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Identifying colorectal cancer caused by biallelic MUTYH pathogenic variants using tumor mutational signatures.


ABSTRACT: 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 × 10-23 and p = 6 × 10-11, respectively). Here, we demonstrate the potential application of mutational signatures to tumor sequencing workflows to improve the identification of biallelic MUTYH carriers.

SUBMITTER: Georgeson P 

PROVIDER: S-EPMC9170691 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Identifying colorectal cancer caused by biallelic MUTYH pathogenic variants using tumor mutational signatures.

Georgeson Peter P   Harrison Tabitha A TA   Pope Bernard J BJ   Zaidi Syed H SH   Qu Conghui C   Steinfelder Robert S RS   Lin Yi Y   Joo Jihoon E JE   Mahmood Khalid K   Clendenning Mark M   Walker Romy R   Amitay Efrat L EL   Berndt Sonja I SI   Brenner Hermann H   Campbell Peter T PT   Cao Yin Y   Chan Andrew T AT   Chang-Claude Jenny J   Doheny Kimberly F KF   Drew David A DA   Figueiredo Jane C JC   French Amy J AJ   Gallinger Steven S   Giannakis Marios M   Giles Graham G GG   Gsur Andrea A   Gunter Marc J MJ   Hoffmeister Michael M   Hsu Li L   Huang Wen-Yi WY   Limburg Paul P   Manson JoAnn E JE   Moreno Victor V   Nassir Rami R   Nowak Jonathan A JA   Obón-Santacana Mireia M   Ogino Shuji S   Phipps Amanda I AI   Potter John D JD   Schoen Robert E RE   Sun Wei W   Toland Amanda E AE   Trinh Quang M QM   Ugai Tomotaka T   Macrae Finlay A FA   Rosty Christophe C   Hudson Thomas J TJ   Jenkins Mark A MA   Thibodeau Stephen N SN   Winship Ingrid M IM   Peters Ulrike U   Buchanan Daniel D DD  

Nature communications 20220606 1


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 independ  ...[more]

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