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Genomic Instability — an Evolving Hallmark of Cancer

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Genomic Instability — an Evolving Hallmark of Cancer REVIEWS Genomic instability — an evolving hallmark of cancer Simona Negrini*, Vassilis G. Gorgoulis‡ and Thanos D. Halazonetis*§ Abstract | Genomic instability is a characteristic of most cancers. In hereditary cancers, genomic instability results from mutations in DNA repair genes and drives cancer development, as predicted by the mutator hypothesis. In sporadic (non-hereditary) cancers the molecular basis of genomic instability remains unclear, but recent high-throughput sequencing studies suggest that mutations in DNA repair genes are infrequent before therapy, arguing against the mutator hypothesis for these cancers. Instead, the mutation patterns of the tumour suppressor TP53 (which encodes p53), ataxia telangiectasia mutated (ATM) and cyclin-dependent kinase inhibitor 2A (CDKN2A; which encodes p16INK4A and p14ARF) support the oncogene-induced DNA replication stress model, which attributes genomic instability and TP53 and ATM mutations to oncogene-induced DNA damage. Hereditary non-polyposis Genomic instability is a characteristic of almost all best­documented examples is hereditary non-polyposis colon cancer human cancers, but at what stage of cancer development colon cancer (HNPCC; also known as Lynch syndrome), An autosomal dominant it arises and what its molecular basis is are questions to in which mutations in DNA mismatch repair genes lead to disease that is characterized which we are only beginning to get answers. There are MSI6,7. Another example is hereditary MYH-associated by increased susceptibility to polyposis colon carcinoma and other various forms of genomic instability. Most cancers have a , in which biallelic germline mutations in MYH forms of cancer owing to an form that is called chromosomal instability (CIN), which (also known as MUTYH) — a DNA base excision repair inherited defect in DNA refers to the high rate by which chromosome structure (BER) gene — result in increased G•C to T•A transver­ mismatch repair genes. and number changes over time in cancer cells compared sion frequencies and cancer8. In hereditary cancers that with normal cells. Abnormal chromosome structures are characterized by the presence of CIN, the genomic DNA mismatch repair The repair of DNA base-pair and numbers and abnormal mitoses associated with CIN instability can also be attributed to mutations in DNA 1,2 mismatches that arise as a were first visualized more than a hundred years ago . repair genes. For example, germline mutations in breast result of replication errors or Some of these chromosomal changes were seen in all cancer susceptibility 1 (BRCA1), BRCA2, partner and after exposure to several DNA cells of a tumour but others were not, suggesting that localizer of BRCA2 (PALB2), BRCA1­interacting pro­ damaging agents. tumour cells are the progeny of a genetically unstable tein 1 (BRIP1), RAD50, Nijmegen breakage syndrome MYH-associated polyposis single cell, which continues to acquire chromosomal protein 1 (NBS1; also known as NBN), Werner syndrome An autosomal recessive abnormalities over time3,4. The presence of CIN has also helicase (WRN), Bloom syndrome helicase (BLM), RecQ disease that predisposes to been confirmed in cancer cells grown in tissue culture5. protein­like 4 (RECQL4) and the Fanconi anaemia genes, colorectal cancer and is caused Although CIN is the major form of genomic insta­ all of which have been linked to the repair of DNA double­ by germline mutations in the DNA repair gene MYH. bility in human cancers, other forms of genomic strand breaks (DSBs) or DNA interstrand cross links, pre­ instability have also been described. These include dispose to the development of various cancers, including 9–11 *Department of Molecular microsatellite instability (MSI; also known as MIN), a breast and ovarian cancer, leukaemias and lymphomas . Biology and §Department of form of genomic instability that is characterized by the Finally, germline mutations in nucleotide excision DNA Biochemistry, University of expansion or contraction of the number of oligonucleo­ repair genes predispose to skin cancer12. Geneva, CH-1205 Geneva, 6,7 Switzerland. ‡Department of tide repeats present in microsatellite sequences , and The identification of mutations in DNA repair genes Histology and Embryology, forms of genomic instability that are characterized by in hereditary cancers provides strong support for the School of Medicine, increased frequencies of base­pair mutations8. mutator hypothesis, which states that genomic instability University of Athens, is present in precancerous lesions and drives tumour GR-11527 Athens, Greece. Hereditary versus sporadic cancers development by increasing the spontaneous mutation Correspondance to T.D.H. 4,13 e-mail: In hereditary cancers, the presence of both CIN rate . Proponents of the mutator hypothesis attribute [email protected] and non­CIN forms of genomic instability has been the genomic instability in precancerous lesions to muta­ doi:10.1038/nrm2858 linked to mutations in DNA repair genes. One of the tions in caretaker genes; that is, genes that primarily 220 | MARCH 2010 | VOLUME 11 www.nature.com/reviews/molcellbio © 2010 Macmillan Publishers Limited. All rights reserved FOCUS ON GENOME INSREVIEWSTABILITY function to maintain genomic stability4,13,14. Indeed, in 1,137 genes. When these genes were sequenced in an inherited cancers, germline mutations targeting DNA additional 24 breast cancers, mutations were found in repair genes are present in every cell of the patient’s 167 of them. In the colorectal cancers, 848 genes with body. Thus, a single event — loss of the remaining wild­ mutations were identified in the initial discovery screen. type allele — would lead to genomic instability and In the validation screen, in which 24 additional colon drive tumour development, as predicted by the mutator cancers were sequenced, mutations were found in 183 of hypothesis. the 848 genes. The classical caretaker genes are DNA repair genes The same group of investigators also analysed the and mitotic checkpoint genes. The tumour suppres­ coding sequences of 20,661 genes in 24 advanced pan­ sor gene TP53, which encodes p53, and the ataxia creatic adenocarcinomas26 and in 22 glioblastomas27. telangiectasia mutated (ATM) gene could also be con­ The pancreatic adenocarcinomas were examined as sidered as caretaker genes because they both function early passage xenografts or cancer cell lines. Of the in the DNA damage response. However, as discussed 22 glio blastomas, 7 were examined immediately after below, TP53 and ATM are subject to selective pres­ removal from the patient and 15 were first passaged sure for inactivation in cancer, whereas the classical as xenografts. Genomic deletions and amplifications caretaker genes are not. Because of this difference, when in these cancer genomes were also identified using we refer to caretaker genes in this Review we do not single nucleotide poly morphism arrays. In the pancre­ include TP53 and ATM. atic adeno carcinomas, 1,327 genes were mutated in at Germline mutations in caretaker genes can explain least one sample. In the glioblastomas, 685 genes were the presence of genomic instability in inherited cancers. mutated at least once. In a subsequent validation phase, However, efforts to identify caretaker genes, the inacti­ 39 genes were sequenced in an additional 90 pancreatic vation of which leads to genomic instability in sporadic cancers and 21 genes were sequenced in an additional (non­hereditary) cancers, have met with limited success15. 83 glioblastomas, thus allowing a better estimate of the For example, mutations in the mitotic checkpoint gene mutation frequencies of the genes identified in the initial budding uninhibited by benzimidazole 1 (BUB1) can lead screen to be frequently targeted in these cancers. to CIN in experimental models, but in human cancers Glioblastomas were also studied by The Cancer BUB1 mutations are rare16,17. Furthermore, a systematic Genome Atlas Research Network28. Primary tissue from analysis of the sequences of 100 cell cycle checkpoint and 72 newly diagnosed, untreated glioblastomas and 19 DNA repair genes in early passage human colon cancer treated cases was examined for mutations in 601 cancer­ cell lines identified very few mutations18. relevant genes. Genomic deletions and amplific ations Thus, unlike hereditary cancers, the molecular basis were also identified in these samples. In the treated of genomic instability in sporadic cancers remains and untreated cases combined (91 in total), 223 genes unclear. In this Review, we consider two models that were mutated, 79 of which were mutated in more than could explain the presence of CIN — the main form of one sample. genomic instability — in sporadic cancers. The first is the The largest study, in terms of the number of cancers mutator hypothesis described above and the second is examined, was carried out by many of the same groups the oncogene­induced DNA replication stress model for comprising the Cancer Genome Atlas Research Network. cancer development19–23. According to the latter model, In this study, 623 cancer­relevant genes were sequenced CIN in sporadic cancers results from the oncogene­ in 188 primary lung adenocarcinomas29. Mutations were induced collapse of DNA replication forks, which in identified in 356 genes, 193 of which were mutated more Base excision repair A pathway of DNA repair in turn leads to DNA DSBs and genomic instability. These than once. Genomic deletions and amplifications were which a single damaged base is two models are
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