1932

Abstract

The search for somatic mutations that drive the initiation and progression of human tumors has dominated recent cancer research. While much emphasis has been placed on characterizing the prevalence and function of driver mutations, comparatively less is known about their serial genetic evolution. Indeed, study of this phenomenon has largely focused on tumor-suppressor genes recessive at the cellular level or mechanisms of resistance in tumors with mutant oncogenes targeted by therapy. There is, however, a growing appreciation that despite a decades-old presumption of heterozygosity, changes in mutant oncogene zygosity are common and drive dosage and stoichiometry changes that lead to selective growth advantages. Here, we review the recent progress in understanding mutant allele imbalance and its implications for tumor biology, cancer evolution, and response to anticancer therapy.

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2021-03-04
2024-04-19
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Literature Cited

  1. Ambrogio C, Köhler J, Zhou Z-W, Wang H, Paranal R et al. 2018. KRAS dimerization impacts MEK inhibitor sensitivity and oncogenic activity of mutant KRAS. Cell 172:4857–68.e15
    [Google Scholar]
  2. Avner P, Heard E. 2001. X-chromosome inactivation: counting, choice and initiation. Nat. Rev. Genet. 2:159–67
    [Google Scholar]
  3. Baca SC, Prandi D, Lawrence MS, Mosquera JM, Romanel A et al. 2013. Punctuated evolution of prostate cancer genomes. Cell 153:3666–77
    [Google Scholar]
  4. Bentley C, Jurinka SS, Kljavin NM, Vartanian S, Ramani SR et al. 2013. A requirement for wild-type Ras isoforms in mutant KRas-driven signalling and transformation. Biochem. J. 452:2313–20
    [Google Scholar]
  5. Berenjeno IM, Piñeiro R, Castillo SD, Pearce W, McGranahan N et al. 2017. Oncogenic PIK3CA induces centrosome amplification and tolerance to genome doubling. Nat. Commun. 8:11773
    [Google Scholar]
  6. Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S et al. 2010. The landscape of somatic copy-number alteration across human cancers. Nature 463:7283899–905
    [Google Scholar]
  7. Bielski CM, Donoghue MTA, Gadiya M, Hanrahan AJ, Won HH et al. 2018a. Widespread selection for oncogenic mutant allele imbalance in cancer. Cancer Cell 34:5852–62.e4
    [Google Scholar]
  8. Bielski CM, Zehir A, Penson AV, Donoghue MTA, Chatila W et al. 2018b. Genome doubling shapes the evolution and prognosis of advanced cancers. Nat. Genet. 50:81189–95
    [Google Scholar]
  9. Birchler JA, Bhadra U, Bhadra MP, Auger DL 2001. Dosage-dependent gene regulation in multicellular eukaryotes: implications for dosage compensation, aneuploid syndromes, and quantitative traits. Dev. Biol. 234:2275–88
    [Google Scholar]
  10. Birchler JA, Riddle NC, Auger DL, Veitia RA 2005. Dosage balance in gene regulation: biological implications. Trends Genet 21:4219–26
    [Google Scholar]
  11. Blakeslee AF, Belling J, Farnham ME 1920. Chromosomal duplication and mendelian phenomena in Datura mutants. Science 52:1347388–90
    [Google Scholar]
  12. Bremner R, Balmain A. 1990. Genetic changes in skin tumor progression: correlation between presence of a mutant ras gene and loss of heterozygosity on mouse chromosome 7. Cell 61:3407–17
    [Google Scholar]
  13. Brenan L, Andreev A, Cohen O, Pantel S, Kamburov A et al. 2016. Phenotypic characterization of a comprehensive set of MAPK1/ERK2 missense mutants. Cell Rep 17:41171–83
    [Google Scholar]
  14. Burgess MR, Hwang E, Mroue R, Bielski CM, Wandler AM et al. 2017. KRAS allelic imbalance enhances fitness and modulates MAP kinase dependence in cancer. Cell 168:5817–29.e15
    [Google Scholar]
  15. Canon J, Rex K, Saiki AY, Mohr C, Cooke K et al. 2019. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature 575:7781217–23
    [Google Scholar]
  16. Carter NP. 2007. Methods and strategies for analyzing copy number variation using DNA microarrays. Nat. Genet. 39:S16–21
    [Google Scholar]
  17. Carter SL, Cibulskis K, Helman E, McKenna A, Shen H et al. 2012. Absolute quantification of somatic DNA alterations in human cancer. Nat. Biotechnol. 30:5413–21
    [Google Scholar]
  18. Chakravarty D, Gao J, Phillips SM, Kundra R, Zhang H et al. 2017. OncoKB: a precision oncology knowledge base. JCO Precis. Oncol.
    [Google Scholar]
  19. Collins S, Groudine M. 1982. Amplification of endogenous myc-related DNA sequences in a human myeloid leukaemia cell line. Nature 298:5875679–81
    [Google Scholar]
  20. Corcoran RB, Dias-Santagata D, Bergethon K, Iafrate AJ, Settleman J, Engelman JA 2010. BRAF gene amplification can promote acquired resistance to MEK inhibitors in cancer cells harboring the BRAF V600E mutation. Sci. Signal. 3:149ra84
    [Google Scholar]
  21. Dalla-Favera R, Wong-Staal F, Gallo RC 1982. onc gene amplification in promyelocytic leukaemia cell line HL-60 and primary leukaemic cells of the same patient. Nature 299:587861–63
    [Google Scholar]
  22. Davies BR, Greenwood H, Dudley P, Crafter C, Yu D-H et al. 2012. Preclinical pharmacology of AZD5363, an inhibitor of AKT: pharmacodynamics, antitumor activity, and correlation of monotherapy activity with genetic background. Mol. Cancer Ther. 11:4873–87
    [Google Scholar]
  23. Dewhurst SM, McGranahan N, Burrell RA, Rowan AJ, Grönroos E et al. 2014. Tolerance of whole-genome doubling propagates chromosomal instability and accelerates cancer genome evolution. Cancer Discov 4:2175–85
    [Google Scholar]
  24. Downward J. 2003. Targeting RAS signalling pathways in cancer therapy. Nat. Rev. Cancer 3:111–22
    [Google Scholar]
  25. Dvinge H, Kim E, Abdel-Wahab O, Bradley RK 2016. RNA splicing factors as oncoproteins and tumour suppressors. Nat. Rev. Cancer 16:7413–30
    [Google Scholar]
  26. Ercan D, Zejnullahu K, Yonesaka K, Xiao Y, Capelletti M et al. 2010. Amplification of EGFR T790M causes resistance to an irreversible EGFR inhibitor. Oncogene 29:162346–56
    [Google Scholar]
  27. Gao Y, Chang MT, McKay D, Na N, Zhou B et al. 2018. Allele-specific mechanisms of activation of MEK1 mutants determine their properties. Cancer Discov 8:5648–61
    [Google Scholar]
  28. Garraway LA, Lander ES. 2013. Lessons from the cancer genome. Cell 153:117–37
    [Google Scholar]
  29. Gonçalves E, Fragoulis A, Garcia-Alonso L, Cramer T, Saez-Rodriguez J, Beltrao P 2017. Widespread post-transcriptional attenuation of genomic copy-number variation in cancer. Cell Syst 5:4386–98.e4
    [Google Scholar]
  30. Gorelick AN, Sánchez-Rivera FJ, Cai Y, Bielski CM, Biederstedt E et al. 2020. Phase and context shape the function of composite oncogenic mutations. Nature 582:7810100–3
    [Google Scholar]
  31. Gould SJ, Vrba ES. 1982. Exaptation—a missing term in the science of form. Paleobiology 8:014–15
    [Google Scholar]
  32. Gustin JP, Karakas B, Weiss MB, Abukhdeir AM, Lauring J et al. 2009. Knockin of mutant PIK3CA activates multiple oncogenic pathways. PNAS 106:82835–40
    [Google Scholar]
  33. Haigis KM. 2017. KRAS alleles: The devil is in the detail. Trends Cancer 3:10686–97
    [Google Scholar]
  34. Hallin J, Engstrom LD, Hargis L, Calinisan A, Aranda R et al. 2020. The KRASG12C inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients. Cancer Discov 10:154–71
    [Google Scholar]
  35. Hanahan D, Weinberg RA. 2000. The hallmarks of cancer. Cell 100:157–70
    [Google Scholar]
  36. Hyman DM, Smyth LM, Donoghue MTA, Westin SN, Bedard PL et al. 2017a. AKT inhibition in solid tumors with AKT1 mutations. J. Clin. Oncol. 35:202251–59
    [Google Scholar]
  37. Hyman DM, Taylor BS, Baselga J 2017b. Implementing genome-driven oncology. Cell 168:4584–99
    [Google Scholar]
  38. Isakoff SJ, Engelman JA, Irie HY, Luo J, Brachmann SM et al. 2005. Breast cancer–associated PIK3CA mutations are oncogenic in mammary epithelial cells. Cancer Res 65:2310992–11000
    [Google Scholar]
  39. Keppler-Noreuil KM, Rios JJ, Parker VER, Semple RK, Lindhurst MJ et al. 2015. PIK3CA-related overgrowth spectrum (PROS): diagnostic and testing eligibility criteria, differential diagnosis, and evaluation. Am. J. Med. Genet. A. 167:2287–95
    [Google Scholar]
  40. Kinross KM, Montgomery KG, Kleinschmidt M, Waring P, Ivetac I et al. 2012. An activating Pik3ca mutation coupled with Pten loss is sufficient to initiate ovarian tumorigenesis in mice. J. Clin. Investig. 122:2553–57
    [Google Scholar]
  41. Klein G. 1981. The role of gene dosage and genetic transpositions in carcinogenesis. Nature 294:5839313–18
    [Google Scholar]
  42. Knudson AG. 1971. Mutation and cancer: statistical study of retinoblastoma. PNAS 68:4820–23
    [Google Scholar]
  43. Koren S, Reavie L, Couto JP, De Silva D, Stadler MB et al. 2015. PIK3CAH1047R induces multipotency and multi-lineage mammary tumours. Nature 525:7567114–18
    [Google Scholar]
  44. Lee SC-W, Dvinge H, Kim E, Cho H, Micol J-B et al. 2016. Modulation of splicing catalysis for therapeutic targeting of leukemia with mutations in genes encoding spliceosomal proteins. Nat. Med. 22:6672–78
    [Google Scholar]
  45. Lee SC-W, North K, Kim E, Jang E, Obeng E et al. 2018. Synthetic lethal and convergent biological effects of cancer-associated spliceosomal gene mutations. Cancer Cell 34:2225–41.e8
    [Google Scholar]
  46. Liu P, Cheng H, Roberts TM, Zhao JJ 2009. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat. Rev. Drug Discov. 8:8627–44
    [Google Scholar]
  47. Liu P, Cheng H, Santiago S, Raeder M, Zhang F et al. 2011. Oncogenic PIK3CA-driven mammary tumors frequently recur via PI3K pathway–dependent and PI3K pathway–independent mechanisms. Nat. Med. 17:91116–20
    [Google Scholar]
  48. Maciejowski J, Li Y, Bosco N, Campbell PJ, de Lange T 2015. Chromothripsis and kataegis induced by telomere crisis. Cell 163:71641–54
    [Google Scholar]
  49. Madsen RR, Knox RG, Pearce W, Lopez S, Mahler-Araujo B et al. 2019. Oncogenic PIK3CA promotes cellular stemness in an allele dose-dependent manner. PNAS 116:178380–89
    [Google Scholar]
  50. Madsen RR, Vanhaesebroeck B, Semple RK 2018. Cancer-associated PIK3CA mutations in overgrowth disorders. Trends Mol. Med. 24:10856–70
    [Google Scholar]
  51. McCormick F. 2015. KRAS as a therapeutic target. Clin. Cancer Res. 21:81797–1801
    [Google Scholar]
  52. McGranahan N, Favero F, de Bruin EC, Birkbak NJ, Szallasi Z, Swanton C 2015. Clonal status of actionable driver events and the timing of mutational processes in cancer evolution. Sci. Transl. Med. 7:283283ra54
    [Google Scholar]
  53. Meyer DS, Brinkhaus H, Müller U, Müller M, Cardiff RD, Bentires-Alj M 2011. Luminal expression of PIK3CA mutant H1047R in the mammary gland induces heterogeneous tumors. Cancer Res 71:134344–51
    [Google Scholar]
  54. Meyerson M, Gabriel S, Getz G 2010. Advances in understanding cancer genomes through second-generation sequencing. Nat. Rev. Genet. 11:10685–96
    [Google Scholar]
  55. Mueller S, Engleitner T, Maresch R, Zukowska M, Lange S et al. 2018. Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes. Nature 554:769062–68
    [Google Scholar]
  56. Nan X, Tamgüney TM, Collisson EA, Lin L-J, Pitt C et al. 2015. Ras-GTP dimers activate the mitogen-activated protein kinase (MAPK) pathway. PNAS 112:267996–8001
    [Google Scholar]
  57. Nguyen DK, Disteche CM. 2006. Dosage compensation of the active X chromosome in mammals. Nat. Genet. 38:147–53
    [Google Scholar]
  58. Okabe T, Okamoto I, Tamura K, Terashima M, Yoshida T et al. 2007. Differential constitutive activation of the epidermal growth factor receptor in non–small cell lung cancer cells bearing EGFR gene mutation and amplification. Cancer Res 67:52046–53
    [Google Scholar]
  59. Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM 2013. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503:7477548–51
    [Google Scholar]
  60. Patricelli MP, Janes MR, Li L-S, Hansen R, Peters U et al. 2016. Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state. Cancer Discov 6:3316–29
    [Google Scholar]
  61. Pires JC, Conant GC. 2016. Robust yet fragile: expression noise, protein misfolding, and gene dosage in the evolution of genomes. Annu. Rev. Genet. 50:113–31
    [Google Scholar]
  62. Raznahan A, Parikshak NN, Chandran V, Blumenthal JD, Clasen LS et al. 2018. Sex-chromosome dosage effects on gene expression in humans. PNAS 115:287398–403
    [Google Scholar]
  63. Rodon J, Dienstmann R, Serra V, Tabernero J 2013. Development of PI3K inhibitors: lessons learned from early clinical trials. Nat. Rev. Clin. Oncol. 10:3143–53
    [Google Scholar]
  64. Saito Y, Koya J, Araki M, Kogure Y, Shingaki S et al. 2020. Landscape and function of multiple mutations within individual oncogenes. Nature 582:781095–99
    [Google Scholar]
  65. Shen R, Seshan VE. 2016. FACETS: allele-specific copy number and clonal heterogeneity analysis tool for high-throughput DNA sequencing. Nucleic Acids Res 44:16e131
    [Google Scholar]
  66. Smyth LM, Piha-Paul SA, Won HH, Schram AM, Saura C et al. 2020. Efficacy and determinants of response to HER kinase inhibition in HER2-mutant metastatic breast cancer. Cancer Discov 10:2198–213
    [Google Scholar]
  67. Speicher MR, Carter NP. 2005. The new cytogenetics: blurring the boundaries with molecular biology. Nat. Rev. Genet. 6:10782–92
    [Google Scholar]
  68. Stephen AG, Esposito D, Bagni RK, McCormick F 2014. Dragging Ras back in the ring. Cancer Cell 25:3272–81
    [Google Scholar]
  69. Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR et al. 2011. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144:127–40
    [Google Scholar]
  70. Stingele S, Stoehr G, Peplowska K, Cox J, Mann M, Storchova Z 2012. Global analysis of genome, transcriptome and proteome reveals the response to aneuploidy in human cells. Mol. Syst. Biol. 8:608
    [Google Scholar]
  71. Tikoo A, Roh V, Montgomery KG, Ivetac I, Waring P et al. 2012. Physiological levels of Pik3caH1047R mutation in the mouse mammary gland results in ductal hyperplasia and formation of ERα-positive tumors. PLOS ONE 7:5e36924
    [Google Scholar]
  72. To MD, Rosario RD, Westcott PMK, Banta KL, Balmain A 2013. Interactions between wild-type and mutant Ras genes in lung and skin carcinogenesis. Oncogene 32:344028–33
    [Google Scholar]
  73. Toy W, Shen Y, Won H, Green B, Sakr RA et al. 2013. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat. Genet. 45:121439–45
    [Google Scholar]
  74. Umbreit NT, Zhang C-Z, Lynch LD, Blaine LJ, Cheng AM et al. 2020. Mechanisms generating cancer genome complexity from a single cell division error. Science 368:6488eaba0712
    [Google Scholar]
  75. Van Keymeulen A, Lee MY, Ousset M, Brohée S, Rorive S et al. 2015. Reactivation of multipotency by oncogenic PIK3CA induces breast tumour heterogeneity. Nature 525:7567119–23
    [Google Scholar]
  76. Van Loo P, Nordgard SH, Lingjærde OC, Russnes HG, Rye IH et al. 2010. Allele-specific copy number analysis of tumors. PNAS 107:3916910–15
    [Google Scholar]
  77. Varmus HE. 1984. The molecular genetics of cellular oncogenes. Annu. Rev. Genet. 18:553–612
    [Google Scholar]
  78. Vasan N, Razavi P, Johnson JL, Shao H, Shah H et al. 2019. Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3Kα inhibitors. Science 366:6466714–23
    [Google Scholar]
  79. Vivanco I, Sawyers CL. 2002. The phosphatidylinositol 3-kinase–AKT pathway in human cancer. Nat. Rev. Cancer 2:7489–501
    [Google Scholar]
  80. Wang YK, Bashashati A, Anglesio MS, Cochrane DR, Grewal DS et al. 2017. Genomic consequences of aberrant DNA repair mechanisms stratify ovarian cancer histotypes. Nat. Genet. 49:6856–65
    [Google Scholar]
  81. Westcott PMK, Halliwill KD, To MD, Rashid M, Rust AG et al. 2015. The mutational landscapes of genetic and chemical models of Kras-driven lung cancer. Nature 517:7535489–92
    [Google Scholar]
  82. Yao Z, Torres NM, Tao A, Gao Y, Luo L et al. 2015. BRAF mutants evade ERK-dependent feedback by different mechanisms that determine their sensitivity to pharmacologic inhibition. Cancer Cell 28:3370–83
    [Google Scholar]
  83. Yao Z, Yaeger R, Rodrik-Outmezguine VS, Tao A, Torres NM et al. 2017. Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS. Nature 548:7666234–38
    [Google Scholar]
  84. Yoshida K, Sanada M, Shiraishi Y, Nowak D, Nagata Y et al. 2011. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 478:736764–69
    [Google Scholar]
  85. Yuan TL, Cantley LC. 2008. PI3K pathway alterations in cancer: variations on a theme. Oncogene 27:415497–510
    [Google Scholar]
  86. Yuan W, Stawiski E, Janakiraman V, Chan E, Durinck S et al. 2013. Conditional activation of Pik3caH1047R in a knock-in mouse model promotes mammary tumorigenesis and emergence of mutations. Oncogene 32:3318–26
    [Google Scholar]
  87. Yueh AE, Payne SN, Leystra AA, Van De Hey DR, Foley TM et al. 2016. Colon cancer tumorigenesis initiated by the H1047R mutant PI3K. PLOS ONE 11:2e0148730
    [Google Scholar]
  88. Zack TI, Schumacher SE, Carter SL, Cherniack AD, Saksena G et al. 2013. Pan-cancer patterns of somatic copy number alteration. Nat. Genet. 45:101134–40
    [Google Scholar]
  89. Zhang Z, Wang Y, Vikis HG, Johnson L, Liu G et al. 2001. Wildtype Kras2 can inhibit lung carcinogenesis in mice. Nat. Genet. 29:125–33
    [Google Scholar]
  90. Zhou Q, Derti A, Ruddy D, Rakiec D, Kao I et al. 2015. A chemical genetics approach for the functional assessment of novel cancer genes. Cancer Res 75:101949–58
    [Google Scholar]
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