Synthetic Genetic Approaches in Colorectal Cancer: Exploiting and Targeting Genome Instability

  • Babu V. Sajesh
  • Amy L. Cisyk
  • Kirk J. McManusEmail author
Part of the Cancer Metastasis - Biology and Treatment book series (CMBT, volume 20)


Colorectal cancer is the third leading cause of cancer-related deaths throughout the world. Surgery is effective against early stage tumors but advanced stage tumors lack an effective targeting strategy. For nearly 50 years, 5-fluorouracil has been the standard of care for advanced disease, but the overall 5-year survival rate remains at only 6 %. Accordingly, novel therapeutic strategies are urgently needed to decrease morbidity and mortality rates. Synthetic genetic approaches are well established in model organisms, and have recently garnered much attention in humans for their potential implications in cancer targeting. Synthetic lethality and synthetic dosage lethality are innovative strategies designed to specifically exploit and kill cancer cells based on the loss-of-function associated with tumor suppressors or the gain-of-function associated with oncogenes, respectively. By definition, these approaches are highly specific and restricted to tumor cells, and are expected to decrease side effects associated with current strategies. Both synthetic genetic approaches have been applied extensively in pre-clinical studies and numerous candidate drug targets have been identified, including some that have entered clinical trials. The focus of this chapter is to present the pathways that drive tumorigenesis in colorectal cancer, and describe how synthetic lethality and synthetic dosage lethality can exploit these origins for enhanced killing of tumor cells. Finally, we summarize the current status of the field and relate how these novel strategies can be custom-tailored to target advanced stage colorectal cancer as we enter the personalized medicine era.


Colorectal cancer Metastatic disease Chromosome instability Genome instability Therapeutic targeting Treatment Synthetic genetic approaches Synthetic lethality Synthetic dosage lethality Personalized medicine 





Adenomatous polyposis coli


CpG island methylator phenotype


Chromosome instability


Colorectal cancer


Deoxyribonucleic acid


Kirsten rat sarcoma viral oncogene homolog


Mismatch repair


Microsatellite instability


Numerical CIN


Structural CIN


  1. 1.
    Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C et al (2013) GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on CancerGoogle Scholar
  2. 2.
    Kinzler KW (2002) Colorectal tumors. In: Vogelstein BK (ed) The genetic basis of human cancer. McGraw-Hill, New YorkGoogle Scholar
  3. 3.
    Rouleau M, Patel A, Hendzel MJ, Kaufmann SH, Poirier GG (2010) PARP inhibition: PARP1 and beyond. Nat Rev Cancer 10:293–301PubMedCentralPubMedGoogle Scholar
  4. 4.
    Markowitz SD, Bertagnolli MM (2009) Molecular origins of cancer: molecular basis of colorectal cancer. N Engl J Med 361:2449–2460PubMedCentralPubMedGoogle Scholar
  5. 5.
    Howlader NNA, Krapcho M, Garshell J, Neyman N et al (2014) SEER Cancer Statistics Review, 1975–2011. National Cancer Institute, BethesdaGoogle Scholar
  6. 6.
    Andre T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T et al (2004) Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 350:2343–2351PubMedGoogle Scholar
  7. 7.
    Compton CHE, Grochow L, Lee F, Ritter M et al (2008) Colon cancer. In: Abeloff MD, Niederhuber JE; Kastan MB; McKenna GW (eds) Abeloff’s clinical oncology. Churchill Livingstone, PhiladelphiaGoogle Scholar
  8. 8.
    von Hansemann D (1890) Ueber asymmetrische Zelltheilung in epithel Krebsen und deren biologische Bedeutung. Virchows Arch A Pathol Anat Histopathol 119:299–326Google Scholar
  9. 9.
    Boveri T (1914) Zur Frage der Entstehung maligner Tumoren. G. Fischer, JenaGoogle Scholar
  10. 10.
    Cahill DP, Kinzler KW, Vogelstein B, Lengauer C (1999) Genetic instability and darwinian selection in tumours. Trends Cell Biol 9:M57–M60PubMedGoogle Scholar
  11. 11.
    Lengauer C, Kinzler KW, Vogelstein B (1998) Genetic instabilities in human cancers. Nature 396:643–649PubMedGoogle Scholar
  12. 12.
    Rajagopalan H, Jallepalli PV, Rago C, Velculescu VE, Kinzler KW, Vogelstein B et al (2004) Inactivation of hCDC4 can cause chromosomal instability. Nature 428:77–81PubMedGoogle Scholar
  13. 13.
    Issa JP (2004) CpG island methylator phenotype in cancer. Nat Rev Cancer 4:988–993PubMedGoogle Scholar
  14. 14.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674PubMedGoogle Scholar
  15. 15.
    Boyer JC, Umar A, Risinger JI, Lipford JR, Kane M, Yin S et al (1995) Microsatellite instability, mismatch repair deficiency, and genetic defects in human cancer cell lines. Cancer Res 55:6063–6070PubMedGoogle Scholar
  16. 16.
    Loeb LA (1991) Mutator phenotype may be required for multistage carcinogenesis. Cancer Res 51:3075–3079PubMedGoogle Scholar
  17. 17.
    Loeb LA, Bielas JH, Beckman RA (2008) Cancers exhibit a mutator phenotype: clinical implications. Cancer Res 68:3551–3557; discussion 7PubMedGoogle Scholar
  18. 18.
    Chung DC, Rustgi AK (1995) DNA mismatch repair and cancer. Gastroenterology 109:1685–1699PubMedGoogle Scholar
  19. 19.
    Jiricny J (2006) The multifaceted mismatch-repair system. Nat Rev Mol Cell Biol 7:335–346PubMedGoogle Scholar
  20. 20.
    Aaltonen LA, Peltomaki P, Leach FS, Sistonen P, Pylkkanen L, Mecklin JP et al (1993) Clues to the pathogenesis of familial colorectal cancer. Science 260:812–816PubMedGoogle Scholar
  21. 21.
    Bocker T, Schlegel J, Kullmann F, Stumm G, Zirngibl H, Epplen JT et al (1996) Genomic instability in colorectal carcinomas: comparison of different evaluation methods and their biological significance. J Pathol 179:15–19PubMedGoogle Scholar
  22. 22.
    Boland CR, Goel A (2010) Microsatellite instability in colorectal cancer. Gastroenterology 138:2073–87e3PubMedCentralPubMedGoogle Scholar
  23. 23.
    Ionov Y, Peinado MA, Malkhosyan S, Shibata D, Perucho M (1993) Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 363:558–561PubMedGoogle Scholar
  24. 24.
    Thibodeau SN, Bren G, Schaid D (1993) Microsatellite instability in cancer of the proximal colon. Science 260:816–819PubMedGoogle Scholar
  25. 25.
    Vilar E, Gruber SB (2010) Microsatellite instability in colorectal cancer-the stable evidence. Nat Rev Clin Oncol 7:153–162PubMedCentralPubMedGoogle Scholar
  26. 26.
    Salovaara R, Loukola A, Kristo P, Kaariainen H, Ahtola H, Eskelinen M et al (2000) Population-based molecular detection of hereditary nonpolyposis colorectal cancer. J Clin Oncol 18:2193–2200PubMedGoogle Scholar
  27. 27.
    Peel DJ, Ziogas A, Fox EA, Gildea M, Laham B, Clements E et al (2000) Characterization of hereditary nonpolyposis colorectal cancer families from a population-based series of cases. J Natl Cancer Inst 92:1517–1522PubMedGoogle Scholar
  28. 28.
    Fishel R, Lescoe MK, Rao MR, Copeland NG, Jenkins NA, Garber J et al (1993) The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 75:1027–1038PubMedGoogle Scholar
  29. 29.
    Miyaki M, Konishi M, Tanaka K, Kikuchi-Yanoshita R, Muraoka M, Yasuno M et al (1997) Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. Nat Genet 17:271–272PubMedGoogle Scholar
  30. 30.
    Nicolaides NC, Papadopoulos N, Liu B, Wei YF, Carter KC, Ruben SM et al (1994) Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature 371:75–80PubMedGoogle Scholar
  31. 31.
    Cunningham JM, Christensen ER, Tester DJ, Kim CY, Roche PC, Burgart LJ et al (1998) Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. Cancer Res 58:3455–3460PubMedGoogle Scholar
  32. 32.
    Kuismanen SA, Holmberg MT, Salovaara R, de la CA, Peltomaki P (2000) Genetic and epigenetic modification of MLH1 accounts for a major share of microsatellite-unstable colorectal cancers. Am J Pathol 156:1773–1779PubMedCentralPubMedGoogle Scholar
  33. 33.
    Herman JG, Umar A, Polyak K, Graff JR, Ahuja N, Issa JP et al (1998) Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci U S A 95:6870–6875PubMedCentralPubMedGoogle Scholar
  34. 34.
    Kane MF, Loda M, Gaida GM, Lipman J, Mishra R, Goldman H et al (1997) Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res 57:808–811PubMedGoogle Scholar
  35. 35.
    Weaver BA, Cleveland DW (2006) Does aneuploidy cause cancer? Curr Opin Cell Biol 18:658–67PubMedGoogle Scholar
  36. 36.
    Foijer F, Draviam VM, Sorger PK (2008) Studying chromosome instability in the mouse. Biochim Biophys Acta 1786:73–82PubMedCentralPubMedGoogle Scholar
  37. 37.
    Cahill DP, Lengauer C, Yu J, Riggins GJ, Willson JK, Markowitz SD et al (1998) Mutations of mitotic checkpoint genes in human cancers. Nature 392:300–303PubMedGoogle Scholar
  38. 38.
    Danes BS, Alm T (1979) In vitro studies on adenomatosis of the colon and rectum. J Med Genet 16:417–422PubMedCentralPubMedGoogle Scholar
  39. 39.
    Lengauer C, Kinzler KW, Vogelstein B (1997) Genetic instability in colorectal cancers. Nature 386:623–627PubMedGoogle Scholar
  40. 40.
    Gardner EJ, Rogers SW, Woodward S (1982) Numerical and structural chromosome aberrations in cultured lymphocytes and cutaneous fibroblasts of patients with multiple adenomas of the colorectum. Cancer 49:1413–1419PubMedGoogle Scholar
  41. 41.
    Gordon DJ, Resio B, Pellman D (2012) Causes and consequences of aneuploidy in cancer. Nat Rev Genet 13:189–203PubMedGoogle Scholar
  42. 42.
    Rajagopalan H, Nowak MA, Vogelstein B, Lengauer C (2003) The significance of unstable chromosomes in colorectal cancer. Nature Rev Cancer 3:695–701Google Scholar
  43. 43.
    Goncalves Dos Santos Silva A, Sarkar R, Harizanova J, Guffei A, Mowat M, Garini Y et al (2008) Centromeres in cell division, evolution, nuclear organization and disease. J Cell Biochem 104:2040–2058PubMedGoogle Scholar
  44. 44.
    Mai S (2010) Initiation of telomere-mediated chromosomal rearrangements in cancer. J Cell Biochem 109:1095–1102PubMedGoogle Scholar
  45. 45.
    Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M et al (1988) Genetic alterations during colorectal-tumor development. N Engl J Med 319:525–532PubMedGoogle Scholar
  46. 46.
    Kaplan KB, Burds AA, Swedlow JR, Bekir SS, Sorger PK, Nathke IS (2001) A role for the Adenomatous Polyposis Coli protein in chromosome segregation. Nat Cell Biol 3:429–432PubMedGoogle Scholar
  47. 47.
    Fodde R, Kuipers J, Rosenberg C, (SMI)ts R, Kielman M, Gaspar C et al (2001) Mutations in the APC tumour suppressor gene cause chromosomal instability. Nat Cell Biol 3:433–438Google Scholar
  48. 48.
    Powell SM, Zilz N, Beazer-Barclay Y, Bryan TM, Hamilton SR, Thibodeau SN et al (1992) APC mutations occur early during colorectal tumorigenesis. Nature 359:235–237PubMedGoogle Scholar
  49. 49.
    Jallepalli PV, Lengauer C (2001) Chromosome segregation and cancer: cutting through the mystery. Nat Rev Cancer 1:109–117PubMedGoogle Scholar
  50. 50.
    Barber TD, McManus K, Yuen KW, Reis M, Parmigiani G, Shen D et al (2008) Chromatid cohesion defects may underlie chromosome instability in human colorectal cancers. Proc Natl Acad Sci U S A 105:3443–3448PubMedCentralPubMedGoogle Scholar
  51. 51.
    Wang Z, Cummins JM, Shen D, Cahill DP, Jallepalli PV, Wang TL et al (2004) Three classes of genes mutated in colorectal cancers with chromosomal instability. Cancer Res 64:2998–3001PubMedGoogle Scholar
  52. 52.
    Gollin SM (2005) Mechanisms leading to chromosomal instability. Sem Cancer Biol 15:33–42Google Scholar
  53. 53.
    Rao CV, Yamada HY (2013) Genomic instability and colon carcinogenesis: from the perspective of genes. Front Oncol 3:130PubMedCentralPubMedGoogle Scholar
  54. 54.
    Chang SC, Lin JK, Lin TC, Liang WY (2005) Loss of heterozygosity: an independent prognostic factor of colorectal cancer. World J Gastroenterol 11:778–784PubMedGoogle Scholar
  55. 55.
    Lurje G, Zhang W, Lenz HJ (2007) Molecular prognostic markers in locally advanced colon cancer. Clin Colorectal Cancer 6:683–690PubMedGoogle Scholar
  56. 56.
    Sheffer M, Bacolod MD, Zuk O, Giardina SF, Pincas H, Barany F et al (2009) Association of survival and disease progression with chromosomal instability: a genomic exploration of colorectal cancer. Proc Natl Acad Sci USA 106:7131–7136PubMedCentralPubMedGoogle Scholar
  57. 57.
    Walther A, Houlston R, Tomlinson I (2008) Association between chromosomal instability and prognosis in colorectal cancer: a meta-analysis. Gut 57:941–950PubMedGoogle Scholar
  58. 58.
    Watanabe T, Kobunai T, Yamamoto Y, Matsuda K, Ishihara S, Nozawa K et al (2012) Chromosomal instability (CIN) phenotype, CIN high or CIN low, predicts survival for colorectal cancer. J Clin Oncol 30:2256–2264PubMedGoogle Scholar
  59. 59.
    Lee AJ, Endesfelder D, Rowan AJ, Walther A, Birkbak NJ, Futreal PA et al (2011) Chromosomal instability confers intrinsic multidrug resistance. Cancer Res 71:1858–1870PubMedCentralPubMedGoogle Scholar
  60. 60.
    McClelland SE, Burrell RA, Swanton C (2009) Chromosomal instability: a composite phenotype that influences sensitivity to chemotherapy. Cell Cycle 8:3262–3266PubMedGoogle Scholar
  61. 61.
    Swanton C, Tomlinson I, Downward J (2006) Chromosomal instability, colorectal cancer and taxane resistance. Cell Cycle 5:818–823PubMedGoogle Scholar
  62. 62.
    Baylin SB, Jones PA (2011) A decade of exploring the cancer epigenome–biological and translational implications. Nat Rev Cancer 11:726–734PubMedCentralPubMedGoogle Scholar
  63. 63.
    Bird AP (1986) CpG-rich islands and the function of DNA methylation. Nature 321:209–213PubMedGoogle Scholar
  64. 64.
    Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB, Issa JP (1999) CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci U S A 96:8681–8686PubMedCentralPubMedGoogle Scholar
  65. 65.
    Curtin K, Slattery ML, Samowitz WS (2011) CpG island methylation in colorectal cancer: past, present and future. Patholog Res Int 2011:902674PubMedCentralPubMedGoogle Scholar
  66. 66.
    Issa JP, Vertino PM, Wu J, Sazawal S, Celano P, Nelkin BD et al (1993) Increased cytosine DNA-methyltransferase activity during colon cancer progression. J Natl Cancer Inst 85:1235–1240PubMedGoogle Scholar
  67. 67.
    Easwaran HP, Van Neste L, Cope L, Sen S, Mohammad HP, Pageau GJ et al (2010) Aberrant silencing of cancer-related genes by CpG hypermethylation occurs independently of their spatial organization in the nucleus. Cancer Res 70:8015–8024PubMedCentralPubMedGoogle Scholar
  68. 68.
    Esteller M (2007) Epigenetic gene silencing in cancer: the DNA hypermethylome. Hum Mol Genet 16(Spec No 1):R50–R59PubMedGoogle Scholar
  69. 69.
    Topkan E, Onal HC, Yavuz MN (2008) Managing liver metastases with conformal radiation therapy. J Support Oncol 6(1):9–13, 15PubMedGoogle Scholar
  70. 70.
    Rodriguez-Bigas MA, Chang GJ, Skibber JM (2010) Multidisciplinary approach to recurrent/unresectable rectal cancer: how to prepare for the extent of resection. Surg Oncol Clin N Am 19:847–859PubMedGoogle Scholar
  71. 71.
    Herman J, Messer(SMI)th W, Suh WW, Blackstock W, Cosman BC, Mohiuddin M et al (2010) ACR Appropriateness Criteria: rectal cancer-metastatic disease at presentation. Curr Probl Cancer 34:201–210Google Scholar
  72. 72.
    Rodriguez AM, Kuo YF, Goodwin JS (2014) Risk of colorectal cancer among long-term cervical cancer survivors. Med Oncol 31:943PubMedGoogle Scholar
  73. 73.
    Musunuru H, Mason M, Murray L, Al-Qaisieh B, Bownes P, (SMI)th J et al (2014) Second primary cancers occurring after I-125 brachytherapy as monotherapy for early prostate cancer. Clin Oncol (R Coll Radiol) 26:210–215Google Scholar
  74. 74.
    Murray L, Henry A, Hoskin P, Siebert FA, Venselaar J, PgotG ESTRO (2014) Second primary cancers after radiation for prostate cancer: a systematic review of the clinical data and impact of treatment technique. Radiother Oncol 110:213–228Google Scholar
  75. 75.
    Sautter-Bihl ML, Sedlmayer F (2013) [Second primary cancers after radiotherapy in breast cancer patients]. Strahlentherapie und Onkologie: Organ der Deutschen Rontgengesellschaft [et al.] Strahlenther Onkol 189:902–903PubMedGoogle Scholar
  76. 76.
    Longley DB, Harkin DP, Johnston PG (2003) 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 3:330–338PubMedGoogle Scholar
  77. 77.
    Heidelberger C, Chaudhuri NK, Danneberg P, Mooren D, Griesbach L, Duschinsky R et al (1957) Fluorinated pyrimidines, a new class of tumour-inhibitory compounds. Nature 179:663–666PubMedGoogle Scholar
  78. 78.
    Johnston PG, Kaye S (2001) Capecitabine: a novel agent for the treatment of solid tumors. Anticancer Drugs 12:639–646PubMedGoogle Scholar
  79. 79.
    Wyeth-Canada. Lederle LEUCOVORIN® calcium folinate tablets Product Monograph. Montreal, Quebec2004Google Scholar
  80. 80.
    Iwamoto S, Hazama S, Kato T, Miyake Y, Fukunaga M, Matsuda C et al (2014) Multicenter phase II study of second-line cetuximab plus folinic acid/5-fluorouracil/irinotecan (FOLFIRI) in KRAS wild-type metastatic colorectal cancer: the FLIER study. Anticancer Res 34:1967–1973PubMedGoogle Scholar
  81. 81.
    Morganti AG, Mignogna S, Caravatta L, Deodato F, Macchia G, Plantamura NM et al (2014) FOLFIRI-bevacizumab and concurrent low-dose radiotherapy in metastatic colorectal cancer: preliminary results of a phase I-II study. J Chemother :1973947813Y0000000163 [Epub ahead of print]Google Scholar
  82. 82.
    Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M et al (2014) Final results from PRIME: randomized phase 3 study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol 25:1346–1355PubMedGoogle Scholar
  83. 83.
    Loree JM, Mulder KE, Ghosh S, Spratlin JL (2014) CAPOX associated with toxicities of higher grade but improved disease-free survival when compared with FOLFOX in the adjuvant treatment of stage III colon cancer. Clin Colorectal Cancer 13:172–177PubMedGoogle Scholar
  84. 84.
    Dobzhansky T (1946) Genetics of natural populations. Xiii. Recombination and variability in populations of drosophila pseudoobscura. Genetics 31:269–290PubMedCentralGoogle Scholar
  85. 85.
    Davierwala AP, Haynes J, Li Z, Brost RL, Robinson MD, Yu L et al (2005) The synthetic genetic interaction spectrum of essential genes. Nat Genet 37:1147–1152PubMedGoogle Scholar
  86. 86.
    Measday V, Baetz K, Guzzo J, Yuen K, Kwok T, Sheikh B et al (2005) Systematic yeast synthetic lethal and synthetic dosage lethal screens identify genes required for chromosome segregation. Proc Natl Acad Sci U S A 102:13956–13961PubMedCentralPubMedGoogle Scholar
  87. 87.
    Pan X, Yuan DS, Xiang D, Wang X, Sookhai-Mahadeo S, Bader JS et al (2004) A robust toolkit for functional profiling of the yeast genome. Mol Cell 16:487–496PubMedGoogle Scholar
  88. 88.
    Tong AH, Evangelista M, Parsons AB, Xu H, Bader GD, Page N et al (2001) Systematic genetic analysis with ordered arrays of yeast deletion mutants. Science 294:2364–2368PubMedGoogle Scholar
  89. 89.
    Tong AH, Lesage G, Bader GD, Ding H, Xu H, Xin X et al (2004) Global mapping of the yeast genetic interaction network. Science 303:808–813PubMedGoogle Scholar
  90. 90.
    Collins SR, Miller KM, Maas NL, Roguev A, Fillingham J, Chu CS et al (2007) Functional dissection of protein complexes involved in yeast chromosome biology using a genetic interaction map. Nature 446:806–810PubMedGoogle Scholar
  91. 91.
    Fiedler D, Braberg H, Mehta M, Chechik G, Cagney G, Mukherjee P et al (2009) Functional organization of the S. cerevisiae phosphorylation network. Cell 136:952–963PubMedCentralPubMedGoogle Scholar
  92. 92.
    Lin YY, Qi Y, Lu JY, Pan X, Yuan DS, Zhao Y et al (2008) A comprehensive synthetic genetic interaction network governing yeast histone acetylation and deacetylation. Genes Dev 22:2062–2074PubMedCentralPubMedGoogle Scholar
  93. 93.
    Montpetit B, Thorne K, Barrett I, Andrews K, Jadusingh R, Hieter P et al (2005) Genome-wide synthetic lethal screens identify an interaction between the nuclear envelope protein, Apq12p, and the kinetochore in Saccharomyces cerevisiae. Genetics 171:489–501PubMedCentralPubMedGoogle Scholar
  94. 94.
    Zhao R, Davey M, Hsu YC, Kaplanek P, Tong A, Parsons AB et al (2005) Navigating the chaperone network: an integrative map of physical and genetic interactions mediated by the hsp90 chaperone. Cell 120:715–727PubMedGoogle Scholar
  95. 95.
    Hartwell LH, Szankasi P, Roberts CJ, Murray AW, Friend SH (1997) Integrating genetic approaches into the discovery of anticancer drugs. Science 278:1064–1068PubMedGoogle Scholar
  96. 96.
    Dixon SJ, Fedyshyn Y, Koh JL, Prasad TS, Chahwan C, Chua G et al (2008) Significant conservation of synthetic lethal genetic interaction networks between distantly related eukaryotes. Proc Natl Acad Sci U S A 105:16653–16658PubMedCentralPubMedGoogle Scholar
  97. 97.
    McManus KJ, Barrett IJ, Nouhi Y, Hieter P (2009) Specific synthetic lethal killing of RAD54B-deficient human colorectal cancer cells by FEN1 silencing. Proc Natl Acad Sci U S A 106:3276–3281PubMedCentralPubMedGoogle Scholar
  98. 98.
    Cancer Genome Atlas Network (2012) Comprehensive molecular portraits of human breast tumours. Nature 490:61–70Google Scholar
  99. 99.
    Cancer Genome Atlas Network (2012) Comprehensive molecular characterization of human colon and rectal cancer. Nature 487:330–337Google Scholar
  100. 100.
    Cancer Genome Atlas Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068Google Scholar
  101. 101.
    Cancer Genome Atlas Research Network (2011) Integrated genomic analyses of ovarian carcinoma. Nature 474:609–615Google Scholar
  102. 102.
    Cancer Genome Atlas Research Network (2012) Comprehensive genomic characterization of squamous cell lung cancers. Nature 489:519–525Google Scholar
  103. 103.
    Roy R, Chun J, Powell SN (2012) BRCA1 and BRCA2: different roles in a common pathway of genome protection. Nat Rev Cancer 12:68–78Google Scholar
  104. 104.
    El-Khamisy SF, Masutani M, Suzuki H, Caldecott KW (2003) A requirement for PARP-1 for the assembly or stability of XRCC1 nuclear foci at sites of oxidative DNA damage. Nucleic Acids Res 31:5526–5533PubMedCentralPubMedGoogle Scholar
  105. 105.
    Okano S, Lan L, Caldecott KW, Mori T, Yasui A (2003) Spatial and temporal cellular responses to single-strand breaks in human cells. Mol Cell Biol 23:3974–3981PubMedCentralPubMedGoogle Scholar
  106. 106.
    Strom CE, Johansson F, Uhlen M, Szigyarto CA, Erixon K, Helleday T (2011) Poly (ADP-ribose) polymerase (PARP) is not involved in base excision repair but PARP inhibition traps a single-strand intermediate. Nucleic Acids Res 39:3166–3175PubMedCentralPubMedGoogle Scholar
  107. 107.
    Kraus WL, Hottiger MO (2013) PARP-1 and gene regulation: progress and puzzles. Mol Aspects Med 34:1109–1123PubMedGoogle Scholar
  108. 108.
    Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E et al (2005) Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434:913–917PubMedGoogle Scholar
  109. 109.
    Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB et al (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434:917–921PubMedGoogle Scholar
  110. 110.
    Papeo G, Casale E, Montagnoli A, Cirla A (2013) PARP inhibitors in cancer therapy: an update. Expert Opin Ther Pat 23:503–514PubMedGoogle Scholar
  111. 111.
    van Pel DM, Barrett IJ, Shimizu Y, Sajesh BV, Guppy BJ, Pfeifer T et al (2013) An evolutionarily conserved synthetic lethal interaction network identifies FEN1 as a broad-spectrum target for anticancer therapeutic development. PLoS Genet 9:e1003254PubMedCentralPubMedGoogle Scholar
  112. 112.
    Sajesh BV, Bailey M, Lichtensztejn Z, Hieter P, McManus KJ (2013) Synthetic lethal targeting of superoxide dismutase 1 selectively kills RAD54B-deficient colorectal cancer cells. Genetics 195:757–767PubMedCentralPubMedGoogle Scholar
  113. 113.
    Culotta VC, Klomp LW, Strain J, Casareno RL, Krems B, Gitlin JD (1997) The copper chaperone for superoxide dismutase. J Biol Chem 272:23469–23472PubMedGoogle Scholar
  114. 114.
    Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA et al (2012) The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2:401–404PubMedGoogle Scholar
  115. 115.
    Reinhardt HC, Schumacher B (2012) The p53 network: cellular and systemic DNA damage responses in aging and cancer. Trends Genet 28:128–136PubMedCentralPubMedGoogle Scholar
  116. 116.
    Hamelin R, Laurent-Puig P, Olschwang S, Jego N, Asselain B, Remvikos Y et al (1994) Association of p53 mutations with short survival in colorectal cancer. Gastroenterology 106:42–48PubMedGoogle Scholar
  117. 117.
    Leroy K, Haioun C, Lepage E, Le Metayer N, Berger F, Labouyrie E et al (2002) p53 gene mutations are associated with poor survival in low and low-intermediate risk diffuse large B-cell lymphomas. Ann Oncol 13:1108–1115PubMedGoogle Scholar
  118. 118.
    Wattel E, Preudhomme C, Hecquet B, Vanrumbeke M, Quesnel B, Dervite I et al (1994) p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies. Blood 84:3148–3157PubMedGoogle Scholar
  119. 119.
    Xie L, Gazin C, Park SM, Zhu LJ, Debily MA, Kittler EL et al (2012) A synthetic interaction screen identifies factors selectively required for proliferation and TERT transcription in p53-deficient human cancer cells. PLoS Genet 8:e1003151PubMedCentralPubMedGoogle Scholar
  120. 120.
    Marechal A, Zou L (2013) DNA damage sensing by the ATM and ATR kinases. Cold Spring Harb Perspect Biol 5(9):a012716Google Scholar
  121. 121.
    Oh S, Shin S, Janknecht R (2012) ETV1, 4 and 5: an oncogenic subfamily of ETS transcription factors. Biochim Biophys Acta 1826:1–12PubMedCentralPubMedGoogle Scholar
  122. 122.
    Kroll ES, Hyland KM, Hieter P, Li JJ (1996) Establishing genetic interactions by a synthetic dosage lethality phenotype. Genetics 143:95–102PubMedCentralPubMedGoogle Scholar
  123. 123.
    Yan H, Gibson S, Tye BK (1991) Mcm2 and Mcm3, two proteins important for ARS activity, are related in structure and function. Genes Dev 5:944–957PubMedGoogle Scholar
  124. 124.
    Li JJ, Herskowitz I (1993) Isolation of ORC6, a component of the yeast origin recognition complex by a one-hybrid system. Science 262:1870–1874PubMedGoogle Scholar
  125. 125.
    Sajesh BV, Guppy BJ, McManus KJ (2013) Synthetic genetic targeting of genome instability in cancer. Cancers (Basel) 5:739–761Google Scholar
  126. 126.
    Normanno N, Tejpar S, Morgillo F, De Luca A, Van Cutsem E, Ciardiello F (2009) Implications for KRAS status and EGFR-targeted therapies in metastatic CRC. Nat Rev Clin Oncol 6:519–527PubMedGoogle Scholar
  127. 127.
    Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D (2011) RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer 11:761–774PubMedCentralPubMedGoogle Scholar
  128. 128.
    Tan C, Du X (2012) KRAS mutation testing in metastatic colorectal cancer. World J Gastroenterol 18:5171–5180PubMedCentralPubMedGoogle Scholar
  129. 129.
    Neumann J, Zeindl-Eberhart E, Kirchner T, Jung A (2009) Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer. Pathol Res Pract 205:858–862PubMedGoogle Scholar
  130. 130.
    Barbie DA, Tamayo P, Boehm JS, Kim SY, Moody SE, Dunn IF et al (2009) Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature 462:108–112PubMedCentralPubMedGoogle Scholar
  131. 131.
    Luo J, Emanuele MJ, Li D, Creighton CJ, Schlabach MR, Westbrook TF et al (2009) A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 137:835–848PubMedCentralPubMedGoogle Scholar
  132. 132.
    Scholl C, Frohling S, Dunn IF, Schinzel AC, Barbie DA, Kim SY et al (2009) Synthetic lethal interaction between oncogenic KRAS dependency and STK33 suppression in human cancer cells. Cell 137:821–834PubMedGoogle Scholar
  133. 133.
    Brauksiepe B, Mujica AO, Herrmann H, Schmidt ER (2008) The Serine/threonine kinase Stk33 exhibits autophosphorylation and phosphorylates the intermediate filament protein Vimentin. BMC Biochem 9:25PubMedCentralPubMedGoogle Scholar
  134. 134.
    Babij C, Zhang Y, Kurzeja RJ, Munzli A, Shehabeldin A, Fernando M et al (2011) STK33 kinase activity is nonessential in KRAS-dependent cancer cells. Cancer Res 71:5818–5826PubMedGoogle Scholar
  135. 135.
    Spankuch-Schmitt B, Bereiter-Hahn J, Kaufmann M, Strebhardt K (2002) Effect of RNA silencing of polo-like kinase-1 (PLK1) on apoptosis and spindle formation in human cancer cells. J Natl Cancer Inst 94:1863–1877PubMedGoogle Scholar
  136. 136.
    Liu X, Erikson RL (2003) Polo-like kinase (Plk)1 depletion induces apoptosis in cancer cells. Proc Natl Acad Sci U S A 100:5789–5794PubMedCentralPubMedGoogle Scholar
  137. 137.
    Sun C, Hobor S, Bertotti A, Zecchin D, Huang S, Galimi F et al (2014) Intrinsic resistance to MEK inhibition in KRAS mutant lung and colon cancer through transcriptional induction of ERBB3. Cell Rep 7:86–93PubMedGoogle Scholar
  138. 138.
    Bernards R (2012) A missing link in genotype-directed cancer therapy. Cell 151:465–468PubMedGoogle Scholar
  139. 139.
    Ebi H, Faber AC, Engelman JA, Yano S (2014) Not just gRASping at flaws: finding vulnerabilities to develop novel therapies for treating KRAS mutant cancers. Cancer Sci 105:499–505PubMedGoogle Scholar
  140. 140.
    Migliardi G, Sassi F, Torti D, Galimi F, Zanella ER, Buscarino M et al (2012) Inhibition of MEK and PI3K/mTOR suppresses tumor growth but does not cause tumor regression in patient-derived xenografts of RAS-mutant colorectal carcinomas. Clin Cancer Res 18:2515–2525PubMedGoogle Scholar
  141. 141.
    Steckel M, Molina-Arcas M, Weigelt B, Marani M, Warne PH, Kuznetsov H et al (2012) Determination of synthetic lethal interactions in KRAS oncogene-dependent cancer cells reveals novel therapeutic targeting strategies. Cell Res 22:1227–1245PubMedCentralPubMedGoogle Scholar
  142. 142.
    Corcoran RB, Cheng KA, Hata AN, Faber AC, Ebi H, Coffee EM et al (2013) Synthetic lethal interaction of combined BCL-XL and MEK inhibition promotes tumor regressions in KRAS mutant cancer models. Cancer Cell 23:121–128PubMedCentralPubMedGoogle Scholar
  143. 143.
    Furey TS (2012) ChIP-seq and beyond: new and improved methodologies to detect and characterize protein-DNA interactions. Nat Rev Genet 13:840–852PubMedCentralPubMedGoogle Scholar
  144. 144.
    Neff T, Armstrong SA (2009) Chromatin maps, histone modifications and leukemia. Leukemia 23:1243–1251PubMedGoogle Scholar
  145. 145.
    Robertson AG, Bilenky M, Tam A, Zhao Y, Zeng T, Thiessen N et al (2008) Genome-wide relationship between histone H3 lysine 4 mono-and tri-methylation and transcription factor binding. Genome Res 18:1906–1917PubMedCentralPubMedGoogle Scholar
  146. 146.
    Varley KE, Gertz J, Bowling KM, Parker SL, Reddy TE, Pauli-Behn F et al (2013) Dynamic DNA methylation across diverse human cell lines and tissues. Genome Res 23:555–567PubMedCentralPubMedGoogle Scholar
  147. 147.
    Australian Institute of Health and Welfare & Australasian Association of Cancer Registries (2012) Cancer in Australia: an overview, 2012. Cancer series no. 74. Cat. no. CAN 70. Canberra, Australia: AIHWGoogle Scholar
  148. 148.
    Canadian Cancer Society’s Advisory Committee on Cancer Statistics (2013) Canadian cancer statistics 2013. Toronto: Canadian Cancer SocietyGoogle Scholar
  149. 149.
    Cancer Research UK (2014) Cancer statistics report: cancer incidence and mortality in the UK. London: Cancer Research UKGoogle Scholar
  150. 150.
    American Cancer Society.(2014) Colorectal cancer facts & figs. 2014–2016. Atlanta: American Cancer SocietyGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Manitoba Institute of Cell Biology, Department of Biochemistry and Medical GeneticsUniversity of ManitobaWinnipegCanada

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