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

Peter Georgeson; Tabitha A. Harrison; Bernard J. Pope; Syed H. Zaidi; Conghui Qu; Robert S. Steinfelder; Yi Lin; Jihoon E. Joo; Khalid Mahmood; Mark Clendenning; Romy Walker; Efrat L. Amitay; Sonja I. Berndt; Hermann Brenner; Peter T. Campbell; Yin Cao; Andrew T. Chan; Jenny Chang-Claude; Kimberly F. Doheny; David A. Drew; Jane C. Figueiredo; Amy J. French; Steven Gallinger; Marios Giannakis; Graham G. Giles; Andrea Gsur; Marc J. Gunter; Michael Hoffmeister; Li Hsu; Wen Yi Huang; Paul Limburg; Jo Ann E. Manson; Victor Moreno; Rami Nassir; Jonathan A. Nowak; Mireia Obón-Santacana; Shuji Ogino; Amanda I. Phipps; John D. Potter; Robert E. Schoen; Wei Sun; Amanda E. Toland; Quang M. Trinh; Tomotaka Ugai; Finlay A. Macrae; Christophe Rosty; Thomas J. Hudson; Mark A. Jenkins; Stephen N. Thibodeau; Ingrid M. Winship; Ulrike Peters; Daniel D. Buchanan

doi:10.1038/s41467-022-30916-1

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

Peter Georgeson, Tabitha A. Harrison, Bernard J. Pope, Syed H. Zaidi, Conghui Qu, Robert S. Steinfelder, Yi Lin, Jihoon E. Joo, Khalid Mahmood, Mark Clendenning, Romy Walker, Efrat L. Amitay, Sonja I. Berndt, Hermann Brenner, Peter T. Campbell, Yin Cao, Andrew T. Chan, Jenny Chang-Claude, Kimberly F. Doheny, David A. DrewJane C. Figueiredo, Amy J. French, Steven Gallinger, Marios Giannakis, Graham G. Giles, Andrea Gsur, Marc J. Gunter, Michael Hoffmeister, Li Hsu, Wen Yi Huang, Paul Limburg, Jo Ann E. Manson, Victor Moreno, Rami Nassir, Jonathan A. Nowak, Mireia Obón-Santacana, Shuji Ogino, Amanda I. Phipps, John D. Potter, Robert E. Schoen, Wei Sun, Amanda E. Toland, Quang M. Trinh, Tomotaka Ugai, Finlay A. Macrae, Christophe Rosty, Thomas J. Hudson, Mark A. Jenkins, Stephen N. Thibodeau, Ingrid M. Winship, Ulrike Peters, Daniel D. Buchanan

Epidemiology & Population Health

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

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.

Original language	English (US)
Article number	3254
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-30916-1
State	Published - Dec 2022

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-022-30916-1

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Georgeson, P., Harrison, T. A., Pope, B. J., Zaidi, S. H., Qu, C., Steinfelder, R. S., Lin, Y., Joo, J. E., Mahmood, K., Clendenning, M., Walker, R., Amitay, E. L., Berndt, S. I., Brenner, H., Campbell, P. T., Cao, Y., Chan, A. T., Chang-Claude, J., Doheny, K. F., ... Buchanan, D. D. (2022). Identifying colorectal cancer caused by biallelic MUTYH pathogenic variants using tumor mutational signatures. Nature communications, 13(1), Article 3254. https://doi.org/10.1038/s41467-022-30916-1

Georgeson, P, Harrison, TA, Pope, BJ, Zaidi, SH, Qu, C, Steinfelder, RS, Lin, Y, Joo, JE, Mahmood, K, Clendenning, M, Walker, R, Amitay, EL, Berndt, SI, Brenner, H, Campbell, PT, Cao, Y, Chan, AT, Chang-Claude, J, Doheny, KF, Drew, DA, Figueiredo, JC, French, AJ, Gallinger, S, Giannakis, M, Giles, GG, Gsur, A, Gunter, MJ, Hoffmeister, M, Hsu, L, Huang, WY, Limburg, P, Manson, JAE, Moreno, V, Nassir, R, Nowak, JA, Obón-Santacana, M, Ogino, S, Phipps, AI, Potter, JD, Schoen, RE, Sun, W, Toland, AE, Trinh, QM, Ugai, T, Macrae, FA, Rosty, C, Hudson, TJ, Jenkins, MA, Thibodeau, SN, Winship, IM, Peters, U & Buchanan, DD 2022, 'Identifying colorectal cancer caused by biallelic MUTYH pathogenic variants using tumor mutational signatures', Nature communications, vol. 13, no. 1, 3254. https://doi.org/10.1038/s41467-022-30916-1

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title = "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.",

author = "Peter Georgeson and Harrison, {Tabitha A.} and Pope, {Bernard J.} and Zaidi, {Syed H.} and Conghui Qu and Steinfelder, {Robert S.} and Yi Lin and Joo, {Jihoon E.} and Khalid Mahmood and Mark Clendenning and Romy Walker and Amitay, {Efrat L.} and Berndt, {Sonja I.} and Hermann Brenner and Campbell, {Peter T.} and Yin Cao and Chan, {Andrew T.} and Jenny Chang-Claude and Doheny, {Kimberly F.} and Drew, {David A.} and Figueiredo, {Jane C.} and French, {Amy J.} and Steven Gallinger and Marios Giannakis and Giles, {Graham G.} and Andrea Gsur and Gunter, {Marc J.} and Michael Hoffmeister and Li Hsu and Huang, {Wen Yi} and Paul Limburg and Manson, {Jo Ann E.} and Victor Moreno and Rami Nassir and Nowak, {Jonathan A.} and Mireia Ob{\'o}n-Santacana and Shuji Ogino and Phipps, {Amanda I.} and Potter, {John D.} and Schoen, {Robert E.} and Wei Sun and Toland, {Amanda E.} and Trinh, {Quang M.} and Tomotaka Ugai and Macrae, {Finlay A.} and Christophe Rosty and Hudson, {Thomas J.} and Jenkins, {Mark A.} and Thibodeau, {Stephen N.} and Winship, {Ingrid M.} and Ulrike Peters and Buchanan, {Daniel D.}",

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doi = "10.1038/s41467-022-30916-1",

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AU - Georgeson, Peter

AU - Harrison, Tabitha A.

AU - Pope, Bernard J.

AU - Zaidi, Syed H.

AU - Qu, Conghui

AU - Steinfelder, Robert S.

AU - Lin, Yi

AU - Joo, Jihoon E.

AU - Mahmood, Khalid

AU - Clendenning, Mark

AU - Walker, Romy

AU - Amitay, Efrat L.

AU - Berndt, Sonja I.

AU - Brenner, Hermann

AU - Campbell, Peter T.

AU - Cao, Yin

AU - Chan, Andrew T.

AU - Chang-Claude, Jenny

AU - Doheny, Kimberly F.

AU - Drew, David A.

AU - Figueiredo, Jane C.

AU - French, Amy J.

AU - Gallinger, Steven

AU - Giannakis, Marios

AU - Giles, Graham G.

AU - Gsur, Andrea

AU - Gunter, Marc J.

AU - Hoffmeister, Michael

AU - Hsu, Li

AU - Huang, Wen Yi

AU - Limburg, Paul

AU - Manson, Jo Ann E.

AU - Moreno, Victor

AU - Nassir, Rami

AU - Nowak, Jonathan A.

AU - Obón-Santacana, Mireia

AU - Ogino, Shuji

AU - Phipps, Amanda I.

AU - Potter, John D.

AU - Schoen, Robert E.

AU - Sun, Wei

AU - Toland, Amanda E.

AU - Trinh, Quang M.

AU - Ugai, Tomotaka

AU - Macrae, Finlay A.

AU - Rosty, Christophe

AU - Hudson, Thomas J.

AU - Jenkins, Mark A.

AU - Thibodeau, Stephen N.

AU - Winship, Ingrid M.

AU - Peters, Ulrike

AU - Buchanan, Daniel D.

PY - 2022/12

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N2 - 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.

AB - 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.

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

Abstract

ASJC Scopus subject areas

UN SDGs

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