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Stains

KRAS


Reviewer: Nat Pernick, M.D. (see Reviewers page)
Revised: 27 December 2012, last major update December 2012
Copyright: (c) 2002-2012, PathologyOutlines.com, Inc.

Definition
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● Kirsten ras oncogene homolog gene; produces a small G protein downstream of epidermal growth factor receptor (EGFR)
● A single amino acid substitution causes an activating mutation
● Germline mutations are associated with cardiofaciocutaneous syndrome (OMIM #115150), Costello syndrome (OMIM #218040), Noonan syndrome (OMIM #163950), and combinations of these syndromes (Mol Cell Biol 2007;27:7765, Eur J Pediatr 2009;168:919)
● Somatic (non-germline) mutations are frequently detected in endoderm derived tumors, including colon, lung and pancreas, perhaps because activated Kras promotes the expansion of an endodermal stem / progenitor cell and blocks its differentiation (Cell Cycle 2008;7:1332, Mol Cell Biol 2008;28:2659)
● Can detect Kras mutations with high resolution melting analysis, a rapid and inexpensive screening method (BMC Cancer 2008;8:142, Am J Clin Pathol 2008;130:247)
● Can perform molecular testing on cytologic smears (Am J Clin Pathol 2011;136:564) or H&E stained slides (Am J Clin Pathol 2012;138:122)



Diagrams of signaling pathways



Kras and colorectal cancer

General
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● RAS signaling pathway (Kras, BRAF, NF1 and RASSF1A), also called Chromosomal instability pathway, shows dysregulation in at least one gene in 70%+ of colorectal carcinomas (Neoplasia 2008;10:680)
● Activating Kras mutations found in 30-40%, associated with poor response to anti-EGFR therapies in primary (Virchows Arch 2008;453:417, N Engl J Med 2008;359:1757) or metastatic disease (J Clin Oncol 2008;26:1626, J Clin Oncol 2008;26:374)
● Kras mutations also found in 35% of polyps (BMC Cancer 2008;8:255), including 46% of serrated adenomas (Am J Clin Pathol 2012;138:356) and 30% of hyperplastic polyps (Am J Surg Pathol 2011;35:1274)
● High rate of concordance for Kras status between primaries and metastases (Oncologist 2008;13:1270)
● Patterns of Kras mutation vary based on germline mismatch repair defects and hMLH1 methylation status (Hum Mol Genet 2004;13:2303)
● Updated National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Colon Cancer now recommend that tumors from all patients with stage IV disease be tested for the Kras gene; only patients whose tumors have normal (wild-type) Kras should receive cetuximab and panitumumab (news item, Arch Pathol Lab Med 2012 Oct 3 [Epub ahead of print], Arch Pathol Lab Med 2012;136:1298 )



Diagram of signaling pathways



Kras and lung cancer

General
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● High Kras mutation rate in Western countries in lung adenocarcinoma / non-small cell lung cancer (25%), but less in Asian countries (0% in China, Onkologie 2008;31:174, 5% in Taiwan, Cancer 2008;113:3199 and 11% in Japan, Oncol Rep 2007;18:623)
● Associated with mucinous versus non-mucinous adenocarcinoma (J Mol Diagn 2007;9:320)
● In Western patients, similar rate of mutations between never, former and current smokers, although mutations were different (Clin Cancer Res 2008;14:5731)
● Kras mutations are associated with poor prognosis and resistance to EGFR tyrosine kinase inhibitors (Curr Opin Pharmacol 2008;8:413); including Erlotinib
● KRAS status in primary lung carcinoma and matched metastases discordant in 22% (Hum Pathol 2010;41:94)



Diagram of signaling pathways



Micro images
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H&E and FISH


Kras and pancreatic adenocarcinoma

General
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● Kras mutations occur early during carcinogenesis, are present in 90% of tumors and associated with poor prognosis (Cancer 2007;109:1561)
● Exon 1 mutations occur in 47% of intraductal papillary mucinous neoplasms (Langenbecks Arch Surg 2008;393:289); also found in Undifferentiated carcinoma/Osteoclastic giant cell tumors
● Kras mutation analysis of FNAs facilitates risk stratification of patients with a pancreatic mass (J Clin Gastroenterol 2007;41:906)

Additional references
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Johns Hopkins


Other carcinomas

General
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● ALL of children (6%, Genes Chromosomes Cancer 2008;47:26)
● Ampulla adenocarcinoma (40%, Am J Clin Pathol 2011;135:202)
● Appendiceal adenocarcinoma (55%, Mod Pathol 2002;15:599)
● Melanoma (57% have mutations in Nras, Kras or BRAF, Int J Cancer 2004;109:377)
● Ovarian endometriosis-associated low grade endometrioid adenocarcinomas (29%, Hum Pathol 2012;43:1177)
● Penile (3%, J Urol 2008;179:2030)
● Prostate (7%, Int J Cancer 2006;119:1858)

End of Stains > KRAS


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