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Serebriiskii IG , Connelly C , Frampton G , Newberg J , Cooke M , Miller V , Ali S , Ross JS , Handorf E , Arora S , Lieu C , Golemis EA , Meyer JE
Comprehensive characterization of RAS mutations in colon and rectal cancers in old and young patients
Nat Commun. 2019 Aug 19;10(1) :3722
PMID: 31427573    PMCID: PMC6700103   
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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.
2041-1723//Serebriiskii, Ilya G//Connelly, Caitlin//Frampton, Garrett//Newberg, Justin//Cooke, Matthew//Miller, Vince//Ali, Siraj//Ross, Jeffrey S//Handorf, Elizabeth//Arora, Sanjeevani//Orcid: 0000-0002-8273-589x//Lieu, Christopher//Orcid: 0000-0002-4852-4642//Golemis, Erica A//Orcid: 0000-0003-3618-3673//Meyer, Joshua E//Orcid: 0000-0002-7585-5738//R01 CA229259/CA/NCI NIH HHS/United States//R01 DK108195/DK/NIDDK NIH HHS/United States//P30 CA006927/CA/NCI NIH HHS/United States//Journal Article//Research Support, N.I.H., Extramural//Research Support, Non-U.S. Gov't//Research Support, U.S. Gov't, Non-P.H.S.//England//Nat Commun. 2019 Aug 19;10(1):3722. doi: 10.1038/s41467-019-11530-0.