfill strict criteria. Prophylactic gastrectomy is the only option to prevent gastric cancer in individuals with a CDH1 mutation. However, in the majority of families with multiple cases of gastric cancer no germline genetic abnormality can be identified and therefore preventive measures are not available, except for general lifestyle advice. Future research should focus on identifying new genetic predisposing factors for all types of familial gastric cancer.