Biological and Therapeutic Impact of Intratumor Heterogeneity in Cancer Evolution
2015; Cell Press; Volume: 27; Issue: 1 Linguagem: Inglês
10.1016/j.ccell.2014.12.001
ISSN1878-3686
AutoresNicholas McGranahan, Charles Swanton,
Tópico(s)Cancer-related Molecular Pathways
ResumoPrecision medicine requires an understanding of cancer genes and mutational processes, as well as an appreciation of the extent to which these are found heterogeneously in cancer cells during tumor evolution. Here, we explore the processes shaping the cancer genome, placing these within the context of tumor evolution and their impact on intratumor heterogeneity and drug development. We review evidence for constraints and contingencies to tumor evolution and highlight the clinical implications of diversity within tumors. We outline the limitations of genome-driven targeted therapies and explore future strategies, including immune and adaptive approaches, to address this therapeutic challenge. Precision medicine requires an understanding of cancer genes and mutational processes, as well as an appreciation of the extent to which these are found heterogeneously in cancer cells during tumor evolution. Here, we explore the processes shaping the cancer genome, placing these within the context of tumor evolution and their impact on intratumor heterogeneity and drug development. We review evidence for constraints and contingencies to tumor evolution and highlight the clinical implications of diversity within tumors. We outline the limitations of genome-driven targeted therapies and explore future strategies, including immune and adaptive approaches, to address this therapeutic challenge. Given the size of the human diploid genome (∼6 billion base pairs), even without an elevated mutation rate, the potential for the acquisition of mutations over the course of a human lifetime is vast (Lynch, 2010Lynch M. Rate, molecular spectrum, and consequences of human mutation.Proc. Natl. Acad. Sci. USA. 2010; 107: 961-968Crossref PubMed Scopus (158) Google Scholar). Tumors sequenced at the exome level have been found to harbor anything from merely one or two to thousands of somatic aberrations, ranging from base-pair substitutions to whole-genome doublings. Tumors accumulate somatic aberrations through an evolutionary process (Nowell, 1976Nowell P.C. The clonal evolution of tumor cell populations.Science (New York, NY). 1976; 194: 23-28Crossref Google Scholar). While the majority of these aberrations are likely to be passenger events that do not provide any selective benefit to the cancer cell, a small subset will represent cancer driver events, conferring a selective advantage (Kandoth et al., 2013Kandoth C. McLellan M.D. Vandin F. Ye K. Niu B. Lu C. Xie M. Zhang Q. McMichael J.F. Wyczalkowski M.A. et al.Mutational landscape and significance across 12 major cancer types.Nature. 2013; 502: 333-339Crossref PubMed Scopus (146) Google Scholar, Lawrence et al., 2014Lawrence M.S. Stojanov P. Mermel C.H. Robinson J.T. Garraway L.A. Golub T.R. Meyerson M. Gabriel S.B. Lander E.S. Getz G. Discovery and saturation analysis of cancer genes across 21 tumour types.Nature. 2014; 505: 495-501Crossref PubMed Scopus (105) Google Scholar). Accumulating evidence suggests that not every mutation, whether driver or passenger, will be found in every cancer cell within a tumor (see reviews Swanton, 2012Swanton C. Intratumor heterogeneity: evolution through space and time.Cancer Res. 2012; 72: 4875-4882Crossref PubMed Scopus (93) Google Scholar, Yates and Campbell, 2012Yates L.R. Campbell P.J. Evolution of the cancer genome.Nat. Rev. Genet. 2012; 13: 795-806Crossref PubMed Scopus (64) Google Scholar). While the types and distribution of mutations across the genome in a cancer cell can be used to decipher the mutational processes that have been active during its evolutionary history (Helleday et al., 2014Helleday T. Eshtad S. Nik-Zainal S. Mechanisms underlying mutational signatures in human cancers.Nat. Rev. Genet. 2014; 15: 585-598Crossref PubMed Scopus (2) Google Scholar), the extent of heterogeneity and its dynamics over time can reveal a tumor’s life history (Burrell et al., 2013aBurrell R.A. McGranahan N. Bartek J. Swanton C. The causes and consequences of genetic heterogeneity in cancer evolution.Nature. 2013; 501: 338-345Crossref PubMed Scopus (93) Google Scholar, Yates and Campbell, 2012Yates L.R. Campbell P.J. Evolution of the cancer genome.Nat. Rev. Genet. 2012; 13: 795-806Crossref PubMed Scopus (64) Google Scholar). The heterogeneity observed within tumors and the myriad of genome instability processes that shape tumor evolution over space and time have important clinical implications and may reflect the mismatch between cost and benefit of some anticancer therapies (Fojo et al., 2014Fojo T. Mailankody S. Lo A. Unintended Consequences of Expensive Cancer Therapeutics-The Pursuit of Marginal Indications and a Me-Too Mentality That Stifles Innovation and Creativity: The John Conley Lecture.JAMA Otolaryngol. Head Neck Surg. 2014; (Published July 28, 2014)https://doi.org/10.1001/jamaoto.2014.1570Crossref PubMed Scopus (1) Google Scholar). For instance, between 2002 and 2012, of 71 anticancer drugs approved by the Food and Drug Administration, including 52 targeted medicines, the median overall survival benefit was 2.1 months, balanced against an estimated $10,000 per month on therapy at a cost of $2.7 million per life year saved (Kantarjian and Zwelling, 2013Kantarjian H. Zwelling L. Cancer drug prices and the free-market forces.Cancer. 2013; 119: 3903-3905Crossref PubMed Google Scholar). Targeted therapies will likely only have maximal efficacy when targeting somatic events present in all cancer cells and may be complicated by evidence that the number of cancer drivers in advanced tumors may be substantial (Gerlinger et al., 2014Gerlinger M. Horswell S. Larkin J. Rowan A.J. Salm M.P. Varela I. Fisher R. McGranahan N. Matthews N. Santos C.R. et al.Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing.Nat. Genet. 2014; 46: 225-233Crossref PubMed Scopus (27) Google Scholar). Moreover, increasing evidence is emerging for the presence of polygenic drug-resistance mechanisms in subclones prior to the initiation of therapy (Bozic et al., 2013Bozic I. Reiter J.G. Allen B. Antal T. Chatterjee K. Shah P. Moon Y.S. Yaqubie A. Kelly N. Le D.T. et al.Evolutionary dynamics of cancer in response to targeted combination therapy.eLife. 2013; 2: e00747Crossref Scopus (22) Google Scholar) and that low-frequency subclones can support the growth of the dominant clone. Future drug development strategies must therefore take into account clonal heterogeneity, as well as evidence that subclones can compete and synergize for growth in a symbiotic manner. In this review, we explore the processes shaping the cancer genome and place these in the context of intratumor heterogeneity. We review the extent to which rules for tumor evolution, which may guide precision medicine, can be deciphered and outline the clinical implications associated with diversity within tumors. Finally, we explore strategies that could be adopted to help address this therapeutic challenge. Genome instability processes result in an elevated rate of somatic aberrations, ranging from point mutations to chromosomal and whole-genome doublings. This instability can contribute to intratumor heterogeneity by providing a pool of mutations upon which selection can act in a given microenvironmental context (Burrell et al., 2013aBurrell R.A. McGranahan N. Bartek J. Swanton C. The causes and consequences of genetic heterogeneity in cancer evolution.Nature. 2013; 501: 338-345Crossref PubMed Scopus (93) Google Scholar). Thus, an understanding of genome instability processes is required to understand a biological basis for tumor heterogeneity. The characteristic mutations associated with a particular genome instability process can be considered a “mutational signature,” reflecting the imprint of the type of DNA damage that has occurred. Such mutational signatures may exist at both the nucleotide and chromosomal level simultaneously. For example, non-small-cell lung tumors (NSCLCs) from heavy cigarette smokers display a preponderance of C > A transversions and significantly more copy number gains and mutations compared with nonsmokers (Govindan et al., 2012Govindan R. Ding L. Griffith M. Subramanian J. Dees N.D. Kanchi K.L. Maher C.A. Fulton R. Fulton L. Wallis J. et al.Genomic landscape of non-small cell lung cancer in smokers and never-smokers.Cell. 2012; 150: 1121-1134Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar, Huang et al., 2011Huang Y.T. Lin X. Liu Y. Chirieac L.R. McGovern R. Wain J. Heist R. Skaug V. Zienolddiny S. Haugen A. et al.Cigarette smoking increases copy number alterations in nonsmall-cell lung cancer.Proc. Natl. Acad. Sci. USA. 2011; 108: 16345-16350Crossref PubMed Scopus (15) Google Scholar, Pleasance et al., 2010Pleasance E.D. Stephens P.J. O’Meara S. McBride D.J. Meynert A. Jones D. Lin M.L. Beare D. Lau K.W. Greenman C. et al.A small-cell lung cancer genome with complex signatures of tobacco exposure.Nature. 2010; 463: 184-190Crossref PubMed Scopus (505) Google Scholar), while colorectal cancers with endogenous mismatch repair deficiency exhibit an enrichment of C > T transitions, particularly at CpG sites, and generally show low levels of chromosomal alterations. Recently, mathematical frameworks have been developed to quantify the number and contributions of mutational signatures operating within cancers at the single-nucleotide level (Alexandrov et al., 2013Alexandrov L.B. Nik-Zainal S. Wedge D.C. Aparicio S.A. Behjati S. Biankin A.V. Bignell G.R. Bolli N. Borg A. Børresen-Dale A.L. et al.Australian Pancreatic Cancer Genome InitiativeICGC Breast Cancer ConsortiumICGC MMML-Seq ConsortiumICGC PedBrainSignatures of mutational processes in human cancer.Nature. 2013; 500: 415-421Crossref PubMed Scopus (210) Google Scholar, Fischer et al., 2013Fischer A. Illingworth C.J. Campbell P.J. Mustonen V. EMu: probabilistic inference of mutational processes and their localization in the cancer genome.Genome Biol. 2013; 14: R39Crossref PubMed Scopus (3) Google Scholar). Application of nonnegative matrix factorization to more than 7,000 tumors from over 30 cancer types identified 20 distinct mutational signatures (Alexandrov et al., 2013Alexandrov L.B. Nik-Zainal S. Wedge D.C. Aparicio S.A. Behjati S. Biankin A.V. Bignell G.R. Bolli N. Borg A. Børresen-Dale A.L. et al.Australian Pancreatic Cancer Genome InitiativeICGC Breast Cancer ConsortiumICGC MMML-Seq ConsortiumICGC PedBrainSignatures of mutational processes in human cancer.Nature. 2013; 500: 415-421Crossref PubMed Scopus (210) Google Scholar). The plethora of mutational signatures identified reflects the diverse array of endogenous and exogenous genome instability processes that can operate in cancers during evolution. Intriguingly, in many cases, the underlying etiology of these mutational signatures remains unknown (Helleday et al., 2014Helleday T. Eshtad S. Nik-Zainal S. Mechanisms underlying mutational signatures in human cancers.Nat. Rev. Genet. 2014; 15: 585-598Crossref PubMed Scopus (2) Google Scholar). In the majority of cancer samples analyzed, at least two mutational processes were identified, consistent with an elevated mutation rate in most cancers (Alexandrov et al., 2013Alexandrov L.B. Nik-Zainal S. Wedge D.C. Aparicio S.A. Behjati S. Biankin A.V. Bignell G.R. Bolli N. Borg A. Børresen-Dale A.L. et al.Australian Pancreatic Cancer Genome InitiativeICGC Breast Cancer ConsortiumICGC MMML-Seq ConsortiumICGC PedBrainSignatures of mutational processes in human cancer.Nature. 2013; 500: 415-421Crossref PubMed Scopus (210) Google Scholar). The most widespread mutational signature, identified in 25 cancer types, was characterized by C > T transitions at CpG sites, probably reflecting deamination of 5-methylcytosines at CpG sites. This signature correlated with patient age (Alexandrov et al., 2013Alexandrov L.B. Nik-Zainal S. Wedge D.C. Aparicio S.A. Behjati S. Biankin A.V. Bignell G.R. Bolli N. Borg A. Børresen-Dale A.L. et al.Australian Pancreatic Cancer Genome InitiativeICGC Breast Cancer ConsortiumICGC MMML-Seq ConsortiumICGC PedBrainSignatures of mutational processes in human cancer.Nature. 2013; 500: 415-421Crossref PubMed Scopus (210) Google Scholar), consistent with a large proportion of these mutations having been acquired prior to tumorigenesis. Another pervasive mutational signature, identified in 15 cancer types, has been linked to the endogenous activity of apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) cytidine deaminases and is characterized by C > T and C > G mutations at TpC sites (Alexandrov et al., 2013Alexandrov L.B. Nik-Zainal S. Wedge D.C. Aparicio S.A. Behjati S. Biankin A.V. Bignell G.R. Bolli N. Borg A. Børresen-Dale A.L. et al.Australian Pancreatic Cancer Genome InitiativeICGC Breast Cancer ConsortiumICGC MMML-Seq ConsortiumICGC PedBrainSignatures of mutational processes in human cancer.Nature. 2013; 500: 415-421Crossref PubMed Scopus (210) Google Scholar, Burns et al., 2013Burns M.B. Temiz N.A. Harris R.S. Evidence for APOBEC3B mutagenesis in multiple human cancers.Nat. Genet. 2013; 45: 977-983Crossref PubMed Scopus (45) Google Scholar, Roberts et al., 2013Roberts S.A. Lawrence M.S. Klimczak L.J. Grimm S.A. Fargo D. Stojanov P. Kiezun A. Kryukov G.V. Carter S.L. 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Moreover, in NSCLC, our group found evidence that while early mutations were dominated by smoking induced C > A transversions, APOBEC-mediated mutagenesis was the dominant mutational force later in tumor evolution, conceivably providing a fertile substrate for tumor adaptation to environmental and targeted, cytotoxic, or radiation therapy-induced selection pressures (de Bruin et al., 2014de Bruin E.C. McGranahan N. Mitter R. Salm M. Wedge D.C. Yates L. Jamal-Hanjani M. Shafi S. Murugaesu N. Rowan A.J. et al.Spatial and temporal diversity in genomic instability processes defines lung cancer evolution.Science (New York, NY). 2014; 346: 251-256Crossref Scopus (4) Google Scholar). Consistent with the importance of this mutational process later in NSCLC evolution, over 15% subclonal mutations in driver genes, including PIK3CA, TGFBR1, and PTPRD, were found within an APOBEC context. Additionally, geographically distinct regions of the same tumor displayed different levels of APOBEC-mediated mutagenesis (de Bruin et al., 2014de Bruin E.C. McGranahan N. Mitter R. Salm M. Wedge D.C. Yates L. Jamal-Hanjani M. Shafi S. Murugaesu N. Rowan A.J. et al.Spatial and temporal diversity in genomic instability processes defines lung cancer evolution.Science (New York, NY). 2014; 346: 251-256Crossref Scopus (4) Google Scholar), suggesting drivers of diversity themselves can be both spatially heterogeneous and alter in dominance over time. Therapy may also act as an exogenous source of genome instability (Cahill et al., 2007Cahill D.P. Levine K.K. Betensky R.A. Codd P.J. Romany C.A. Reavie L.B. Batchelor T.T. Futreal P.A. Stratton M.R. Curry W.T. et al.Loss of the mismatch repair protein MSH6 in human glioblastomas is associated with tumor progression during temozolomide treatment.Clin. 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In these examples, therapy was not acting merely as an exogenous source of mutations but also as a selection barrier, shaping the evolutionary trajectory of a tumor and its progression to a more aggressive phase. Consistent with therapy acting as a selection barrier, in NSCLC, chemotherapy was found to reduce EGFR mutation frequency (Bai et al., 2012Bai H. Wang Z. Chen K. Zhao J. Lee J.J. Wang S. Zhou Q. Zhuo M. Mao L. An T. et al.Influence of chemotherapy on EGFR mutation status among patients with non-small-cell lung cancer.J. Clin. Oncol. 2012; 30: 3077-3083Crossref PubMed Scopus (54) Google Scholar), and treatment of colorectal cancer clones with oxaliplatin resulted in outgrowth of previously dormant, resting clones (Kreso et al., 2013Kreso A. O’Brien C.A. van Galen P. Gan O.I. Notta F. Brown A.M. Ng K. Ma J. Wienholds E. Dunant C. et al.Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer.Science. 2013; 339: 543-548Crossref PubMed Scopus (114) Google Scholar). In this case, chemotherapy did not act as an exogenous source of mutations, as the effect was independent of acquired genetic mutations, highlighting the importance of nongenetic mechanisms in generating diversity within tumors. In support of this, phenotypic behavior and fate of identical daughter cancer cells can be vastly different upon treatment despite identical genetic backgrounds (Gascoigne and Taylor, 2008Gascoigne K.E. Taylor S.S. Cancer cells display profound intra- and interline variation following prolonged exposure to antimitotic drugs.Cancer Cell. 2008; 14: 111-122Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar). Interestingly, in AML, while morphological and phenotypic features as well as growth properties were found to correlate with distinct genetically defined subclones, the engraftment of AML cells in mice did not relate to the genetically defined evolutionary hierarchy (Klco et al., 2014Klco J.M. Spencer D.H. Miller C.A. Griffith M. Lamprecht T.L. O’Laughlin M. Fronick C. Magrini V. Demeter R.T. Fulton R.S. et al.Functional heterogeneity of genetically defined subclones in acute myeloid leukemia.Cancer Cell. 2014; 25: 379-392Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar). Genome instability processes and mutational signatures can also be deciphered through copy number analysis. Homologous recombination (HR) deficiency is thought to lead to a specific copy number profile, resulting in allelic imbalance (Abkevich et al., 2012Abkevich V. Timms K.M. Hennessy B.T. Potter J. Carey M.S. Meyer L.A. Smith-McCune K. Broaddus R. Lu K.H. 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The clinical importance of this HR signature is underscored by the observations that it predicts cisplatin sensitivity in vitro and response to preoperative cisplatin treatment in patients with triple-negative breast cancer (Birkbak et al., 2012Birkbak N.J. Wang Z.C. Kim J.Y. Eklund A.C. Li Q. Tian R. Bowman-Colin C. Li Y. Greene-Colozzi A. Iglehart J.D. et al.Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA-damaging agents.Cancer Discov. 2012; 2: 366-375Crossref PubMed Scopus (20) Google Scholar). Copy number aberrations can also be used to quantify the level of chromosomal instability (CIN) (Birkbak et al., 2011Birkbak N.J. Eklund A.C. Li Q. McClelland S.E. Endesfelder D. Tan P. Tan I.B. Richardson A.L. Szallasi Z. Swanton C. Paradoxical relationship between chromosomal instability and survival outcome in cancer.Cancer Res. 2011; 71: 3447-3452Crossref PubMed Scopus (60) Google Scholar), a driving force of intercellular genetic heterogeneity (Lengauer et al., 1997Lengauer C. Kinzler K.W. Vogelstein B. Genetic instability in colorectal cancers.Nature. 1997; 386: 623-627Crossref PubMed Scopus (1241) Google Scholar). In colorectal cancer, aneuploid tumors frequently harbor loss of chromosome 18q. We have found that loss of three “CIN-suppressor genes” encoded on 18q is an early event in tumor evolution occurring at the onset of aneuploidy. Depletion of these three genes in vitro initiates replication stress and generation of structural CIN and numerical CIN defined by centromeric fluorescence in situ hybridization, resulting in intercellular heterogeneity (Burrell et al., 2013bBurrell R.A. McClelland S.E. Endesfelder D. Groth P. Weller M.C. Shaikh N. Domingo E. Kanu N. Dewhurst S.M. Gronroos E. et al.Replication stress links structural and numerical cancer chromosomal instability.Nature. 2013; 494: 492-496Crossref PubMed Scopus (75) Google Scholar). Chromothripsis, a single event that results in tens to thousands of chromosomal rearrangements localized to one or a few chromosomes (Stephens et al., 2011Stephens P.J. Greenman C.D. Fu B. Yang F. Bignell G.R. Mudie L.J. Pleasance E.D. Lau K.W. Beare D. Stebbings L.A. et al.Massive genomic rearrangement acquired in a single catastrophic event during cancer development.Cell. 2011; 144: 27-40Abstract Full Text Full Text PDF PubMed Scopus (478) Google Scholar), is thought to occur in 5% of cancers and can be detected using allele-specific copy number data (Zack et al., 2013Zack T.I. Schumacher S.E. Carter S.L. Cherniack A.D. Saksena G. Tabak B. Lawrence M.S. Zhang C.Z. Wala J. Mermel C.H. et al.Pan-cancer patterns of somatic copy number alteration.Nat. 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Ward R.L. et al.Tolerance of whole-genome doubling propagates chromosomal instability and accelerates cancer genome evolution.Cancer Discov. 2014; 4: 175-185Crossref PubMed Scopus (5) Google Scholar, Zack et al., 2013Zack T.I. Schumacher S.E. Carter S.L. Cherniack A.D. Saksena G. Tabak B. Lawrence M.S. Zhang C.Z. Wala J. Mermel C.H. et al.Pan-cancer patterns of somatic copy number alteration.Nat. Genet. 2013; 45: 1134-1140Crossref PubMed Scopus (48) Google Scholar). Although the underlying causes and tolerance mechanisms of genome doubling remain unclear, it has been postulated to represent a macroevolutionary leap in the development of tumors. This is supported by observations that genome doubling is associated with accelerated cancer genome evolution and elevated levels of chromosomal alterations (Dewhurst et al., 2014Dewhurst S.M. McGranahan N. Burrell R.A. Rowan A.J. Gronroos E. Endesfelder D. Joshi T. Mouradov D. Gibbs P. Ward R.L. et al.Tolerance of whole-genome doubling propagates chromosomal instability and accelerates cancer genome evolution.Cancer Discov. 2014; 4: 175-185Crossref PubMed Scopus (5) Google Scholar, Zack et al., 2013Zack T.I. Schumacher S.E. Carter S.L. Cherniack A.D. Saksena G. Tabak B. Lawrence M.S. Zhang C.Z. Wala J. Mermel C.H. et al.Pan-cancer patterns of somatic copy number alteration.Nat. Genet. 2013; 45: 1134-1140Crossref PubMed Scopus (48) Google Scholar). While analysis of individual cancer genomes can shed light on the mutational processes that have been operative during tumor evolution, from a therapeutic perspective, there is a need to determine whether trends and patterns in the evolution of cancer genomes through space and time can be deciphered. This issue is reminiscent of the long-standing and contentious debate on whether macroevolutionary trends and rules exist and Gould’s famous assertion that if the tape of life were rewound and played again a different evolutionary outcome would result (Gould, 1989Gould S.J. Wonderful Life: The Burgess Shale and the Nature of History. W.W. Norton & Co., New York1989Google Scholar). Such a notion does not imply evolution is random; rather, the final outcome is contingent upon the sequence of antecedent steps (Gould, 1989Gould S.J. Wonderful Life: The Burgess Shale and the Nature of History. W.W. Norton & Co., New York1989Google Scholar). Convergence, on the hand, has been championed as an opposing theory to contingency, suggesting that constraints to evolution may lead to a limited set of potentially repeated outcomes. Studies exploring evolutionary histories of tumors and epistatic interactions have begun to shed light on the interplay between contingency and convergence in cancer development and the possibility of an evolutionary rulebook dictating cancer evolutionary routes (Ashworth et al., 2011Ashworth A. Lord C.J. Reis-Filho J.S. Genetic interactions in cancer progression and treatment.Cell. 2011; 145: 30-38Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). Longitudinal (Johnson et al., 2014Johnson B.E. Mazor T. Hong C. Barnes M. Aihara K. McLean C.Y. Fouse S.D. Yamamoto S. Ueda H. Tatsuno K. et al.Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma.Science. 2014; 343: 189-193Crossref PubMed Scopus
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