KRAS mutational concordance between primary and metastatic colorectal adenocarcinoma

Paliogiannis,Panagiotis; Cossu,Antonio; Tanda,Francesco; Palmieri,Giuseppe; Palomba,Grazia

doi:10.3892/ol.2014.2411

KRAS mutational concordance between primary and metastatic colorectal adenocarcinoma

Authors:
- Panagiotis Paliogiannis
- Antonio Cossu
- Francesco Tanda
- Giuseppe Palmieri
- Grazia Palomba
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Affiliations: Department of Surgical, Microsurgical and Medical Sciences, University of Sassari, Sassari I‑07100, Italy, Institute of Biomolecular Chemistry, Cancer Genetics Unit, National Research Council, Sassari I‑07040, Italy
Published online on: August 4, 2014 https://doi.org/10.3892/ol.2014.2411
Pages: 1422-1426

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Abstract

KRAS mutation analysis is commonly performed on tissue samples obtained from primary colorectal cancers (CRCs). The metastatic lesions of CRC are usually considered as qualitatively similar or even identical to the primary tumors. The aim of this study was to evaluate the spectrum and distribution of KRAS mutations in a large collection of CRCs, while also evaluating the concordance of primary and metastatic lesions among available paired specimens from the same patients. A total of 729 patients with histologically confirmed advanced CRC at the University Hospital and Local Health Unit (Sassari, Italy) were included. Clinical and pathological features were obtained from medical records and/or pathology reports. Formalin‑fixed, paraffin‑embedded tissue samples were used for mutation analysis. Genomic DNA was isolated using a standard protocol; the coding sequence and splice junctions of exons 2 and 3 in the KRAS gene were screened by direct automated sequencing. Overall, 219 (30%) KRAS mutations were found; 208 (30.1%) were identified in the 690 primary tumors and 11 (28.2%) in the 39 metastatic tissue samples. Among the 31 (4.3%) patients who had paired samples of primary CRC and synchronous or asynchronous metastases, 28 (90.3%) showed consistent mutation patterns between the primary tumors and metastatic lesions. In one case, an additive mutation (Q61L) was found in the metastatic tissue, while two other discrepant cases exhibited a different mutation distribution; Q61H in the primitive lesion and G13V in the metastatic lesion in one case, and a mutated primary tumor (Q61L) and wild‑type metastasis in another case. The results of this study confirm that a high concordance exists between the results of KRAS mutation analysis performed in primitive and metastatic CRCs; independent subclones may be generated in a limited amount of patients.

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1	Jemal A, Center MM, DeSantis C and Ward EM: Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol Biomarkers Prev. 19:1893–1907. 2010.
2	Palmieri G, Paliogiannis P, Scognamillo F, et al: Colorectal cancer epidemiology in an area with a spontaneous screening program. Acta Medica Mediterr. 29:231–234. 2013.
3	National Cancer Institute. Cancer Trends Progress Report - 2011/2012 Update. http://progressreport.cancer.gov/doc_detail.asp?pid=1&did=2011&chid=105&coid=1026&mid=. Accessed December 5, 2013
4	Yabroff KR, Mariotto AB, Feuer E and Brown ML: Projections of the costs associated with colorectal cancer care in the United States, 2000–2020. Health Econ. 17:947–959. 2008.
5	Edwards BK, Ward E, Kohler BA, et al: Annual report to the nation on the status of cancer, 1975–2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates. Cancer. 116:544–573. 2010.
6	Jorissen RN, Walker F, Pouliot N, et al: Epidermal growth factor receptor: mechanisms of activation and signaling. Exp Cell Res. 284:31–53. 2003.
7	Yuan ZX, Wang XY, Qin QY, et al: The prognostic role of BRAF mutation in metastatic colorectal cancer receiving anti-EGFR monoclonal antibodies: a meta-analysis. PLoS One. 8:e659952013.
8	Malumbres M and Barbacid M: RAS Oncogenes: the first 30 years. Nat Rev Cancer. 3:459–485. 2003.
9	Heinemann V, Stintzing S, Kirchner T, Boeck S and Jung A: Clinical relevance of EGFR- and KRAS-status in colorectal cancer patients treated with monoclonal antibodies directed against the EGFR. Cancer Treat Rev. 35:262–271. 2009.
10	Bardelli A and Siena S: Molecular mechanisms of resistance to cetuximab and panitumumab in colorectal cancer. J Clin Oncol. 28:1254–1261. 2010.
11	Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 351:337–345. 2004.
12	Markowitz SD and Bertagnolli MM: Molecular basis of colorectal cancer. N Engl J Med. 361:2404–2460. 2009.
13	Peltomäki P: Mutations and epimutations in the origin of cancer. Exp Cell Res. 318:299–310. 2012.
14	Boland CR and Goel A: Microsatellite instability in colorectal cancer. Gastroenterology. 138:2073–2087. 2010.
15	Jiang L, Huang M, Wang L, et al: Overexpression of MEKK2 is associated with colorectal carcinogenesis. Oncol Lett. 6:1333–1337. 2013.
16	Barzi A, Lenz AM, Labonte MJ and Lenz HJ: Molecular pathways: estrogen pathway in colorectal cancer. Clin Cancer Res. 19:5842–5848. 2013.
17	Vermaat JS, Nijman IJ, Koudijs MJ, et al: Primary colorectal cancers and their subsequent hepatic metastases are genetically different: implications for selection of patients for targeted treatment. Clin Cancer Res. 18:688–699. 2012.
18	Palomba G, Colombino M, Contu A, et al: Prevalence of KRAS, BRAF, and PIK3CA somatic mutations in patients with colorectal carcinoma may vary in the same population: clues from Sardinia. J Transl Med. 10:1782012.
19	Ciavarella S, Milano A, Dammacco F and Silvestris F: Targeted therapies in cancer. BioDrugs. 24:77–88. 2010.
20	Winawer SJ: Natural history of colorectal cancer. Am J Med. 106:3S–6S; discussion, 50S–51S. 1999.
21	Swanton C: Intratumor heterogeneity: evolution through space and time. Cancer Res. 72:4875–4882. 2012.
22	Nassar A, Radhakrishnan A, Cabrero IA, Cotsonis GA and Cohen C: Intratumoral heterogeneity of immunohistochemical marker expression in breast carcinoma: a tissue microarray-based study. Appl Immunohistochem Mol Morphol. 18:433–441. 2010.
23	Vignot S, Besse B, André F, Spano JP and Soria JC: Discrepancies between primary tumor and metastasis: a literature review on clinically established biomarkers. Crit Rev Oncol Hematol. 84:301–313. 2012.
24	Shah SP, Morin RD, Khattra J, et al: Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution. Nature. 461:809–813. 2009.
25	Ding L, Ellis MJ, Li S, et al: Genome remodelling in a basal-like breast cancer metastasis and xenograft. Nature. 464:999–1005. 2010.
26	Campbell PJ, Yachida S, Mudie LJ, et al: The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature. 467:1109–1113. 2010.
27	Yachida S, Jones S, Bozic I, et al: Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature. 467:1114–1117. 2010.
28	Goranova TE, Ohue M, Shimoharu Y and Kato K: Dynamics of cancer cell subpopulations in primary and metastatic colorectal tumors. Clin Exp Metastasis. 28:427–435. 2011.
29	Neumann J, Zeindl-Eberhart E, Kirchner T and Jung A: Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer. Pathol Res Pract. 205:858–862. 2009.
30	Knijn N, Mekenkamp LJ, Klomp M, et al: KRAS mutation analysis: a comparison between primary tumours and matched liver metastases in 305 colorectal cancer patients. Br J Cancer. 104:1020–1026. 2011.
31	Cejas P, López-Gómez M, Aguayo C, et al: KRAS mutations in primary colorectal cancer tumors and related metastases: a potential role in prediction of lung metastasis. PLoS One. 4:e81992009.
32	Santini D, Loupakis F, Vincenzi B, et al: High concordance of KRAS status between primary colorectal tumors and related metastatic sites: implications for clinical practice. Oncologist. 13:1270–1275. 2008.
33	Etienne-Grimaldi MC, Formento JL, Francoual M, et al: K-Ras mutations and treatment outcome in colorectal cancer patients receiving exclusive fluoropyrimidine therapy. Clin Cancer Res. 14:4830–4835. 2008.
34	Park JH, Han SW, Oh DY, et al: Analysis of KRAS, BRAF, PTEN, IGF1R, EGFR intron 1 CA status in both primary tumors and paired metastases in determining benefit from cetuximab therapy in colon cancer. Cancer Chemother Pharmacol. 68:1045–1055. 2011.
35	Watanabe T, Kobunai T, Yamamoto Y, et al: Heterogeneity of KRAS status may explain the subset of discordant KRAS status between primary and metastatic colorectal cancer. Dis Colon Rectum. 54:1170–1178. 2011.
36	Molinari F, Martin V, Saletti P, et al: Differing deregulation of EGFR and downstream proteins in primary colorectal cancer and related metastatic sites may be clinically relevant. Br J Cancer. 100:1087–1094. 2009.
37	Loupakis F, Pollina L, Stasi I, et al: PTEN expression and KRAS mutations on primary tumors and metastases in the prediction of benefit from cetuximab plus irinotecan for patients with metastatic colorectal cancer. J Clin Oncol. 27:2622–2629. 2009.
38	Mariani P, Lae M, Degeorges A, et al: Concordant analysis of KRAS status in primary colon carcinoma and matched metastasis. Anticancer Res. 30:4229–4235. 2010.
39	Baldus SE, Schaefer KL, Engers R, et al: Prevalence and heterogeneity of KRAS, BRAF, and PIK3CA mutations in primary colorectal adenocarcinomas and their corresponding metastases. Clin Cancer Res. 16:790–799. 2010.
40	Italiano A, Hostein I, Soubeyran I, et al: KRAS and BRAF mutational status in primary colorectal tumors and related metastatic sites: biological and clinical implications. Ann Surg Oncol. 17:1429–1434. 2010.
41	Han CB, Li F, Ma JT and Zou HW: Concordant KRAS mutations in primary and metastatic colorectal cancer tissue specimens: a meta-analysis and systematic review. Cancer Invest. 30:741–747. 2012.
42	Tolmachev V, Stone-Elander S and Orlova A: Radiolabelled receptor-tyrosine-kinase targeting drugs for patient stratification and monitoring of therapy response: prospects and pitfalls. Lancet Oncol. 11:992–1000. 2010.