Comprehensive characterization of RAS mutations in colon and rectal cancers in old and young patients

Ilya G. Serebriiskii; Caitlin Connelly; Garrett Frampton; Justin Newberg; Matthew Cooke; Vince Miller; Siraj Ali; Jeffrey S. Ross; Elizabeth Handorf; Sanjeevani Arora; Christopher Lieu; Erica A. Golemis; Joshua E. Meyer

doi:10.1038/s41467-019-11530-0

Comprehensive characterization of RAS mutations in colon and rectal cancers in old and young patients

Ilya G. Serebriiskii, Caitlin Connelly, Garrett Frampton, Justin Newberg, Matthew Cooke, Vince Miller, Siraj Ali, Jeffrey S. Ross, Elizabeth Handorf, Sanjeevani Arora, Christopher Lieu, Erica A. Golemis, Joshua E. Meyer

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

164 Scopus citations

Abstract

Colorectal cancer (CRC) is increasingly appreciated as a heterogeneous disease, with factors such as microsatellite instability (MSI), cancer subsite within the colon versus rectum, and age of diagnosis associated with specific disease course and therapeutic response. Activating oncogenic mutations in KRAS and NRAS are common in CRC, driving tumor progression and influencing efficacy of both cytotoxic and targeted therapies. The RAS mutational spectrum differs substantially between tumors arising from distinct tissues. Structure-function analysis of relatively common somatic RAS mutations in G12, Q61, and other codons is characterized by differing potency and modes of action. Here we show the mutational profile of KRAS, NRAS, and the less common HRAS in 13,336 CRC tumors, comparing the frequency of specific mutations based on age of diagnosis, MSI status, and colon versus rectum subsite. We identify mutation hotspots, and unexpected differences in mutation spectrum, based on these clinical parameters.

Original language	English
Article number	3722
Pages (from-to)	3722
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-11530-0
State	Published - Aug 19 2019

Keywords

Colonic Neoplasms/genetics
Female
GTP Phosphohydrolases/genetics
Genetic Variation/genetics
Genome, Human/genetics
Humans
Male
Membrane Proteins/genetics
Microsatellite Instability
Middle Aged
Mutation Rate
Mutation/genetics
Proto-Oncogene Proteins p21(ras)/genetics
Rectal Neoplasms/genetics
Structure-Activity Relationship

UN SDGs

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

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10.1038/s41467-019-11530-0

Cite this

Serebriiskii, I. G., Connelly, C., Frampton, G., Newberg, J., Cooke, M., Miller, V., Ali, S., Ross, J. S., Handorf, E., Arora, S., Lieu, C., Golemis, E. A., & Meyer, J. E. (2019). Comprehensive characterization of RAS mutations in colon and rectal cancers in old and young patients. Nature Communications, 10(1), 3722. Article 3722. https://doi.org/10.1038/s41467-019-11530-0

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title = "Comprehensive characterization of RAS mutations in colon and rectal cancers in old and young patients",

abstract = "Colorectal cancer (CRC) is increasingly appreciated as a heterogeneous disease, with factors such as microsatellite instability (MSI), cancer subsite within the colon versus rectum, and age of diagnosis associated with specific disease course and therapeutic response. Activating oncogenic mutations in KRAS and NRAS are common in CRC, driving tumor progression and influencing efficacy of both cytotoxic and targeted therapies. The RAS mutational spectrum differs substantially between tumors arising from distinct tissues. Structure-function analysis of relatively common somatic RAS mutations in G12, Q61, and other codons is characterized by differing potency and modes of action. Here we show the mutational profile of KRAS, NRAS, and the less common HRAS in 13,336 CRC tumors, comparing the frequency of specific mutations based on age of diagnosis, MSI status, and colon versus rectum subsite. We identify mutation hotspots, and unexpected differences in mutation spectrum, based on these clinical parameters.",

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doi = "10.1038/s41467-019-11530-0",

language = "English",

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AU - Serebriiskii, Ilya G.

AU - Connelly, Caitlin

AU - Frampton, Garrett

AU - Newberg, Justin

AU - Cooke, Matthew

AU - Miller, Vince

AU - Ali, Siraj

AU - Ross, Jeffrey S.

AU - Handorf, Elizabeth

AU - Arora, Sanjeevani

AU - Lieu, Christopher

AU - Golemis, Erica A.

AU - Meyer, Joshua E.

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N2 - Colorectal cancer (CRC) is increasingly appreciated as a heterogeneous disease, with factors such as microsatellite instability (MSI), cancer subsite within the colon versus rectum, and age of diagnosis associated with specific disease course and therapeutic response. Activating oncogenic mutations in KRAS and NRAS are common in CRC, driving tumor progression and influencing efficacy of both cytotoxic and targeted therapies. The RAS mutational spectrum differs substantially between tumors arising from distinct tissues. Structure-function analysis of relatively common somatic RAS mutations in G12, Q61, and other codons is characterized by differing potency and modes of action. Here we show the mutational profile of KRAS, NRAS, and the less common HRAS in 13,336 CRC tumors, comparing the frequency of specific mutations based on age of diagnosis, MSI status, and colon versus rectum subsite. We identify mutation hotspots, and unexpected differences in mutation spectrum, based on these clinical parameters.

AB - Colorectal cancer (CRC) is increasingly appreciated as a heterogeneous disease, with factors such as microsatellite instability (MSI), cancer subsite within the colon versus rectum, and age of diagnosis associated with specific disease course and therapeutic response. Activating oncogenic mutations in KRAS and NRAS are common in CRC, driving tumor progression and influencing efficacy of both cytotoxic and targeted therapies. The RAS mutational spectrum differs substantially between tumors arising from distinct tissues. Structure-function analysis of relatively common somatic RAS mutations in G12, Q61, and other codons is characterized by differing potency and modes of action. Here we show the mutational profile of KRAS, NRAS, and the less common HRAS in 13,336 CRC tumors, comparing the frequency of specific mutations based on age of diagnosis, MSI status, and colon versus rectum subsite. We identify mutation hotspots, and unexpected differences in mutation spectrum, based on these clinical parameters.

KW - Colonic Neoplasms/genetics

KW - Female

KW - GTP Phosphohydrolases/genetics

KW - Genetic Variation/genetics

KW - Genome, Human/genetics

KW - Humans

KW - Male

KW - Membrane Proteins/genetics

KW - Microsatellite Instability

KW - Middle Aged

KW - Mutation Rate

KW - Mutation/genetics

KW - Proto-Oncogene Proteins p21(ras)/genetics

KW - Rectal Neoplasms/genetics

KW - Structure-Activity Relationship

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JO - Nature Communications

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ER -

Comprehensive characterization of RAS mutations in colon and rectal cancers in old and young patients

Abstract

Keywords

UN SDGs

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Biostatistics and Bioinformatics Facility

Molecular Modeling Facility

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Comprehensive characterization of RAS mutations in colon and rectal cancers in old and young patients

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Equipment

Biostatistics and Bioinformatics Facility

Molecular Modeling Facility

Cite this