Carriers of germline biallelic pathogenic variants in the MUTYH gene have a high risk of colorectal cancer. We test 5649 colorectal cancers to evaluate the discriminatory potential of a tumor mutational signature specific to MUTYH for identifying biallelic carriers and classifying variants of uncertain clinical significance (VUS). Using a tumor and matched germline targeted multi-gene panel approach, our classifier identifies all biallelic MUTYH carriers and all known non-carriers in an independent test set of 3019 colorectal cancers (accuracy = 100% (95% confidence interval 99.87-100%)). All monoallelic MUTYH carriers are classified with the non-MUTYH carriers. The classifier provides evidence for a pathogenic classification for two VUS and a benign classification for five VUS. Somatic hotspot mutations KRAS p.G12C and PIK3CA p.Q546K are associated with colorectal cancers from biallelic MUTYH carriers compared with non-carriers (p = 2 × 10 and p = 6 × 10, respectively). Here, we demonstrate the potential application of mutational signatures to tumor sequencing workflows to improve the identification of biallelic MUTYH carriers.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9170691 | PMC |
| http://dx.doi.org/10.1038/s41467-022-30916-1 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Glucagon-Producing Pancreatic Neuroendocrine Tumors (Glucagonomas) are Enriched in Aggressive Neoplasms with ARX and PDX1 Co-expression, DAXX/ATRX Mutations, and ALT (Alternative Lengthening of Telomeres).
Endocr Pathol
December 2024
Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Piazzale L.A. Scuro, 10, 37134, Verona, Italy.
Article Synopsis
- Glucagonomas are special tumors in the pancreas that cause a syndrome and were studied in six patients to understand their features better.
- These tumors were mostly large and showed a common skin symptom called necrolytic migratory erythema in all patients.
- The tumors had specific changes in their genes and were linked to serious aggressive behavior, which means they can spread or grow badly in some patients.
Adenomas from individuals with pathogenic biallelic variants in the and genes demonstrate base excision repair tumour mutational signature profiles similar to colorectal cancers, expanding potential diagnostic and variant classification applications.
medRxiv
August 2024
Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, 3010, Australia.
Article Synopsis
- Colorectal cancers (CRCs) linked to biallelic germline variants show specific mutational signatures (SBS18+SBS36 and SBS30) that could also be present in adenomas, which are precursors to CRCs.
- A study sequenced DNA from adenomas and CRCs in biallelic cases and compared them with sporadic cases to investigate these signatures.
- Results indicated that adenomas in biallelic cases had similar mutational signature proportions as their corresponding CRCs, suggesting testing adenomas could enhance the detection of biallelic cases and improve variant classification for better CRC prevention strategies.
-associated polyposis (MAP) is an autosomal recessive disorder where the inheritance of constitutional biallelic pathogenic variants predisposes a person to the development of adenomas and colorectal cancer (CRC). It is also associated with extracolonic and extraintestinal manifestations that may overlap with the phenotype of familial adenomatous polyposis (FAP). Currently, there are discrepancies in the literature regarding whether certain phenotypes are truly associated with MAP.
View Article and Find Full Text PDFA comprehensive characterization of the spectrum of MUTYH germline pathogenic variants in Latin America.
Fam Cancer
November 2024
Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, 0379, Oslo, Norway.
MUTYH-Associated Polyposis (MAP) is caused by biallelic pathogenic germline variants in the MUTYH gene. However, individuals harboring monoallelic MUTYH pathogenic variants in the presence of a positive family history have been reported to have a twofold increased risk of colorectal cancer (CRC) and extra colonic cancers. Our aim was to characterize the spectrum of monoallelic and biallelic germline MUTYH pathogenic variants in Latin American patients and to describe their clinical and genetic characteristics.
View Article and Find Full Text PDFGenetic Complexity in Recurrent Basal Cell Carcinoma: A MUTYH Variant Case Report.
Cureus
March 2024
Internal Medicine, Memorial Sloan Kettering Cancer Center, Brooklyn, USA.
The MYUTH gene plays a critical role in preserving the integrity of the human genome, with mutations being identified in several different cancer diagnoses. It serves its purpose by encoding a DNA glycosylase enzyme responsible for preventing oxidative damage through the excision of adenine that is incorrectly paired with guanine or cytosine. Mutations of the MUTYH gene have been most frequently associated with MUTYH-associated polyposis (MAP) and colorectal cancer.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!