Advances in Molecular OncologyAdvances in Molecular OncologyУспехи молекулярной онкологии2313-805X2413-3787Publishing House ABV Press8510.17650/2313-805X-2017-4-1-24-34REVIEW ARTICLESОБЗОРНЫЕ СТАТЬИHeterogeneity and clonal evolution of colorectal cancerВнутриопухолевая гетерогенность и клональная эволюция рака толстой кишкиFedyaninM. Yu.ФедянинМ. Ю.
Russian Federation

Department of Clinical Pharmacology and Chemotherapy

23 Kashirskoye Shosse, Moscow 115478, Russia

Отделение клинической фармакологии и химиотерапии

Россия, 115478 Москва, Каширское шоссе, 23

fedianinmu@mail.ruElsnukaevaH. H.-M.ЭльснукаеваХ. Х.-М.
Russian Federation

Department of Clinical Pharmacology and Chemotherapy

23 Kashirskoye Shosse, Moscow 115478, Russia

Отделение клинической фармакологии и химиотерапии

Россия, 115478 Москва, Каширское шоссе, 23

 

TjulandinS. A.ТюляндинС. А.
Russian Federation

Department of Clinical Pharmacology and Chemotherapy

23 Kashirskoye Shosse, Moscow 115478, Russia

Отделение клинической фармакологии и химиотерапии

Россия, 115478 Москва, Каширское шоссе, 23

N.N. Blokhin Russian Cancer Research Center, Ministry of Health of RussiaФГБУ «Российский онкологический научный центр им. Н.Н. Блохина» Минздрава России150120174124341804201718042017Copyright ©; 2017, Fedyanin M.Y., Elsnukaeva H.H., Tjulandin S.A.Copyright ©; 2017, Федянин М.Ю., Эльснукаева Х.Х., Тюляндин С.А.2017Fedyanin M.Y., Elsnukaeva H.H., Tjulandin S.A.Федянин М.Ю., Эльснукаева Х.Х., Тюляндин С.А.https://creativecommons.org/licenses/by/4.0https://umo.abvpress.ru/jour/article/view/85

There are a lot of studies that dedicated to genetic differences between the primary tumor and metastases. This becomes relevant not only for molecular biologists for understanding carcinogenesis, but also becoming increasingly important for medical oncologists, due to the possible impact on the choice of therapy for metastatic disease. In this regard, colon cancer is an interesting model for studying the heterogeneity of the primary tumor and possible clonal evolution, because we have predictive genetic markers for target therapy. In this article, we analyzed studies on the concordance of the mutation status of the genes, intratumoral heterogeneity and processes of clonal evolution in colorectal cancer.

Все больше работ в онкологии посвящается молекулярно-генетическим различиям между первичной опухолью и метастазами. Это становится актуальным не только для молекулярного биолога в рамках понимания фундаментальных процессов канцерогенеза, но приобретает все большее значение и для клинициста в связи с возможным влиянием на выбор терапии метастатического процесса с учетом наличия ряда генетических предикторных маркеров для таргетных препаратов. Рак толстой кишки в этом плане является интересной моделью для изучения как первичной гетерогенности опухоли, так и процессов эволюции заболевания на фоне терапии. В данном обзоре проведен анализ работ по изучению конкордантности мутационного статуса генов при раке толстой кишки, освещены вопросы внутриопухолевой гетерогенности и процессы клональной эволюции при данной патологии.

colorectal cancerintratumoral heterogeneitybiomarkerKRASNRASBRAFclonal evolutiontargeted therapyconcordanceanti-EGFR-monoclonal antibodiesрак толстой кишкивнутриопухолевая гетерогенностьбиомаркерKRASNRASBRAFклональная эволюциятаргетная терапияконкордантностьанти-EGFR-моноклональные антитела1. Al-Mulla F., Keith W.N., Pickford I.R. et al. Comparative genomic hybridization analysis of primary colorectal carcinomas and their synchronous metastases. Genes Chromosomes Cancer 1999;24(4):306–14.Al-Mulla F., Keith W.N., Pickford I.R. et al. Comparative genomic hybridization analysis of primary colorectal carcinomas and their synchronous metastases. Genes Chromosomes Cancer 1999;24(4):306–14.2. Paredes-Zaglul A., Kang J.J., Essig Y.P. et al. Analysis of colorectal cancer by comparative genomic hybridization: evidence for induction of the metastatic phenotype by loss of tumor suppressor genes. Clin Cancer Res 1998;4(4):879–86.Paredes-Zaglul A., Kang J.J., Essig Y.P. et al. Analysis of colorectal cancer by comparative genomic hybridization: evidence for induction of the metastatic phenotype by loss of tumor suppressor genes. Clin Cancer Res 1998;4(4):879–86.3. Korn W.M., Yasutake T., Kuo W.L. et al. Chromosome arm 20q gains and other genomic alterations in colorectal cancer metastatic to liver, as analyzed by comparative genomic hybridization and fluorescence in situ hybridization. Genes Chromosomes Cancer 1999;25(2):82–90.Korn W.M., Yasutake T., Kuo W.L. et al. Chromosome arm 20q gains and other genomic alterations in colorectal cancer metastatic to liver, as analyzed by comparative genomic hybridization and fluorescence in situ hybridization. Genes Chromosomes Cancer 1999;25(2):82–90.4. Blaker H., Graf M., Rieker R.J., Otto H.F. Comparison of losses of heterozygosity and replication errors in primary colorectal carcinomas and corresponding liver metastases. J Pathol 1999;188(3): 258–62.Blaker H., Graf M., Rieker R.J., Otto H.F. Comparison of losses of heterozygosity and replication errors in primary colorectal carcinomas and corresponding liver metastases. J Pathol 1999;188(3): 258–62.5. Munoz-Bellvis L., Fontanillo C., Gonzalez-Gonzalez M. et al. Unique genetic profile of sporadic colorectal cancer liver metastasis versus primary tumors as defined by high- density singlenucleotide polymorphism arrays. Mod Pathol 2012;25(4):590–601.Munoz-Bellvis L., Fontanillo C., Gonzalez-Gonzalez M. et al. Unique genetic profile of sporadic colorectal cancer liver metastasis versus primary tumors as defined by high- density singlenucleotide polymorphism arrays. Mod Pathol 2012;25(4):590–601.6. Bruin S.C., de Ronde J.J., Wiering B. et al. Selection of patients for hepatic surgery of colorectal cancer liver metastasis based on genomic aberrations. Ann Surg Oncol 2013;(Suppl 3):560–9.Bruin S.C., de Ronde J.J., Wiering B. et al. Selection of patients for hepatic surgery of colorectal cancer liver metastasis based on genomic aberrations. Ann Surg Oncol 2013;(Suppl 3):560–9.7. Albanese I., Scibetta A.G., Migliavacca M. et al. Heterogeneity within and between primary colorectal carcinomas and matched metastases as revealed by analysis of Ki-ras and p53 mutations. Biochem Biophys Res Commun 2004;325(3):784–91.Albanese I., Scibetta A.G., Migliavacca M. et al. Heterogeneity within and between primary colorectal carcinomas and matched metastases as revealed by analysis of Ki-ras and p53 mutations. Biochem Biophys Res Commun 2004;325(3):784–91.8. Zauber P., Sabbath-Solitare M,. Marot-ta S.P., Bishop DT. Molecular changes in the Ki-ras and APC genes in primary colorectal carcinoma and synchronous metastases compared with the findings in accompanying adenomas. Mol Pathol 2003;56(3):137–40.Zauber P., Sabbath-Solitare M,. Marot-ta S.P., Bishop DT. Molecular changes in the Ki-ras and APC genes in primary colorectal carcinoma and synchronous metastases compared with the findings in accompanying adenomas. Mol Pathol 2003;56(3):137–40.9. Etienne-Grimaldi M.C., Formento J.L., Francoual M. et al. K-Ras mutations and treatment outcome in colorectal cancer patients receiving exclusive fluoropyrimidine therapy. Clin Cancer Res 2008;14(15):4830–5.Etienne-Grimaldi M.C., Formento J.L., Francoual M. et al. K-Ras mutations and treatment outcome in colorectal cancer patients receiving exclusive fluoropyrimidine therapy. Clin Cancer Res 2008;14(15):4830–5.10. 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 2009;27(16):2622–9.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 2009;27(16):2622–9.11. Scartozzi M., Bearzi I., Berardi R. et al. Epidermal growth factor receptor (EGFR) status in primary colorectal tumors does not correlate with EGFR expression in related metastatic sites: Implications for treatment with EGFR-targeted monoclonal antibodies. J Clin Oncol 2004;22:4772–8.Scartozzi M., Bearzi I., Berardi R. et al. Epidermal growth factor receptor (EGFR) status in primary colorectal tumors does not correlate with EGFR expression in related metastatic sites: Implications for treatment with EGFR-targeted monoclonal antibodies. J Clin Oncol 2004;22:4772–8.12. Scartozzi M., Bearzi I., Berardi R. et al. Epidermal growth factor receptor (EGFR) downstream signalling pathway in primary colorectal tumours and related metastatic sites: Optimising EGFR-targeted treatment options. Br J Cancer 2007; 97(1):92–7.Scartozzi M., Bearzi I., Berardi R. et al. Epidermal growth factor receptor (EGFR) downstream signalling pathway in primary colorectal tumours and related metastatic sites: Optimising EGFR-targeted treatment options. Br J Cancer 2007; 97(1):92–7.13. Scartozzi M., Giampieri R., Maccaroni E. et al. Phosphorylated AKT and MAPK expression in primary tumours and in corresponding metastases and clinical outcome in colorectal cancer patients receiving irinotecan-cetuximab. J Transl Med 2012;10:71.Scartozzi M., Giampieri R., Maccaroni E. et al. Phosphorylated AKT and MAPK expression in primary tumours and in corresponding metastases and clinical outcome in colorectal cancer patients receiving irinotecan-cetuximab. J Transl Med 2012;10:71.14. Italiano A., Saint-Paul M.C., Caroli-Bosc F.X. et al. Epidermal growth factor receptor (EGFR) status in primary colorectal tumors correlates with EGFR expression in related metastatic sites: biological and clinical implications. Ann Oncol 2005;16(9):1503–7.Italiano A., Saint-Paul M.C., Caroli-Bosc F.X. et al. Epidermal growth factor receptor (EGFR) status in primary colorectal tumors correlates with EGFR expression in related metastatic sites: biological and clinical implications. Ann Oncol 2005;16(9):1503–7.15. Bibeau F., Boissiere-Michot F., Sabourin J.C. et al. Assessment of epidermal growth factor receptor (EGFR) expression in primary colorectal carcinomas and their related metastases on tissue sections and tissue microarray. Virchows Arch 2006;449(3):281–7.Bibeau F., Boissiere-Michot F., Sabourin J.C. et al. Assessment of epidermal growth factor receptor (EGFR) expression in primary colorectal carcinomas and their related metastases on tissue sections and tissue microarray. Virchows Arch 2006;449(3):281–7.16. Baldus S.E., Schaefer K.L., Engers R. et al. Prevalence and heterogeneity of KRAS, BRAF, and PIK3CA mutations in primary colorectal adenocarcinomas and their corresponding metastases. Clin Cancer Res 2010;16(3):790–9.Baldus S.E., Schaefer K.L., Engers R. et al. Prevalence and heterogeneity of KRAS, BRAF, and PIK3CA mutations in primary colorectal adenocarcinomas and their corresponding metastases. Clin Cancer Res 2010;16(3):790–9.17. Oliveira C., Velho S., Moutinho C. et al. KRAS and BRAF oncogenic mutations in MSS colorectal carcinoma progression. Oncogene 2007;26(1):158–63.Oliveira C., Velho S., Moutinho C. et al. KRAS and BRAF oncogenic mutations in MSS colorectal carcinoma progression. Oncogene 2007;26(1):158–63.18. Baldus S.E., Schaefer K.L., Engers R. et al. Prevalence and heterogeneity of KRAS, BRAF, and PIK3CA mutations in primary colorectal adenocarcinomas and their corresponding metastases. Clin Cancer Res 2010;16(3):790–9.Baldus S.E., Schaefer K.L., Engers R. et al. Prevalence and heterogeneity of KRAS, BRAF, and PIK3CA mutations in primary colorectal adenocarcinomas and their corresponding metastases. Clin Cancer Res 2010;16(3):790–9.19. Giaretti W., Monaco R., Pujic N. et al. Intratumor heterogeneity of K-ras2 mutations in colorectal adenocarcinomas: association with degree of DNA aneuploidy. Am J Pathol 1996;149(1): 237–45.Giaretti W., Monaco R., Pujic N. et al. Intratumor heterogeneity of K-ras2 mutations in colorectal adenocarcinomas: association with degree of DNA aneuploidy. Am J Pathol 1996;149(1): 237–45.20. Al-Mulla F., Going J.J., Sowden E.T. et al. Heterogeneity of mutant versus wild-type Ki-ras in primary and metastatic colorectal carcinomas, and association of codon-12 valine with early mortality. J Pathol 1998;185(2):130–8.Al-Mulla F., Going J.J., Sowden E.T. et al. Heterogeneity of mutant versus wild-type Ki-ras in primary and metastatic colorectal carcinomas, and association of codon-12 valine with early mortality. J Pathol 1998;185(2):130–8.21. Losi L., Baisse B., Bouzourene H., Benhattar J. Evolution of intratumoral genetic heterogeneity during colorectal cancer progression. Carcinogenesis 2005;26(5):916–22.Losi L., Baisse B., Bouzourene H., Benhattar J. Evolution of intratumoral genetic heterogeneity during colorectal cancer progression. Carcinogenesis 2005;26(5):916–22.22. Knijn N., Mekenkamp L.J., Klomp M. et al. KRAS mutation analysis: a comparison between primary tumours and matched liver metastases in 305 colorectal cancer patients. Br J Cancer 2011;104(6):1020–6.Knijn N., Mekenkamp L.J., Klomp M. et al. KRAS mutation analysis: a comparison between primary tumours and matched liver metastases in 305 colorectal cancer patients. Br J Cancer 2011;104(6):1020–6.23. Gonzalez de Castro D., Angulo B., Gomez B. et al. A comparison of three methods for detecting KRAS mutations in formalin-fixed colorectal cancer specimens. Br J Cancer 2012;107(2):345–51.Gonzalez de Castro D., Angulo B., Gomez B. et al. A comparison of three methods for detecting KRAS mutations in formalin-fixed colorectal cancer specimens. Br J Cancer 2012;107(2):345–51.24. Tougeron D., Lecomte T., Pagès J.C. et al. Effect of low-frequency KRAS mutations on the response to anti-EGFR therapy in metastatic colorectal cancer. Ann Oncol 2013;24(5):1267–73.Tougeron D., Lecomte T., Pagès J.C. et al. Effect of low-frequency KRAS mutations on the response to anti-EGFR therapy in metastatic colorectal cancer. Ann Oncol 2013;24(5):1267–73.25. Baas J.M., Krens L.L., Guchelaar H.J. et al. Concordance of predictive markers for EGFR inhibitors in primary tumors and metastases in colorectal cancer: a review. Oncologist 2011;16(9):1239–49.Baas J.M., Krens L.L., Guchelaar H.J. et al. Concordance of predictive markers for EGFR inhibitors in primary tumors and metastases in colorectal cancer: a review. Oncologist 2011;16(9):1239–49.26. Mostert B., Jiang Y., Sieuwerts A.M. et al. KRAS and BRAF mutation status in circulating colorectal tumor cells and their correlation with primary and metastatic tumor tissue. Int J Cancer 2013;133(1):130–41.Mostert B., Jiang Y., Sieuwerts A.M. et al. KRAS and BRAF mutation status in circulating colorectal tumor cells and their correlation with primary and metastatic tumor tissue. Int J Cancer 2013;133(1):130–41.27. Gasch C., Bauernhofer T., Pichler M. et al. Heterogeneity of epidermal growth factor receptor status and mutations of KRAS/PIK3CA in circulating tumor cells of patients with colorectal cancer. Clin Chem 2013;59(1):252–60.Gasch C., Bauernhofer T., Pichler M. et al. Heterogeneity of epidermal growth factor receptor status and mutations of KRAS/PIK3CA in circulating tumor cells of patients with colorectal cancer. Clin Chem 2013;59(1):252–60.28. Schafroth C., Galván J.A., Centeno I. et al. VE1 immunohistochemistry predicts BRAF V600E mutation status and clinical outcome in colorectal cancer. Oncotarget 2015;6(39):41453–63.Schafroth C., Galván J.A., Centeno I. et al. VE1 immunohistochemistry predicts BRAF V600E mutation status and clinical outcome in colorectal cancer. Oncotarget 2015;6(39):41453–63.29. Bettington M., Walker N., Clouston A. et al. The serrated pathway to colorectal carcinoma: current concepts and challenges. Histopathology 2013;62(3):367–86.Bettington M., Walker N., Clouston A. et al. The serrated pathway to colorectal carcinoma: current concepts and challenges. Histopathology 2013;62(3):367–86.30. Lundberg I.V., Löfgren Burström A., Edin S. et al. SOX2 expression is regulated by BRAF and contributes to poor patient prognosis in colorectal cancer. PLoS One 2014;9(7):e101957.Lundberg I.V., Löfgren Burström A., Edin S. et al. SOX2 expression is regulated by BRAF and contributes to poor patient prognosis in colorectal cancer. PLoS One 2014;9(7):e101957.31. Xie T., Cho Y.B., Wang K. et al. Patterns of somatic alterations between matched primary and metastatic colorectal tumors characterized by whole-genome sequencing. Genomics 2014;104(4): 234–41.Xie T., Cho Y.B., Wang K. et al. Patterns of somatic alterations between matched primary and metastatic colorectal tumors characterized by whole-genome sequencing. Genomics 2014;104(4): 234–41.32. Lim B., Mun J., Kim J.H. et al. Genomewide mutation profiles of colorectal tumors and associated liver metastases at the exome and transcriptome levels. Oncotarget 2015;6(26):22179–90.Lim B., Mun J., Kim J.H. et al. Genomewide mutation profiles of colorectal tumors and associated liver metastases at the exome and transcriptome levels. Oncotarget 2015;6(26):22179–90.33. Tan I.B., Malik S., Ramnarayanan K. et al. High-depth sequencing of over 750 genes supports linear progression of primary tumors and metastases in most patients with liver- limited metastatic colorectal cancer. Genome Biol 2015;16:32.Tan I.B., Malik S., Ramnarayanan K. et al. High-depth sequencing of over 750 genes supports linear progression of primary tumors and metastases in most patients with liver- limited metastatic colorectal cancer. Genome Biol 2015;16:32.34. Vermaat J.S., Nijman I.J., Koudijs M.J. et al. Primary colorectal cancers and their subsequent hepatic metastases are genetically different: implications for selection of patients for targeted treatment. Clin Cancer Res 2012;18(3):688–99.Vermaat J.S., Nijman I.J., Koudijs M.J. et al. Primary colorectal cancers and their subsequent hepatic metastases are genetically different: implications for selection of patients for targeted treatment. Clin Cancer Res 2012;18(3):688–99.35. Han C.B., Li F., Ma J.T., Zou H.W. Concordant KRAS mutations in primary and metastatic colorectal cancer tissue specimens: a meta-analysis and systematic review. Cancer Invest 2012;30(10):741–7.Han C.B., Li F., Ma J.T., Zou H.W. Concordant KRAS mutations in primary and metastatic colorectal cancer tissue specimens: a meta-analysis and systematic review. Cancer Invest 2012;30(10):741–7.36. Mao C., Wu X.Y., Yang Z.Y. et al. Concordant analysis of KRAS, BRAF, PIK3CA mutations, and PTEN expression between primary colorectal cancer and matched metastases. Sci Rep 2015;5:8065.Mao C., Wu X.Y., Yang Z.Y. et al. Concordant analysis of KRAS, BRAF, PIK3CA mutations, and PTEN expression between primary colorectal cancer and matched metastases. Sci Rep 2015;5:8065.37. Morris V., Kopetz S. Clinical biomarkers in colorectal cancer. Clin Adv Hematol Oncol 2013;11(12):768–76.Morris V., Kopetz S. Clinical biomarkers in colorectal cancer. Clin Adv Hematol Oncol 2013;11(12):768–76.38. Andreou A., Kopetz S., Maru D.M. et al. Adjuvant chemotherapy with FOLFOX for primary colorectal cancer is associated with increased somatic gene mutations and inferior survival in patients undergoing hepatectomy for metachronous liver metastases. Ann Surg 2012;256(4):642–50.Andreou A., Kopetz S., Maru D.M. et al. Adjuvant chemotherapy with FOLFOX for primary colorectal cancer is associated with increased somatic gene mutations and inferior survival in patients undergoing hepatectomy for metachronous liver metastases. Ann Surg 2012;256(4):642–50.39. Graham D.M., Arseneault M., Sukhai M.A. et al. Analysis of clonal evolution in colorectal cancer. J Clin Oncol 2014;32:5s(suppl; abstr 3510).Graham D.M., Arseneault M., Sukhai M.A. et al. Analysis of clonal evolution in colorectal cancer. J Clin Oncol 2014;32:5s(suppl; abstr 3510).40. Russo M., Siravegna G., Blaszkowsky L.S. et al. Tumor heterogeneity and lesionspecific response to targeted therapy in colorectal cancer. Cancer Discov 2016;6(2):147–53.Russo M., Siravegna G., Blaszkowsky L.S. et al. Tumor heterogeneity and lesionspecific response to targeted therapy in colorectal cancer. Cancer Discov 2016;6(2):147–53.41. Diaz L.A. Jr, Williams R.T., Wu J. et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature 2012;486(7404):537–40.Diaz L.A. Jr, Williams R.T., Wu J. et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature 2012;486(7404):537–40.42. Bozic I., Nowak M.A. Timing and heterogeneity of mutations associated with drug resistance in metastatic cancers. Proc Natl Acad Sci U S A 2014;111(45):15964–8.Bozic I., Nowak M.A. Timing and heterogeneity of mutations associated with drug resistance in metastatic cancers. Proc Natl Acad Sci U S A 2014;111(45):15964–8.43. Leder K., Foo J., Skaggs B. et al. Fitness conferred by BCR-ABL kinase domain mutations determines the risk of preexisting resistance in chronic myeloid leukemia. PLoS One 2011;6(11):e27682.Leder K., Foo J., Skaggs B. et al. Fitness conferred by BCR-ABL kinase domain mutations determines the risk of preexisting resistance in chronic myeloid leukemia. PLoS One 2011;6(11):e27682.44. Oltedal S., Aasprong O.G., Møller J.H. et al. Heterogeneous distribution of K-ras mutations in primary colon carcinomas: implications for EGFR-directed therapy. Int J Colorectal Dis 2011;26(10):1271–7.Oltedal S., Aasprong O.G., Møller J.H. et al. Heterogeneous distribution of K-ras mutations in primary colon carcinomas: implications for EGFR-directed therapy. Int J Colorectal Dis 2011;26(10):1271–7.45. Kang Y., Siegel P.M., Shu W. et al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 2003;3(6):537–49.Kang Y., Siegel P.M., Shu W. et al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 2003;3(6):537–49.46. Ramaswamy S., Ross K.N., Lander E.S., Golub T.R. A molecular signature of metastasis in primary solid tumors. Nat Genet 2003;33(1):49–54.Ramaswamy S., Ross K.N., Lander E.S., Golub T.R. A molecular signature of metastasis in primary solid tumors. Nat Genet 2003;33(1):49–54.47. Buob D., Fauvel H., Buisine M.P. et al. The complex intratumoral heterogeneity of colon cancer highlighted by laser microdissection. Dig Dis Sci 2012;57(5):1271–80.Buob D., Fauvel H., Buisine M.P. et al. The complex intratumoral heterogeneity of colon cancer highlighted by laser microdissection. Dig Dis Sci 2012;57(5):1271–80.48. Matsuda K., Masaki T., Watanabe T. et al. Clinical significance of MUC1 and MUC2 mucin and p53 protein expression in colorectal carcinoma. Jpn J Clin Oncol 2000;30(2):89–94.Matsuda K., Masaki T., Watanabe T. et al. Clinical significance of MUC1 and MUC2 mucin and p53 protein expression in colorectal carcinoma. Jpn J Clin Oncol 2000;30(2):89–94.49. Zalata K.R., Elshal M.F., Foda A.A., Shoma A. Genetic dissimilarity between primary colorectal carcinomas and their lymph node metastases: ploidy, p53, bcl-2, and c-myc expression – a pilot study. Tumour Biol 2015;36(8):6579–84.Zalata K.R., Elshal M.F., Foda A.A., Shoma A. Genetic dissimilarity between primary colorectal carcinomas and their lymph node metastases: ploidy, p53, bcl-2, and c-myc expression – a pilot study. Tumour Biol 2015;36(8):6579–84.50. McGranahan N., Swanton C. Biological and therapeutic impact of intratumor heterogeneity in cancer evolution. Cancer Cell 2015;27(1):15–26 .McGranahan N., Swanton C. Biological and therapeutic impact of intratumor heterogeneity in cancer evolution. Cancer Cell 2015;27(1):15–26 .51. Gerlinger M., Rowan A.J., Horswell S. et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012;366(10):883–92.Gerlinger M., Rowan A.J., Horswell S. et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012;366(10):883–92.52. Bettegowda C., Sausen M., Leary R.J. et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med 2014;6(224):224ra24.Bettegowda C., Sausen M., Leary R.J. et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med 2014;6(224):224ra24.53. Piotrowska Z., Niederst M.J., Karlovich C.A. et al. Heterogeneity underlies the emergence of EGFRT790 wild-type clones following treatment of T790Mpositive cancers with a third-generation EGFR inhibitor. Cancer Discov 2015;5(7):713–22.Piotrowska Z., Niederst M.J., Karlovich C.A. et al. Heterogeneity underlies the emergence of EGFRT790 wild-type clones following treatment of T790Mpositive cancers with a third-generation EGFR inhibitor. Cancer Discov 2015;5(7):713–22.54. Misale S., Yaeger R., Hobor S. et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature 2012;486(404):532–6.Misale S., Yaeger R., Hobor S. et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature 2012;486(404):532–6.55. Pao W., Miller V.A., Politi K.A. et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2005;2:e73.Pao W., Miller V.A., Politi K.A. et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2005;2:e73.56. Losi L., Benhattar J., Costa J. Stability of K-ras mutations throughout the natural history of human colorectal cancer. Eur J Cancer 1992;28A:1115–20.Losi L., Benhattar J., Costa J. Stability of K-ras mutations throughout the natural history of human colorectal cancer. Eur J Cancer 1992;28A:1115–20.57. Finkelstein S.D., Sayegh R., Christensen S. et al. Genotypic classification of colorectal adenocarcinoma. Cancer 1993;71: 3827–38.Finkelstein S.D., Sayegh R., Christensen S. et al. Genotypic classification of colorectal adenocarcinoma. Cancer 1993;71: 3827–38.58. Kastrinakis W.V., Ramchurren N., Rieger K.M. et al. Increased incidence of p53 mutations is associated with hepatic metastasis in colorectal neoplastic progression. Oncogene 1995;11(4): 647–52.Kastrinakis W.V., Ramchurren N., Rieger K.M. et al. Increased incidence of p53 mutations is associated with hepatic metastasis in colorectal neoplastic progression. Oncogene 1995;11(4): 647–52.59. Zhang J.S., Caplin S., Bosman F.T., Benhattar J. Genetic diversity at the p53 locus between primary human colorectal adenocarcinomas and their lymph-node metastasis. Int J Cancer 1997;70(6):674–8.Zhang J.S., Caplin S., Bosman F.T., Benhattar J. Genetic diversity at the p53 locus between primary human colorectal adenocarcinomas and their lymph-node metastasis. Int J Cancer 1997;70(6):674–8.60. 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 2008;13(12):1270–5.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 2008;13(12):1270–5.61. Artale S., Sartore-Bianchi A., Veronese S.M. et al. Mutations of KRAS and BRAF in primary and matched metastatic sites of colorectal cancer. J Clin Oncol 2008;26(25):4217–9.Artale S., Sartore-Bianchi A., Veronese S.M. et al. Mutations of KRAS and BRAF in primary and matched metastatic sites of colorectal cancer. J Clin Oncol 2008;26(25):4217–9.62. Oudejans J.J., Slebos R.J., Zoetmulder F.A. et al. Differential activation of ras genes by point mutation in human colon cancer with metastases to either lung or liver. Int J Cancer 1991;49(6):875–9.Oudejans J.J., Slebos R.J., Zoetmulder F.A. et al. Differential activation of ras genes by point mutation in human colon cancer with metastases to either lung or liver. Int J Cancer 1991;49(6):875–9.63. Suchy B., Zietz C., Rabes H.M. K-ras point mutations in human colorectal carcinomas: Relation to aneuploidy and metastasis. Int J Cancer 1992;52(1):30–3.Suchy B., Zietz C., Rabes H.M. K-ras point mutations in human colorectal carcinomas: Relation to aneuploidy and metastasis. Int J Cancer 1992;52(1):30–3.64. Tortola S., Steinert R., Hantschick M. et al. Discordance between K-ras mutations in bone marrow micrometastases and the primary tumor in colorectal cancer. J Clin Oncol 2001;19(11):2837–43.Tortola S., Steinert R., Hantschick M. et al. Discordance between K-ras mutations in bone marrow micrometastases and the primary tumor in colorectal cancer. J Clin Oncol 2001;19(11):2837–43.65. 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 2009;100(7):1087–94.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 2009;100(7):1087–94.66. 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 2010;17(5):1429–34.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 2010;17(5):1429–34.67. Miglio U., Mezzapelle R., Paganotti A. et al. Mutation analysis of KRAS in primary colorectal cancer and matched metastases by means of highly sensitivity molecular assay. Pathol Res Pract 2013;209(4):233–6.Miglio U., Mezzapelle R., Paganotti A. et al. Mutation analysis of KRAS in primary colorectal cancer and matched metastases by means of highly sensitivity molecular assay. Pathol Res Pract 2013;209(4):233–6.68. Cejas P., Lopez-Gomez 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 2009;4(12):e8199.Cejas P., Lopez-Gomez 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 2009;4(12):e8199.69. Cejas P., López-Gómez M., Aguayo C. et al. Analysis of the concordance in the EGFR pathway status between primary tumors and related metastases of colorectal cancer patients: implications for cancer therapy. Curr Cancer Drug Targets 2012;12(2):124–31.Cejas P., López-Gómez M., Aguayo C. et al. Analysis of the concordance in the EGFR pathway status between primary tumors and related metastases of colorectal cancer patients: implications for cancer therapy. Curr Cancer Drug Targets 2012;12(2):124–31.70. Perrone F., Lampis A., Orsenigo M. et al. PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients. Ann Oncol 2009;20(1):84–90.Perrone F., Lampis A., Orsenigo M. et al. PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients. Ann Oncol 2009;20(1):84–90.71. Garm Spindler K.L., Pallisgaard N., Rasmussen A.A. et al. The importance of KRAS mutations and EGF61A4G polymorphism to the effect of cetuximab and irinotecan in metastatic colorectal cancer. Ann Oncol 2009;20(5):879–84.Garm Spindler K.L., Pallisgaard N., Rasmussen A.A. et al. The importance of KRAS mutations and EGF61A4G polymorphism to the effect of cetuximab and irinotecan in metastatic colorectal cancer. Ann Oncol 2009;20(5):879–84.72. Weber J.C., Meyer N., Pencreach E. et al. Allelotyping analyses of synchronous primary and metastasis CIN colon cancers identified different subtypes. Int J Cancer 2007;20(3):524–32.Weber J.C., Meyer N., Pencreach E. et al. Allelotyping analyses of synchronous primary and metastasis CIN colon cancers identified different subtypes. Int J Cancer 2007;20(3):524–32.73. Gattenlohner S., Etschmann B., Kunzmann V. et al. Concordance of KRAS/BRAF mutation status in metastatic colorectal cancer before and after anti-EGFR therapy. J Oncol 2009;831626.Gattenlohner S., Etschmann B., Kunzmann V. et al. Concordance of KRAS/BRAF mutation status in metastatic colorectal cancer before and after anti-EGFR therapy. J Oncol 2009;831626.74. Kawamoto Y., Tsuchihara K., Yoshino T. et al. KRAS mutations in primary tumours and post-FOLFOX metastatic lesions in cases of colorectal cancer. Br J Cancer 2012;107(2):340– 4.Kawamoto Y., Tsuchihara K., Yoshino T. et al. KRAS mutations in primary tumours and post-FOLFOX metastatic lesions in cases of colorectal cancer. Br J Cancer 2012;107(2):340– 4.75. Paliogiannis P., Cossu A., Tanda F. et al. KRAS mutational concordance between primary and metastatic colorectal adenocarcinoma. Oncol Lett 2014;8(4):1422–6.Paliogiannis P., Cossu A., Tanda F. et al. KRAS mutational concordance between primary and metastatic colorectal adenocarcinoma. Oncol Lett 2014;8(4):1422–6.76. Park J.H., Han S.W., Oh D.Y. 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 2001;68(4): 1045–55.Park J.H., Han S.W., Oh D.Y. 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 2001;68(4): 1045–55.77. 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 2011;54(9):1170–8.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 2011;54(9):1170–8.78. Mariani P., Lae M., Degeorges A. et al. Concordant analysis of KRAS status in primary colon carcinoma and matched metastasis. Anticancer Res 2010;30(10):4229–35.Mariani P., Lae M., Degeorges A. et al. Concordant analysis of KRAS status in primary colon carcinoma and matched metastasis. Anticancer Res 2010;30(10):4229–35.79. Løes I.M., Immervoll H., Sorbye H. et al. Impact of KRAS, BRAF, PIK3CA, TP53 status and intraindividual mutation heterogeneity on outcome after liver resection for colorectal cancer metastases. Int J Cancer 2016;139(3):647–56.Løes I.M., Immervoll H., Sorbye H. et al. Impact of KRAS, BRAF, PIK3CA, TP53 status and intraindividual mutation heterogeneity on outcome after liver resection for colorectal cancer metastases. Int J Cancer 2016;139(3):647–56.80. Tougeron D., Cortes U., Ferru A. et al. Epidermal growth factor receptor (EGFR) and KRAS mutations during chemotherapy plus anti-EGFR monoclonal antibody treatment in metastatic colorectal cancer. Cancer Chemother Pharmacol 2013;72(2): 397–403.Tougeron D., Cortes U., Ferru A. et al. Epidermal growth factor receptor (EGFR) and KRAS mutations during chemotherapy plus anti-EGFR monoclonal antibody treatment in metastatic colorectal cancer. Cancer Chemother Pharmacol 2013;72(2): 397–403.81. Montagut C., Dalmases A., Bellosillo B. et al. Identification of a mutation in the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal cancer. Nat Med 2012;18(2):221–223.Montagut C., Dalmases A., Bellosillo B. et al. Identification of a mutation in the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal cancer. Nat Med 2012;18(2):221–223.82. Kawamata H., Yamashita K., Kojo K. et al. Discrepancies between the K-ras mutational status of primary colorectal cancers and corresponding liver metastases are found in codon 13. Genomics 2015;106(2):71–5.Kawamata H., Yamashita K., Kojo K. et al. Discrepancies between the K-ras mutational status of primary colorectal cancers and corresponding liver metastases are found in codon 13. Genomics 2015;106(2):71–5.83. Dócs O., Fazakas F., Horváth N.L. et al. Changes of KRAS exon 2 codon 12/13 mutation status in recurrent colorectal cancer. Pathol Oncol Res 2015;21(2): 399–404.Dócs O., Fazakas F., Horváth N.L. et al. Changes of KRAS exon 2 codon 12/13 mutation status in recurrent colorectal cancer. Pathol Oncol Res 2015;21(2): 399–404.84. Vignot S., Lefebvre C., Frampton G.M. et al. Comparative analysis of primary tumour and matched metastases in colorectal cancer patients: evaluation of concordance between genomic and transcriptional profiles. Eur J Cancer 2015;51(7):791–9.Vignot S., Lefebvre C., Frampton G.M. et al. Comparative analysis of primary tumour and matched metastases in colorectal cancer patients: evaluation of concordance between genomic and transcriptional profiles. Eur J Cancer 2015;51(7):791–9.85. Vakiani E., Janakiraman M., Shen R., et al. Comparative genomic analysis of primary versus metastatic colorectal carcinomas. J Clin Oncol 2012;30(24):2956–62.Vakiani E., Janakiraman M., Shen R., et al. Comparative genomic analysis of primary versus metastatic colorectal carcinomas. J Clin Oncol 2012;30(24):2956–62.86. Brannon A.R., Vakiani E., Sylvester B.E. et al. Comparative sequencing analysis reveals high genomic concordance between matched primary and metastatic colorectal cancer lesions. Genome Biol 2014;15(8):454.Brannon A.R., Vakiani E., Sylvester B.E. et al. Comparative sequencing analysis reveals high genomic concordance between matched primary and metastatic colorectal cancer lesions. Genome Biol 2014;15(8):454.87. He Q., Xu Q., Wu W. et al. Comparison of KRAS and PIK3CA gene status between primary tumors and paired metastases in colorectal cancer. Onco Targets Ther 2016;9:2329–35.He Q., Xu Q., Wu W. et al. Comparison of KRAS and PIK3CA gene status between primary tumors and paired metastases in colorectal cancer. Onco Targets Ther 2016;9:2329–35.88. Li Z.Z., Bai L., Wang F. et al. Comparison of KRAS mutation status between primary tumor and metastasis in Chinese colorectal cancer patients. Med Oncol 2016;33(7):71.Li Z.Z., Bai L., Wang F. et al. Comparison of KRAS mutation status between primary tumor and metastasis in Chinese colorectal cancer patients. Med Oncol 2016;33(7):71.89. Kleist B., Kempa M., Novy M. et al. Comparison of neuroendocrine differentiation and KRAS/NRAS/BRAF/PIK3CA/TP53 mutation status in primary and metastatic colorectal cancer. Int J Clin Exp Pathol 2014;7(9):5927–39.Kleist B., Kempa M., Novy M. et al. Comparison of neuroendocrine differentiation and KRAS/NRAS/BRAF/PIK3CA/TP53 mutation status in primary and metastatic colorectal cancer. Int J Clin Exp Pathol 2014;7(9):5927–39.90. Thebo J.S., Senagore A.J., Reinhold D.S., Stapleton S.R. Molecular staging of colorectal cancer: K-ras mutation analysis of lymph nodes upstages Dukes B patients. Dis Colon Rectum 2000;43(2):155–9.Thebo J.S., Senagore A.J., Reinhold D.S., Stapleton S.R. Molecular staging of colorectal cancer: K-ras mutation analysis of lymph nodes upstages Dukes B patients. Dis Colon Rectum 2000;43(2):155–9.91. Schimanski C.C., Linnemann U., Berger M.R. Sensitive detection of K-ras mutations augments diagnosis of colorectal cancer metastases in the liver. Cancer Res 1999;59(20):5169–75.Schimanski C.C., Linnemann U., Berger M.R. Sensitive detection of K-ras mutations augments diagnosis of colorectal cancer metastases in the liver. Cancer Res 1999;59(20):5169–75.92. Kaneko Y., Kuramochi H., Nakajima G. et al. Degraded DNA may induce discordance of KRAS status between primary colorectal cancer and corresponding liver metastases. Int J Clin Oncol 2014;19(1):113–20.Kaneko Y., Kuramochi H., Nakajima G. et al. Degraded DNA may induce discordance of KRAS status between primary colorectal cancer and corresponding liver metastases. Int J Clin Oncol 2014;19(1):113–20.93. Bossard C., Küry S., Jamet P. et al. Delineation of the infrequent mosaicism of KRAS mutational status in metastatic colorectal adenocarcinomas. J Clin Pathol 2012;65(5):466–9.Bossard C., Küry S., Jamet P. et al. Delineation of the infrequent mosaicism of KRAS mutational status in metastatic colorectal adenocarcinomas. J Clin Pathol 2012;65(5):466–9.94. Fabbri F., Carloni S., Zoli W. et al. Detection and recovery of circulating colon cancer cells using a dielectrophoresis-based device: KRAS mutation status in pure CTCs. Cancer Lett 2013;335(1):225–31.Fabbri F., Carloni S., Zoli W. et al. Detection and recovery of circulating colon cancer cells using a dielectrophoresis-based device: KRAS mutation status in pure CTCs. Cancer Lett 2013;335(1):225–31.95. Kim M.J., Lee H.S., Kim J.H. et al. Different metastatic pattern according to the KRAS mutational status and sitespecific discordance of KRAS status in patients with colorectal cancer. BMC Cancer 2012:12:347.Kim M.J., Lee H.S., Kim J.H. et al. Different metastatic pattern according to the KRAS mutational status and sitespecific discordance of KRAS status in patients with colorectal cancer. BMC Cancer 2012:12:347.96. Lee S., Haq F., Kim D. et al. Comparative genomic analysis of primary and synchronous metastatic colorectal cancers. PLoS One 2014;5(9):e90459.Lee S., Haq F., Kim D. et al. Comparative genomic analysis of primary and synchronous metastatic colorectal cancers. PLoS One 2014;5(9):e90459.97. Sood A., McClain D., Seetharam R. et al. Beyond KRAS: The quest for novel genetic markers predictive for response to antiepidermal growth factor receptor (EGFR) therapy in patients with metastatic colorectal cancer (mCRC). J Clin Oncol 2010;28:15s(suppl; abstr 3567).Sood A., McClain D., Seetharam R. et al. Beyond KRAS: The quest for novel genetic markers predictive for response to antiepidermal growth factor receptor (EGFR) therapy in patients with metastatic colorectal cancer (mCRC). J Clin Oncol 2010;28:15s(suppl; abstr 3567).98. Negri F.V., Bozzetti C., Lagrasta C.A. et al. PTEN status in advanced colorectal cancer treated with cetuximab. Br J Cancer 2010;102(1):162–4.Negri F.V., Bozzetti C., Lagrasta C.A. et al. PTEN status in advanced colorectal cancer treated with cetuximab. Br J Cancer 2010;102(1):162–4.99. Xian H.B., Yu H.B., Zhang J.R. Comparison of the grade of concordance in terms of K-ras status between primaries and related liver metastases in colorectal cancer [article in Chinese]. Chinese J Cancer Prev Treat 2010;12:926–9.Xian H.B., Yu H.B., Zhang J.R. Comparison of the grade of concordance in terms of K-ras status between primaries and related liver metastases in colorectal cancer [article in Chinese]. Chinese J Cancer Prev Treat 2010;12:926–9.100. Voutsina A., Tzardi M., Kalikaki A. et al. Combined analysis of KRAS and PIK3CA mutations, MET and PTEN expression in primary tumors and corresponding metastases in colorectal cancer. Mod Pathol 2013;26(2):302–13.Voutsina A., Tzardi M., Kalikaki A. et al. Combined analysis of KRAS and PIK3CA mutations, MET and PTEN expression in primary tumors and corresponding metastases in colorectal cancer. Mod Pathol 2013;26(2):302–13.101. Murata A., Baba Y., Watanabe M. et al. Methylation levels of LINE-1 in primary lesion and matched metastatic lesions of colorectal cancer. Br J Cancer 2013;109(2):408–15.Murata A., Baba Y., Watanabe M. et al. Methylation levels of LINE-1 in primary lesion and matched metastatic lesions of colorectal cancer. Br J Cancer 2013;109(2):408–15.102. Tie J., Lipton L., Desai J. et al. KRAS mutation is associated with lung metastasis in patients with curatively resected colorectal cancer. Clin Cancer Res 2011;17(5):1122–30.Tie J., Lipton L., Desai J. et al. KRAS mutation is associated with lung metastasis in patients with curatively resected colorectal cancer. Clin Cancer Res 2011;17(5):1122–30.103. Melucci E., Conti S., Diodoro M.G. et al. Relationship between K-Ras mutational status and EGFR expression evaluated using Allred score in primary and metastatic colorectal cancer. J Clin Oncol 2010;28:15s(suppl; abstr 3568).Melucci E., Conti S., Diodoro M.G. et al. Relationship between K-Ras mutational status and EGFR expression evaluated using Allred score in primary and metastatic colorectal cancer. J Clin Oncol 2010;28:15s(suppl; abstr 3568).104. Shen Y.Q., Ye Y.B., Zheng X.W. et al. K-ras mutations in colorectal cancer at different stages. Tumor 2010;30:134–7.Shen Y.Q., Ye Y.B., Zheng X.W. et al. K-ras mutations in colorectal cancer at different stages. Tumor 2010;30:134–7.105. Siyar E.A., Demirci U., Cakmak Oksuzoglu B. et al. KRAS discordance between primary and metastatic tumor in patients with metastatic colorectal carcinoma. J BUON 2015;20(1):128–35.Siyar E.A., Demirci U., Cakmak Oksuzoglu B. et al. KRAS discordance between primary and metastatic tumor in patients with metastatic colorectal carcinoma. J BUON 2015;20(1):128–35.