Hotspot oncomutations: implications for personalized cancer treatment

References

• McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM. Reporting Recommendations For Tumor Marker Prognostic Studies (REMARK). Nat. Clin. Pract. Oncol.2(8), 416–422 (2005).
   PubMedGoogle Scholar
• Schubbert S, Shannon K, Bollag G. Hyperactive Ras in developmental disorders and cancer. Nat. Rev. Cancer7(4), 295–308 (2007).
   PubMed Web of Science ®Google Scholar
• Andreyev HJ, Norman AR, Cunningham D, Oates JR, Clarke PA. Kirsten RAS mutations in patients with colorectal cancer: the multicenter ‘RASCAL’ study. J. Natl Cancer Inst.90(9), 675–684 (1998).
   PubMed Web of Science ®Google Scholar
• Andreyev HJ, Norman AR, Cunningham D et al. Kirsten RAS mutations in patients with colorectal cancer: the ‘RASCAL II’ study. Br. J. Cancer85(5), 692–696 (2001).
   PubMed Web of Science ®Google Scholar
• Parsons BL, Meng F. K-RAS mutation in the screening, prognosis and treatment of cancer. Biomark. Med.3(6), 757–769 (2009).
   PubMed Web of Science ®Google Scholar
• Mascaux C, Iannino N, Martin B et al. The role of RAS oncogene in survival of patients with lung cancer: a systematic review of the literature with meta-analysis. Br. J. Cancer92(1), 131–139 (2005).
   PubMed Web of Science ®Google Scholar
• Brugger W, Triller N, Blasinska-Morawiec M et al. Prospective molecular marker analyses of EGFR and KRAS from a randomized, placebo-controlled study of erlotinib maintenance therapy in advanced non-small-cell lung cancer. J. Clin. Oncol.29(31), 4113–4120 (2011).
   PubMed Web of Science ®Google Scholar
• Liu HP, Isaac Wu HD, Chang JW et al. Prognostic implications of epidermal growth factor receptor and KRAS gene mutations and epidermal growth factor receptor gene copy numbers in patients with surgically resectable non-small cell lung cancer in Taiwan. J. Thorac. Oncol.5(8), 1175–1184 (2010).
   PubMed Web of Science ®Google Scholar
• Marks JL, Broderick S, Zhou Q et al. Prognostic and therapeutic implications of EGFR and KRAS mutations in resected lung adenocarcinoma. J. Thorac. Oncol.3(2), 111–116 (2008).
   PubMed Web of Science ®Google Scholar
• Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. N. Engl. J. Med.358(11), 1160–1174 (2008).
   PubMed Web of Science ®Google Scholar
• Amado RG, Wolf M, Peeters M et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J. Clin. Oncol.26(10), 1626–1634 (2008).
   PubMed Web of Science ®Google Scholar
• Karapetis CS, Khambata-Ford S, Jonker DJ et al.K-RAS mutations and benefit from cetuximab in advanced colorectal cancer. N. Engl. J. Med.359(17), 1757–1765 (2008).
   PubMed Web of Science ®Google Scholar
• De Roock W, Claes B, Bernasconi D et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol.11(8), 753–762 (2010).
   PubMed Web of Science ®Google Scholar
• Peeters M, Price TJ, Cervantes A et al. Randomized Phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J. Clin. Oncol.28(31), 4706–4713 (2010).
   PubMed Web of Science ®Google Scholar
• Bokemeyer C, Bondarenko I, Hartmann JT et al. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann. Oncol.22(7), 1535–1546 (2011).
   PubMed Web of Science ®Google Scholar
• Douillard JY, Siena S, Cassidy J et al. Randomized, Phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J. Clin. Oncol.28(31), 4697–4705 (2010).
   PubMed Web of Science ®Google Scholar
• Van Cutsem E, Kohne CH, Lang I et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J. Clin. Oncol.29(15), 2011–2019 (2011).
   PubMed Web of Science ®Google Scholar
• Linardou H, Dahabreh IJ, Kanaloupiti D et al. Assessment of somatic K-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer. Lancet Oncol.9(10), 962–972 (2008).
   PubMed Web of Science ®Google Scholar
• De Roock W, Jonker DJ, Di Nicolantonio F et al. Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA304(16), 1812–1820 (2010).
   PubMed Web of Science ®Google Scholar
• Molinari F, Felicioni L, Buscarino M et al. Increased detection sensitivity for KRAS mutations enhances the prediction of anti-EGFR monoclonal antibody resistance in metastatic colorectal cancer. Clin. Cancer Res.17(14), 4901–4914 (2011).
   PubMed Web of Science ®Google Scholar
• Modest DP, Jung A, Moosmann N et al. The influence of KRAS and BRAF mutations on the efficacy of cetuximab-based first-line therapy of metastatic colorectal cancer: an analysis of the AIO KRK-0104-trial. Int. J. Cancer131(4), 980–986 (2012).
   PubMed Web of Science ®Google Scholar
• Ogino S, Meyerhardt JA, Irahara N et al.KRAS mutation in stage III colon cancer and clinical outcome following intergroup trial CALGB 89803. Clin. Cancer Res.15(23), 7322–7329 (2009).
   PubMed Web of Science ®Google Scholar
• Roth AD, Tejpar S, Delorenzi M et al. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60–00 trial. J. Clin. Oncol.28(3), 466–474 (2010).
   PubMed Web of Science ®Google Scholar
• Conlin A, Smith G, Carey FA, Wolf CR, Steele RJ. The prognostic significance of K-RAS, p53, and APC mutations in colorectal carcinoma. Gut54(9), 1283–1286 (2005).
   PubMed Web of Science ®Google Scholar
• Richman SD, Seymour MT, Chambers P et al.KRAS and KRAS mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or irinotecan: results from the MRC FOCUS trial. J. Clin. Oncol.27(35), 5931–5937 (2009).
   PubMed Web of Science ®Google Scholar
• Yokota T, Ura T, Shibata N et al.KRAS mutation is a powerful prognostic factor in advanced and recurrent colorectal cancer. Br. J. Cancer104(5), 856–862 (2011).
   PubMed Web of Science ®Google Scholar
• Douillard JY, Shepherd FA, Hirsh V et al. Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized Phase III INTEREST trial. J. Clin. Oncol.28(5), 744–752 (2010).
   PubMed Web of Science ®Google Scholar
• Eberhard DA, Johnson BE, Amler LC et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J. Clin. Oncol.23(25), 5900–5909 (2005).
   PubMed Web of Science ®Google Scholar
• Han SW, Kim TY, Jeon YK et al. Optimization of patient selection for gefitinib in non-small cell lung cancer by combined analysis of epidermal growth factor receptor mutation, K-RAS mutation, and Akt phosphorylation. Clin. Cancer Res.12(8), 2538–2544 (2006).
   PubMed Web of Science ®Google Scholar
• Massarelli E, Varella-Garcia M, Tang X et al.KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. Clin. Cancer Res.13(10), 2890–2896 (2007).
   PubMed Web of Science ®Google Scholar
• Pao W, Wang TY, Riely GJ et al.KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med.2(1), e17 (2005).
   PubMed Web of Science ®Google Scholar
• Schneider CP, Heigener D, Schott-von-Romer K et al. Epidermal growth factor receptor-related tumor markers and clinical outcomes with erlotinib in non-small cell lung cancer: an analysis of patients from german centers in the TRUST study. J. Thorac. Oncol.3(12), 1446–1453 (2008).
   PubMed Web of Science ®Google Scholar
• Marchetti A, Milella M, Felicioni L et al. Clinical implications of KRAS mutations in lung cancer patients treated with tyrosine kinase inhibitors: an important role for mutations in minor clones. Neoplasia11(10), 1084–1092 (2009).
   PubMed Web of Science ®Google Scholar
• Khambata-Ford S, Harbison CT, Hart LL et al. Analysis of potential predictive markers of cetuximab benefit in BMS099, a Phase III study of cetuximab and first-line taxane/carboplatin in advanced non-small-cell lung cancer. J. Clin. Oncol.28(6), 918–927 (2010).
   PubMed Web of Science ®Google Scholar
• O’Byrne KJ, Gatzemeier U, Bondarenko I et al. Molecular biomarkers in non-small-cell lung cancer: a retrospective analysis of data from the Phase 3 FLEX study. Lancet Oncol.12(8), 795–805 (2011).
   PubMed Web of Science ®Google Scholar
• Marchetti A, Felicioni L, Malatesta S et al. Clinical features and outcome of patients with non-small-cell lung cancer harboring KRAS mutations. J. Clin. Oncol.29(26), 3574–3579 (2011).
   PubMed Web of Science ®Google Scholar
• Maemondo M, Inoue A, Kobayashi K et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N. Engl. J. Med.362(25), 2380–2388 (2010).
   PubMed Web of Science ®Google Scholar
• Mitsudomi T, Morita S, Yatabe Y et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised Phase 3 trial. Lancet Oncol.11(2), 121–128 (2010).
   PubMed Web of Science ®Google Scholar
• Kosaka T, Yatabe Y, Onozato R, Kuwano H, Mitsudomi T. Prognostic implication of EGFR, KRAS, and TP53 gene mutations in a large cohort of Japanese patients with surgically treated lung adenocarcinoma. J. Thorac. Oncol.4(1), 22–29 (2009).
   PubMed Web of Science ®Google Scholar
• da Cunha Santos G, Dhani N, Tu D et al. Molecular predictors of outcome in a Phase 3 study of gemcitabine and erlotinib therapy in patients with advanced pancreatic cancer: National Cancer Institute of Canada Clinical Trials Group Study PA.3. Cancer116(24), 5599–5607 (2010).
   PubMed Web of Science ®Google Scholar
• Kim ST, Lim do H, Jang KT et al. Impact of KRAS mutations on clinical outcomes in pancreatic cancer patients treated with first-line gemcitabine-based chemotherapy. Mol. Cancer Ther.10(10), 1993–1999 (2011).
   PubMed Web of Science ®Google Scholar
• Caronia LM, Phay JE, Shah MH. Role of KRAS in thyroid oncogenesis. Clin. Cancer Res.17(24), 7511–7517 (2011).
   PubMed Web of Science ®Google Scholar
• Kim TH, Park YJ, Lim JA et al. The association of the KRAS(V600E) mutation with prognostic factors and poor clinical outcome in papillary thyroid cancer: a meta-analysis. Cancer118(7), 1764–1773 (2012).
   PubMed Web of Science ®Google Scholar
• Di Nicolantonio F, Martini M, Molinari F et al. Wild-type KRAS is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J. Clin. Oncol.26(35), 5705–5712 (2008).
   PubMed Web of Science ®Google Scholar
• Loupakis F, Ruzzo A, Cremolini C et al.KRAS codon 61, 146 and KRAS mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer. Br. J. Cancer101(4), 715–721 (2009).
   PubMed Web of Science ®Google Scholar
• Laurent-Puig P, Cayre A, Manceau G et al. Analysis of PTEN, KRAS, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J. Clin. Oncol.27(35), 5924–5930 (2009).
   PubMed Web of Science ®Google Scholar
• Farina-Sarasqueta A, van Lijnschoten G, Moerland E et al. The KRAS V600E mutation is an independent prognostic factor for survival in stage II and stage III colon cancer patients. Ann. Oncol.21(12), 2396–2402 (2010).
   PubMed Web of Science ®Google Scholar
• Ogino S, Nosho K, Kirkner GJ et al. CpG island methylator phenotype, microsatellite instability, KRAS mutation and clinical outcome in colon cancer. Gut58(1), 90–96 (2009).
   PubMed Web of Science ®Google Scholar
• Tol J, Dijkstra JR, Klomp M et al. Markers for EGFR pathway activation as predictor of outcome in metastatic colorectal cancer patients treated with or without cetuximab. Eur. J. Cancer46(11), 1997–2009 (2010).
   PubMed Web of Science ®Google Scholar
• Long GV, Menzies AM, Nagrial AM et al. Prognostic and clinicopathologic associations of oncogenic KRAS in metastatic melanoma. J. Clin. Oncol.29(10), 1239–1246 (2011).
   PubMed Web of Science ®Google Scholar
• Flaherty KT, Puzanov I, Kim KB et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med.363(9), 809–819 (2010).
   PubMed Web of Science ®Google Scholar
• Chapman PB, Hauschild A, Robert C et al. Improved survival with vemurafenib in melanoma with KRAS V600E mutation. N. Engl. J. Med.364(26), 2507–2516 (2011).
   PubMed Web of Science ®Google Scholar
• Rubinstein JC, Sznol M, Pavlick AC et al. Incidence of the V600K mutation among melanoma patients with KRAS mutations, and potential therapeutic response to the specific BRAF inhibitor PLX4032. J. Transl. Med.8, 67 (2010).
   PubMed Web of Science ®Google Scholar
• Carnahan J, Beltran PJ, Babij C et al. Selective and potent Raf inhibitors paradoxically stimulate normal cell proliferation and tumor growth. Mol. Cancer Ther.9(8), 2399–2410 (2010).
   PubMed Web of Science ®Google Scholar
• Hatzivassiliou G, Song K, Yen I et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature464(7287), 431–435 (2010).
   PubMed Web of Science ®Google Scholar
• Heidorn SJ, Milagre C, Whittaker S et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell140(2), 209–221 (2010).
   PubMed Web of Science ®Google Scholar
• Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type KRAS. Nature464(7287), 427–430 (2010).
   PubMed Web of Science ®Google Scholar
• Oberholzer PA, Kee D, Dziunycz P et al.RAS mutations are associated with the development of cutaneous squamous cell tumors in patients treated with RAF inhibitors. J. Clin. Oncol.30(3), 316–321 (2012).
   PubMed Web of Science ®Google Scholar
• Arnault JP, Mateus C, Escudier B et al. Skin tumors induced by sorafenib; paradoxic RAS–RAF pathway activation and oncogenic mutations of HRAS, TP53, and TGFBR1. Clin. Cancer Res.18(1), 263–272 (2012).
   PubMed Web of Science ®Google Scholar
• Su F, Viros A, Milagre C et al.RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N. Engl. J. Med.366(3), 207–215 (2012).
   PubMed Web of Science ®Google Scholar
• Parsons BL, Marchant-Miros KE, Delongchamp RR et al. ACB–PCR quantification of K-RAS codon 12 GAT and GTT mutant fraction in colon tumor and non-tumor tissue. Cancer Invest.28(4), 364–375 (2010).
   PubMed Web of Science ®Google Scholar
• Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nat. Rev. Cancer7(3), 169–181 (2007).
   PubMed Web of Science ®Google Scholar
• Shigematsu H, Lin L, Takahashi T et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J. Natl Cancer Inst.97(5), 339–346 (2005).
   PubMed Web of Science ®Google Scholar
• Zhou C, Wu YL, Chen G et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, Phase 3 study. Lancet Oncol.12(8), 735–742 (2011).
   PubMed Web of Science ®Google Scholar
• Riely GJ, Pao W, Pham D et al. Clinical course of patients with non-small cell lung cancer and epidermal growth factor receptor exon 19 and exon 21 mutations treated with gefitinib or erlotinib. Clin. Cancer Res.12(3 Pt 1), 839–844 (2006).
   PubMed Web of Science ®Google Scholar
• Rosell R, Moran T, Queralt C et al. Screening for epidermal growth factor receptor mutations in lung cancer. N. Engl. J. Med.361(10), 958–967 (2009).
   PubMed Web of Science ®Google Scholar
• Won YW, Han JY, Lee GK et al. Comparison of clinical outcome of patients with non-small-cell lung cancer harbouring epidermal growth factor receptor exon 19 or exon 21 mutations. J. Clin. Pathol.64(11), 947–952 (2011).
   PubMed Web of Science ®Google Scholar
• Kosaka T, Yatabe Y, Endoh H et al. Analysis of epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer and acquired resistance to gefitinib. Clin. Cancer Res.12(19), 5764–5769 (2006).
   PubMed Web of Science ®Google Scholar
• Pao W, Miller VA, Politi KA et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med.2(3), e73 (2005).
   PubMed Web of Science ®Google Scholar
• Sequist LV, Waltman BA, Dias-Santagata D et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci. Transl. Med.3(75), 75ra26 (2011).
   PubMed Web of Science ®Google Scholar
• Balak MN, Gong Y, Riely GJ et al. Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clin. Cancer Res.12(21), 6494–6501 (2006).
   PubMed Web of Science ®Google Scholar
• Bean J, Riely GJ, Balak M et al. Acquired resistance to epidermal growth factor receptor kinase inhibitors associated with a novel T854A mutation in a patient with EGFR-mutant lung adenocarcinoma. Clin. Cancer Res.14(22), 7519–7525 (2008).
   PubMed Web of Science ®Google Scholar
• Costa DB, Schumer ST, Tenen DG, Kobayashi S. Differential responses to erlotinib in epidermal growth factor receptor (EGFR)-mutated lung cancers with acquired resistance to gefitinib carrying the L747S or T790M secondary mutations. J. Clin. Oncol.26(7), 1182–1184; author reply 1184–1186 (2008).
   PubMed Web of Science ®Google Scholar
• Inukai M, Toyooka S, Ito S et al. Presence of epidermal growth factor receptor gene T790M mutation as a minor clone in non-small cell lung cancer. Cancer Res.66(16), 7854–7858 (2006).
   PubMed Web of Science ®Google Scholar
• Maheswaran S, Sequist LV, Nagrath S et al. Detection of mutations in EGFR in circulating lung-cancer cells. N. Engl. J. Med.359(4), 366–377 (2008).
   PubMed Web of Science ®Google Scholar
• Zhao L, Vogt PK. Helical domain and kinase domain mutations in p110alpha of phosphatidylinositol 3-kinase induce gain of function by different mechanisms. Proc. Natl Acad. Sci. USA105(7), 2652–2657 (2008).
   PubMed Web of Science ®Google Scholar
• Saal LH, Holm K, Maurer M et al.PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res.65(7), 2554–2559 (2005).
   PubMed Web of Science ®Google Scholar
• Stemke-Hale K, Gonzalez-Angulo AM, Lluch A et al. An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res.68(15), 6084–6091 (2008).
   PubMed Web of Science ®Google Scholar
• Li SY, Rong M, Grieu F, Iacopetta B. PIK3CA mutations in breast cancer are associated with poor outcome. Breast Cancer Res. Treat.96(1), 91–95 (2006).
   PubMed Web of Science ®Google Scholar
• Lai YL, Mau BL, Cheng WH, Chen HM, Chiu HH, Tzen CY. PIK3CA exon 20 mutation is independently associated with a poor prognosis in breast cancer patients. Ann. Surg. Oncol.15(4), 1064–1069 (2008).
   PubMed Web of Science ®Google Scholar
• Barbareschi M, Buttitta F, Felicioni L et al. Different prognostic roles of mutations in the helical and kinase domains of the PIK3CA gene in breast carcinomas. Clin. Cancer Res.13(20), 6064–6069 (2007).
   PubMed Web of Science ®Google Scholar
• Berns K, Horlings HM, Hennessy BT et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell12(4), 395–402 (2007).
   PubMed Web of Science ®Google Scholar
• Razis E, Bobos M, Kotoula V et al. Evaluation of the association of PIK3CA mutations and PTEN loss with efficacy of trastuzumab therapy in metastatic breast cancer. Breast Cancer Res. Treat.128(2), 447–456 (2011).
   PubMed Web of Science ®Google Scholar
• Ogino S, Nosho K, Kirkner GJ et al.PIK3CA mutation is associated with poor prognosis among patients with curatively resected colon cancer. J. Clin. Oncol.27(9), 1477–1484 (2009).
   PubMed Web of Science ®Google Scholar
• Sartore-Bianchi A, Martini M, Molinari F et al.PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res.69(5), 1851–1857 (2009).
   PubMed Web of Science ®Google Scholar
• Souglakos J, Philips J, Wang R et al. Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer. Br. J. Cancer101(3), 465–472 (2009).
   PubMed Web of Science ®Google Scholar
• Prenen H, De Schutter J, Jacobs B et al.PIK3CA mutations are not a major determinant of resistance to the epidermal growth factor receptor inhibitor cetuximab in metastatic colorectal cancer. Clin. Cancer Res.15(9), 3184–3188 (2009).
   PubMed Web of Science ®Google Scholar
• Ludovini V, Bianconi F, Pistola L et al. Phosphoinositide-3-kinase catalytic alpha and KRAS mutations are important predictors of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in patients with advanced non-small cell lung cancer. J. Thorac. Oncol.6(4), 707–715 (2011).
   PubMed Web of Science ®Google Scholar
• Bando H, Yoshino T, Tsuchihara K et al.KRAS mutations detected by the amplification refractory mutation system-Scorpion assays strongly correlate with therapeutic effect of cetuximab. Br. J. Cancer105(3), 403–406 (2011).
   PubMed Web of Science ®Google Scholar
• Arcila ME, Oxnard GR, Nafa K et al. Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay. Clin. Cancer Res.17(5), 1169–1180 (2011).
   PubMed Web of Science ®Google Scholar
• Jahn SW, Winter G, Stacher E et al. Multiple intratumoral KRAS mutations can clonally segregate to different lymph node metastases in colon cancer. Histopathology59(2), 342–345 (2011).
   PubMed Web of Science ®Google Scholar
• Lamy A, Blanchard F, Le Pessot F et al. Metastatic colorectal cancer KRAS genotyping in routine practice: results and pitfalls. Mod. Pathol.24(8), 1090–1100 (2011).
   PubMed Web of Science ®Google Scholar
• Li Z, Jin K, Lan H, Teng L. Heterogeneity in primary colorectal cancer and its corresponding metastases: a potential reason of EGFR-targeted therapy failure? Hepatogastroenterology58(106), 411–416 (2011)
   PubMedGoogle Scholar
• Jin K, He K, Teng F et al. Heterogeneity in primary tumors and corresponding metastases: could it provide us with any hints to personalize cancer therapy? Pers. Med.8(2), 175–182 (2011).
   PubMed Web of Science ®Google Scholar
• Baldus SE, Schaefer KL, Engers R, Hartleb D, Stoecklein NH, Gabbert HE. Prevalence and heterogeneity of KRAS, KRAS, and PIK3CA mutations in primary colorectal adenocarcinomas and their corresponding metastases. Clin. Cancer Res.16(3), 790–799 (2010).
   PubMed Web of Science ®Google Scholar
• Jensen JD, Laenkholm AV, Knoop A et al.PIK3CA mutations may be discordant between primary and corresponding metastatic disease in breast cancer. Clin. Cancer Res.17(4), 667–677 (2011).
   PubMed Web of Science ®Google Scholar
• Roesch A, Fukunaga-Kalabis M, Schmidt EC et al. A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth. Cell141(4), 583–594 (2010).
   PubMed Web of Science ®Google Scholar
• Rebecca VW, Smalley KS. Tumor heterogeneity and strategies to overcome kinase inhibitor resistance in cancer: lessons from melanoma. Expert Opin. Invest. Drugs20(2), 137–140 (2011).
   PubMed Web of Science ®Google Scholar
• Dieterle CP, Conzelmann M, Linnemann U, Berger MR. detection of isolated tumor cells by polymerase chain reaction-restriction fragment length polymorphism for K-RAS mutations in tissue samples of 199 colorectal cancer patients. Clin. Cancer Res.10(2), 641–650 (2004).
   PubMed Web of Science ®Google Scholar
• Thirlwell C, Will OCC, Domingo E et al. clonality assessment and clonal ordering of individual neoplastic crypts shows polyclonality of colorectal adenomas. Gastroenterology138(4), 1441–1454.e1447 (2010).
   PubMed Web of Science ®Google Scholar
• Navin N, Krasnitz A, Rodgers L et al. Inferring tumor progression from genomic heterogeneity. Genome Res.20(1), 68–80 (2010).
   PubMed Web of Science ®Google Scholar
• Navin N, Kendall J, Troge J et al. Tumour evolution inferred by single-cell sequencing. Nature472(7341), 90–95 (2011).
   PubMed Web of Science ®Google Scholar
• Jones S, Chen WD, Parmigiani G et al. Comparative lesion sequencing provides insights into tumor evolution. Proc. Natl Acad. Sci. USA105(11), 4283–4288 (2008).
   PubMed Web of Science ®Google Scholar
• Grunewald TG, Herbst SM, Heinze J, Burdach S. Understanding tumor heterogeneity as functional compartments – superorganisms revisited. J. Transl. Med.9, 79 (2011).
   PubMed Web of Science ®Google Scholar
• Parsons BL. Many different tumor types have polyclonal tumor origin: evidence and implications. Mut. Res.659(3), 232–247 (2008).
   PubMed Web of Science ®Google Scholar
• Novelli M, Cossu A, Oukrif D et al. X-inactivation patch size in human female tissue confounds the assessment of tumor clonality. Proc. Natl Acad. Sci. USA100(6), 3311–3314 (2003).
   PubMed Web of Science ®Google Scholar
• Visvader JE. Cells of origin in cancer. Nature469(7330), 314–322 (2011).
   PubMed Web of Science ®Google Scholar
• Dai D, Beck B, Wang X, Howk C, Li Y. Quantitative interpretation of a genetic model of carcinogenesis using computer simulations. PloS ONE6(3), e16859 (2011).
   Google Scholar
• Durrett R, Foo J, Leder K, Mayberry J, Michor F. Intratumor heterogeneity in evolutionary models of tumor progression. Genetics188(2), 461–477 (2011).
   PubMed Web of Science ®Google Scholar
• Wu M, Pastor-Pareja JC, Xu T. Interaction between RasV12 and scribbled clones induces tumour growth and invasion. Nature463(7280), 545–548 (2010).
   PubMed Web of Science ®Google Scholar
• Inda MM, Bonavia R, Mukasa A et al. Tumor heterogeneity is an active process maintained by a mutant EGFR-induced cytokine circuit in glioblastoma. Genes Dev.24, 1731–1745 (2011).
   Web of Science ®Google Scholar
• Bonavia R, Inda MD, Cavenee WK, Furnari FB. Heterogeneity maintenance in glioblastoma: a social network. Cancer Res.71(12), 4055–4060 (2011).
   PubMed Web of Science ®Google Scholar
• Tarin D. Cell and tissue interactions in carcinogenesis and metastasis and their clinical significance. Semin. Cancer Biol.21(2), 72–82 (2011).
   PubMed Web of Science ®Google Scholar
• Bissell MJ, Hines WC. Why don’t we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat. Med.17(3), 320–329 (2011).
   PubMed Web of Science ®Google Scholar
• Parsons BL, Myers MB, Meng F, Wang Y, McKinzie PB. Oncomutations as biomarkers of cancer risk. Environ. Mol. Mutagen.51(8–9), 836–850 (2010).
   PubMed Web of Science ®Google Scholar
• Sartore-Bianchi A, Bencardino K, Cassingena A et al. Therapeutic implications of resistance to molecular therapies in metastatic colorectal cancer. Cancer Treat. Rev.36(Suppl. 3), S1–S5 (2010).
   PubMed Web of Science ®Google Scholar
• Heng HH, Liu G, Stevens JB, Bremer SW, Ye KJ, Ye CJ. Genetic and epigenetic heterogeneity in cancer: the ultimate challenge for drug therapy. Curr. Drug Targets11(10), 1304–1316 (2010).
   PubMed Web of Science ®Google Scholar
• MacConaill LE, Hummelen PV, Meyerson M, Hahn WC. Clinical implementation of comprehensive strategies to characterize cancer genomes: opportunities and challenges. Cancer Discov.1, 297–311 (2011).
   PubMed Web of Science ®Google Scholar
• Andersen MH, Junker N, Ellebaek E, Svane IM, Thor Straten P. Therapeutic cancer vaccines in combination with conventional therapy. J. Biomed. Biotechnol.2010, 237623 (2010).
   PubMedGoogle Scholar
• Mumenthaler SM, Foo J, Leder K et al. Evolutionary modeling of combination treatment strategies to overcome resistance to tyrosine kinase inhibitors in non-small cell lung cancer. Mol. Pharm.8(6), 2069–2079 (2011).
   PubMedGoogle Scholar
• Ding L, Ellis MJ, Li S et al. Genome remodelling in a basal-like breast cancer metastasis and xenograft. Nature464(7291), 999–1005 (2010).
   PubMed Web of Science ®Google Scholar
• Rebersek M, Boc M, Cerkovnik P et al. Efficacy of first-line systemic treatment in correlation with KRAS V600E and different KRAS mutations in metastatic colorectal cancer – a single institution retrospective analysis. Radiol. Oncol.45(4), 285–291 (2011).
   PubMed Web of Science ®Google Scholar
• Janku F, Tsimberidou AM, Garrido-Laguna I et al.PIK3CA mutations in patients with advanced cancers treated with PI3K/AKT/mTOR axis inhibitors. Mol. Cancer Ther.10(3), 558–565 (2011).
   PubMed Web of Science ®Google Scholar
• Felip E, Gridelli C, Baas P, Rosell R, Stahel R. Metastatic non-small-cell lung cancer: consensus on pathology and molecular tests, first-line, second-line, and third-line therapy 1st ESMO Consensus Conference in Lung Cancer; Lugano 2010. Ann. Oncol.22(7), 1507–1519 (2011).
   PubMed Web of Science ®Google Scholar
• McKinzie PB, Delongchamp RR, Heflich RH, Parsons BL. Prospects for applying genotypic selection of somatic oncomutation to chemical risk assessment. Mut. Res.489(1), 47–78 (2001).
   PubMed Web of Science ®Google Scholar
• Wang HL, Lopategui J, Amin MB, Patterson SD. KRAS mutation testing in human cancers: the pathologist’s role in the era of personalized medicine. Adv. Anat. Pathol.17(1), 23–32 (2010).
   PubMed Web of Science ®Google Scholar
• Blank PR, Moch H, Szucs TD, Schwenkglenks M. KRAS and KRAS mutation analysis in metastatic colorectal cancer: a cost–effectiveness analysis from a Swiss perspective. Clin. Cancer Res.17(19), 6338–6346 (2011).
   PubMed Web of Science ®Google Scholar
• Carotenuto P, Roma C, Rachiglio AM et al. Detection of KRAS mutations in colorectal carcinoma patients with an integrated PCR/sequencing and real-time PCR approach. Pharmacogenomics11(8), 1169–1179 (2010).
   PubMed Web of Science ®Google Scholar
• Ogino S, Kawasaki T, Brahmandam M et al. Sensitive sequencing method for KRAS mutation detection by pyrosequencing. J. Mol. Diagn.7(3), 413–421 (2005).
   PubMed Web of Science ®Google Scholar
• Walther Z, Sklar J. Molecular tumor profiling for prediction of response to anticancer therapies. Cancer J.17(2), 71–79 (2011).
   PubMed Web of Science ®Google Scholar
• Ma ES, Wong CL, Law FB, Chan WK, Siu D. Detection of KRAS mutations in colorectal cancer by high-resolution melting analysis. J. Clin. Pathol.62(10), 886–891 (2009).
   PubMed Web of Science ®Google Scholar
• Thunnissen E, Bovee JV, Bruinsma H et al. EGFR and KRAS quality assurance schemes in pathology: generating normative data for molecular predictive marker analysis in targeted therapy. J. Clin. Pathol.64(10), 884–892 (2011).
   PubMed Web of Science ®Google Scholar
• Kwon MJ, Lee SE, Kang SY, Choi YL. Frequency of KRAS, KRAS, and PIK3CA mutations in advanced colorectal cancers: comparison of peptide nucleic acid-mediated PCR clamping and direct sequencing in formalin-fixed, paraffin-embedded tissue. Pathol. Res. Pract.207(12), 762–768 (2011).
   PubMed Web of Science ®Google Scholar
• Shen Y, Wan Z, Coarfa C et al. A SNP discovery method to assess variant allele probability from next-generation resequencing data. Genome Res.20(2), 273–280 (2010).
   PubMed Web of Science ®Google Scholar
• Gundry M, Vijg J. Direct mutation analysis by high-throughput sequencing: from germline to low-abundant, somatic variants. Mutat. Res.729(1–2), 1–15 (2012).
   PubMed Web of Science ®Google Scholar
• Bell D, Berchuck A, Birrer M et al. Integrated genomic analyses of ovarian carcinoma. Nature474(7353), 609–615 (2011).
   PubMed Web of Science ®Google Scholar
• Board RE, Thelwell NJ, Ravetto PF et al. Multiplexed assays for detection of mutations in PIK3CA. Clin. Chem.54(4), 757–760 (2008).
   PubMed Web of Science ®Google Scholar
• Horiike A, Kimura H, Nishio K et al. Detection of epidermal growth factor receptor mutation in transbronchial needle aspirates of non-small cell lung cancer. Chest131(6), 1628–1634 (2007).
   PubMed Web of Science ®Google Scholar
• Tol J, Dijkstra JR, Vink-Borger ME et al. High sensitivity of both sequencing and real-time PCR analysis of KRAS mutations in colorectal cancer tissue. J. Cell. Mol. Med.14(8), 2122–2131 (2010).
   PubMed Web of Science ®Google Scholar
• Kitano S, Nakayama M, Yamane A, Tsukahara Y, Amano M. Detection of DNA mutations by fluorescence resonance energy transfer-based preferential homoduplex formation assay. Anal. Biochem.408(2), 197–205 (2011).
   PubMed Web of Science ®Google Scholar
• Tatsumi K, Mitani Y, Watanabe J et al. Rapid screening assay for KRAS mutations by the modified smart amplification process. J. Mol. Diagn.10(6), 520–526 (2008).
   PubMed Web of Science ®Google Scholar