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Journal of Clinical Oncology, Vol 24, No 23 (August 10), 2006: pp. 3799-3808 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.4171
DNA Repair Pathways in Clinical Practice: Lessons From Pediatric Cancer Susceptibility Syndromes
From the Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA Address reprint requests to Alan D. D'Andrea, MD, Dana-Farber Cancer Institute, Department of Radiation Oncology, Harvard Medical School, 44 Binney St, Boston, MA 02115; e-mail: alan_dandrea{at}dfci.harvard.edu
Human cancers exhibit genomic instability and an increased mutation rate due to underlying defects in DNA repair. Cancer cells are often defective in one of six major DNA repair pathways, namely: mismatch repair, base excision repair, nucleotide excision repair, homologous recombination, nonhomologous endjoining and translesion synthesis. The specific DNA repair pathway affected is predictive of the kinds of mutations, the tumor drug sensitivity, and the treatment outcome. The study of rare inherited DNA repair disorders, such as Fanconi anemia, has yielded new insights to drug sensitivity and treatment of sporadic cancers, such as breast or ovarian epithelial tumors, in the general population. The Fanconi anemia pathway is an example of how DNA repair pathways can be deregulated in cancer cells and how biomarkers of the integrity of these pathways could be useful as a guide to cancer management and may be used in the development of novel therapeutic agents.
Genomic Instability in Human Cancer Cancer cells have several phenotypic features that distinguish them from healthy cells. They often have heightened proliferative rates, decreased apoptosis, and an intrinsic ability to invade basement membranes and to metastasize.1 Cancer cells also exhibit genomic instability,2 and this feature allows them to break and reform chromosomes, generate new oncogene fusions, inactivate tumor suppressor genes, amplify drug resistance genes, and consequently become more malignant and drug resistant over time. In short, genomic instability is a critical feature that enables tumor progression. In order to achieve a state of genomic instability, a cancer cell must tolerate DNA damage. This can be achieved through the loss of DNA damage signaling and check pointing pathways, such as those regulated by p53, retinoblastoma proteins, as well as ataxia telangiectasia mutated and ataxia telangiectasia and Rad3-related (ATR) kinases.3,4 Alternatively, as will be discussed in this article, cancer cells may knock out one of six major DNA repair pathways namely: base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), homologous recombination (HR), nonhomologous endjoining (NHEJ), and translesion DNA synthesis (TLS; Table 1) . As will be discussed, current evidence suggests that the Fanconi anemia pathway functions to coordinate the major pathways following a specific form of DNA damage.
Disruption of DNA repair allows an increased rate of chromosome breakage and mutagenesis, but it comes at a cost to the cancer cell that exhibits an increased sensitivity to DNA damage. This damage may result from endogenous replication errors, sustained due to the tumors high proliferation rate, or from exogenous genotoxic stress. A defective DNA repair pathway can account for the increased sensitivity of tumors to therapeutic ionizing radiation and chemotherapy observed in the oncology clinic. There is also considerable redundancy in the function of the DNA repair pathways. When one pathway is disrupted another pathway can partially compensate, especially if the second pathway is upregulated. For instance, a cell that is deficient in HR repair may depend more on the error-prone repair NHEJ pathway for the repair of double-strand breaks (DSBs). Also, thymine dimers that are generated by UV light exposure can be repaired by NER repair or bypassed and effectively ignored by TLS polymerases. In some cases, the absence of one DNA repair pathway results in a hyperdependence on one or more other DNA repair pathways.48,49 Some of the DNA repair pathways are not constitutively activated, but instead are regulated. First, some pathways are activated in response to DNA damage at discrete times in the cell cycle. For instance, HR repair and TLS repair are active during the S phase of the cell cycle. Second, the DNA repair pathways are differentially active in various tissues and cell types. For example, HR and TLS are more active in rapidly growing cells, such as hematopoietic cells, while NHEJ is more active in postreplicative cells. Accordingly, absence of a particular DNA repair pathway may be particularly disruptive to the growth and survival of some specific tissues. Herein is a brief description of the six pathways, with an emphasis on the enzymes in the pathways and the DNA lesions repaired.
Specific Features of the Six DNA Repair Pathways MMR. MMR removes mispaired nucleotides that result from replication errors51 and is involved in the detection and repair of DNA adducts, such as those resulting from platinum-based chemotherapeutic agents.52 Initially, the heterodimeric MSH complex recognizes the nucleotide mismatch, followed by its interaction with MLH1/PMS2 and MLH1/MLH3 complexes. Several proteins participate in the process of nucleotide excision and resynthesis. Tumor cells deficient in MMR have much higher mutation frequencies than normal cells and exhibit microsatellite instability, a genomic biomarker of the underlying defect.53 Several genes including MSH2, MSH3, MSH6, MLH1, MLH3, PMS1, and PMS2 are involved in MMR. Interestingly, an intact MMR pathway is required for cisplatin sensitivity rather than resistance as would be expected.15 This observation suggests that the pathway may promote cell death through excision of cisplatin adducts, thereby causing DNA breaks or alternatively it may have a role independent of DNA repair such as apoptotic signaling. NER. NER acts on a variety of helix-distorting DNA lesions, caused mostly by exogenous sources that interfere with normal base pairing. A major function of NER appears to be the removal of damage, for example pyrimidine dimers that are induced by UV. This pathway may also be particularly important in conferring resistance to adduct forming chemotherapeutic agents such as platinum-based chemotherapy. Members of the NER pathway include the XPA, XPB, XPC, XPD, XPE, XPF, and XPG proteins. As for the other DNA repair pathways, these proteins cooperate to recognize and excise the damaged nucleotides, and resynthesize and ligate the damaged DNA strand.5 Eukaryotic NER includes two major branches, transcription-coupled repair and global genome repair.54,55 Global genome repair is a slow random process of inspecting the entire genome for damage, while transcription-coupled repair is highly specific and efficient and repairs DNA damage that blocks the progression of RNA polymerase II. HR Repair. DNA DSBs can be caused by many different environmental factors, including reactive oxygen species, ionizing radiation and certain antineoplastic drugs, such as bleomycin, anthracyclines, and topoisomerase inhibitors. Alternatively, DSBs can result from endogenous factors, especially during normal S phase progression.56 Failure to repair DSBs can lead to a number of consequences, including mutations, gross chromosomal rearrangements, and other aberrations, and eventually cell death. HR is a process by which DSBs are repaired through the alignment of homologous sequences of DNA and occurs primarily during the late S to M phase of the cell cycle. Initially the RAD50, MRE11, and NBS1 complex, which possesses a 3'–5' exonuclease activity, exposes the 3' ends on either side of the DSB, a process that may also require BRCA1.57 The 3' advancing strand from the damaged chromosome then invades the complementary sequence of the homologous chromosome. The breast cancer susceptibility protein, BRCA2, and the single strand DNA binding protein, RAD51, are required for this process.58,59 The 3' end of this strand is then extended by a DNA polymerase that reads off of the complementary sequence. After replication has extended past the region of the DSB, the 3' end of the advancing strand returns to the original chromosome and replication continues.5,56 NHEJ. NHEJ is another major pathway used to repair DSBs. Similar to HR, this pathway is important in the response to agents that result in DSBs, such as ionizing radiation, bleomycin, topoisomerase poisons, and anthracyclines. The DNA-dependent protein kinase consists of the catalytic subunit and the regulatory subunit (the Ku70/Ku80 heterodimer). The DNA protein kinase catalytic subunit subunit is a serine/threonine kinase that belongs to the phosphatidyl inositol-3 kinase family. The Ku80/Ku70 heterodimer (Ku) exhibits sequence-independent affinity for double-stranded termini and on binding to DNA ends recruits and activates the DNA protein kinase catalytic subunit catalytic subunit. Additional proteins are required for the completion of NHEJ, including the artemis protein and DNA ligase IV.60,61 Importantly, NHEJ is an error-prone repair pathway. Since the process does not use a complementary template, the fusion of the blunt-ended DNA duplexes may result in deletion or insertion of base pairs. TLS. The process of TLS is another mechanism for dealing with thymine dimers and bases with bulky chemical adducts.62 At a DNA replication fork, DNA adducts may cause a replicative polymerase, such as DNA polymerase delta, to stall. Cells have therefore developed sophisticated mechanisms for switching off the replicative polymerase and switching on alternative polymerases (ie, a polymerase such as pol ß, that will replicate past certain DNA lesions with high fidelity). Interestingly, human cells have at least ten DNA polymerases, although the situations and mechanisms of their deployment are largely unknown.63 Cancer cells may have a heightened dependence on one of the error-prone TLS polymerases, such as polymerases ß or kappa, accounting for high rates of mutagenesis.6,64
Inherited Chromosome Instability Syndromes At least five of the major DNA repair pathways have corresponding inherited human diseases (Table 1). Coordination of NER, HR, and TLS repair is thought to be defective in Fanconi anemia cells.65 NER repair is defective in Xeroderma pigmentosum cells and Cockayne syndrome cells.20 MMR is defective in children with Turcot's syndrome and in tumor cells derived from adult patients with hereditary nonpolyposis colorectal cancer.66 TLS repair is defective in patients with the Xeroderma pigmentosum variant disease.67 Most of these pediatric diseases exhibit autosomal recessive inheritance, such as Xeroderma pigmentosum, Fanconi anemia, and Cockayne syndrome.20,68 Turcot's syndrome has been reported to exhibit autosomal dominant or autosomal recessive inheritance depending on the particular mutation affecting MMR.66,69 Inherited mutations in BER genes have not been observed, suggesting that this pathway is essential for human development, however, a polymorphisms of the DNA glycosylase OGG1 and adenosine diphosphate ribosyl transferase have been reported to predispose to lung cancer,7,8 possibly through a requirement for BER in repairing smoking related DNA damage. The systematic study of these rare diseases has led to a better understanding of the genes and proteins involved in the major DNA repair pathways; how an inherited (or germline) defect in a DNA repair pathway can lead to genomic instability, cancer progression, and drug hypersensitivity and; how an acquired (or somatic) defect in a DNA repair pathway can influence tumor progression and drug sensitivity of tumors in the general population. Although the specific detail of these individual inherited diseases is beyond the scope of this review, an example of how a study of these rare diseases can lead to general insights to tumor biology can be appreciated from recent insights into the Fanconi anemia pathway.
Fanconi anemia is an autosomal recessive or X-linked recessive cancer susceptibility syndrome characterized by multiple congenital abnormalities, progressive bone marrow failure, and cellular hypersensitivity to DNA crosslinking agents, such as cisplatin and mitomycin C (MMC). Fanconi anemia patients are prone to developing acute myeloid leukemia (AML) as well as squamous cell carcinomas of the head and neck or gynecologic system.70 The study of Fanconi anemia cells has led to the elucidation of a repair pathway for interstrand DNA crosslinks. Clinically, this pathway is particularly important as many DNA crosslinking agents, such as cisplatin, cyclophosphamide, MMC, or melphalan, are used for cancer treatment. The Fanconi anemia defect results from biallelic mutation of any one of twelve known Fanconi anemia genes (A, B, C, D1, D2, E, F, G, I, J, L, M). The proteins encoded by these Fanconi anemia genes cooperate in a common DNA repair pathway, referred to as the Fanconi anemia /BRCA pathway (Fig 1). In this pathway, eight of the Fanconi anemia proteins (A, B, C, E, F, G, L, M) are subunits of a nuclear E3 ubiquitin ligase (complex 1), required for the monoubiquitination of the downstream D2 protein on lysine 561, which is a critical step for the function of the Fanconi anemia pathway.65 The FANCL subunit is the putative catalytic E3 ligase subunit of the complex.71 Monoubiquitinated FANCD2 interacts with FANCD1/BRCA2 and other DNA repair proteins to form complex 2.72 The recently cloned FANCJ protein is a helicase that may work in concert with monoubiquitinated FANCD2 and BRCA2 or may function independently of the Fanconi anemia pathway.73-76
Recent research has suggested that the Fanconi anemia pathway may have a specific role in coordinating at least three DNA repair pathways following DNA crosslinking damage. Consequently, disruption of any of the Fanconi anemia proteins leads to MMC hypersensitivity and chromosome instability.65,77
The Fanconi Anemia Pathway in Malignancy
Cancer in Fanconi Anemia Patients
Cancer Risk in Heterozygous Carriers of Fanconi Anemia Gene Mutation In addition to BRCA1 and BRCA2, heterozygous mutations in FANCJ (BRIP1) have also been identified in patients with early onset breast cancer,42 although the lifetime risk is unknown. These observations suggest that the Fanconi anemia pathway is important in the prevention of these female malignancies and that unidentified mutations of other Fanconi anemia genes may account for some familial breast/ovarian cancers pedigrees not accounted for by BRCA1, BRCA2/FANCD1, and FANCJ. A heterozygous germline mutation in FANCC has been identified in two of 421 patients with pancreatic cancer.43 Consistent with Knudson's two hit hypothesis for tumor suppressor genes,84 cancer cells taken from these patients exhibited a loss of heterozygosity at the FANCC locus.43 Other studies have identified human pancreatic tumor lines with biallelic loss of FANCC and FANCG.44 These tumor lines were derived from individuals who were heterozygous at these loci. Taken together, these data indicate that heterozygous carriers of FANCC mutation and possibly FANCG mutation have increased pancreatic cancer risk, although at a lower penetrance than BRCA2/FANCD1 mutation. Heterozygous mutation of FANCA appears to contribute to a small percentage of cases of AML. Missense mutations of the FANCA were identified in 7.6% of 79 AML patients in one series45 and 4% of 101 AML patients in another.46 However, to date, the functional consequences of these mutations are unknown.
Somatic Mutation of Fanconi Anemia Genes in Sporadic Cancer Epigenetic silencing of BRCA1 through methylation occurs in 13% of breast cancers,47 23% of advanced ovarian cancers,90 6% of cervical cancers91and 4% of non–small-cell lung cancers.87 Epigenetic disruption of the Fanconi anemia pathway may also be important in the development of sporadic AML where absent or reduced expression of the Fanconi anemia proteins FANCA, FANCC, FANCF, and FANCG have been reported.92 Loss of BRCA2 mRNA and protein expression has been reported in 13% of ovarian adenocarcinomas; in contrast to the other Fanconi anemia genes described, this loss of protein does not result from promoter methylation.93
Biomarkers of the Fanconi Anemia Pathway in Cancer Treatment
Selection of Biomarkers of the Fanconi Anemia Pathway
Functional biomarkers. These are biomarkers that indicate an intact DNA repair pathway. Functional biomarkers have the advantage of giving a measure of the performance of a particular pathway and will detect repair defects due to epigenetic events or gene mutations. Moreover, they give a global measurement of a particular pathway's function without needing to know the identities of all the components, some of which may remain unknown. They may also be used to differentiate between insignificant single nucleotide polymorphisms and functionally important point mutations in DNA repair pathway genes. This approach may be applied to serial tumor samples from the same patient, at diagnosis, and at the time of relapse. In this way, one can determine whether the tumor remains drug sensitive or has restored its DNA repair mechanisms. However functional biomarkers rely on tumor tissue having been exposed to some form of DNA damage in vivo or in vitro before the assay. In the case of the Fanconi anemia pathway, monoubuiquitination of FANCD2 is a biomarker for the integrity of the upstream part of DNA damage response. Abnormal DNA damage induced nuclear foci may identify disruption of the downstream events in the pathway, such as that observed in BRCA1 or BRCA2 deficient cells.57,94 Biomarkers of gene/protein expression. These biomarkers indicate the preexisting function of a DNA damage pathway before damage. Examples are real-time polymerase chain reaction or immunohistochemistry to test for epigenetic silencing of critical DNA repair genes. Some studies have used a microarray approach to look for genetic expression profiles indicative of abnormal DNA repair gene function.95,96 Because some DNA repair genes, such as FANCF, undergo inactivation by methylation, the measurement of gene methylation, using the methylation-PCR assay, can also be applied as a biomarker assay.97 These approaches have the advantage of not requiring prior DNA damage and can be performed on fixed specimens. However, these assays provide only an indirect measurement of the functional capabilities of a DNA repair pathway. In addition, mutant genes can express normal levels of mRNA and mutant protein that would not be detected by this method.
Biomarkers As Predictors of Response to Conventional Therapy Loss or increased activity of particular DNA repair pathways is likely to influence the response to DNA damaging therapeutic strategies. For instance, a failure of a pathway involved in the repair of DNA crosslinks, such as HR, would be predicted to sensitize a tumor to DNA crosslinking agents such as alkylating chemotherapeutic drugs. Indeed, BRCA1 expression levels as measured by real-time polymerase chain reaction have been demonstrated to be a biomarker of survival following cisplatin-based chemotherapy for non–small-cell lung cancer.98 Methylation-specific PCR, which indicates loss of gene expression through promoter methylation, has been used to retrospectively correlate loss of BRCA1 function with cisplatin sensitivity in ovarian cancer.90 Loss of BRCA2/FANCD1 function through mutation in breast or ovarian cancer, has also been reported to correlate with a high response to DNA damaging chemotherapeutic agents in retrospective studies.99,100 Absence of FANCD2 monoubiquitination may be a biomarker for loss of function of upstream Fanconi anemia pathways components and could be expected to predict sensitivity to DNA crosslinking chemotherapy.101 In keeping with this hypothesis, mouse xenograft models using human pancreatic tumor cell lines mutant for FANCC or FANCG and therefore defective for FANCD2 monoubiquitination, have demonstrated hypersensitivity to the DNA crosslinkers cisplatin, chlorambucil, MMC, and melphalan when compared with cell lines with a competent Fanconi anemia pathway.102 The human ovarian cancer cell line 2008 has a methylated FANCF promoter with a loss of FANCF protein expression and a failure to monoubiquitinate FANCD2 after cisplatin treatment. Consistent with the loss of Fanconi anemia pathway function, these cells are sensitive to cisplatin treatment. Prolonged treatment of the 2008 cell line with cisplatin results in restoration of FANCF expression, by demethylation of the FANCF gene, suggesting that correction of the Fanconi anemia pathway may account for acquired resistance to this treatment in a clinical setting (Fig 3). 89
Biomarkers to Guide Chemo- and Radiosensitization Resistance to DNA damaging chemotherapy or radiotherapy may be due to enhanced repair of DNA lesions. Therefore, a possible therapeutic strategy is to use drugs that specifically inhibit DNA repair pathways. Theoretically, this strategy may be limited since the drug may also increase the toxicity of therapeutic DNA damage in normal tissue, such as bone marrow. A therapeutic index can be achieved, in principle, by (1) the selective uptake of the DNA damage sensitizers by the tumor cell, versus the normal cell or (2) by delivering one of the modalities (such as the radiation) directly to the tumor. An understanding of the precise molecular mechanisms of new classes sensitizing agents has important implications. First, if an agent functions by inhibiting a specific DNA repair pathway, then active derivatives of this agent should function similarly. DNA repair pathway inhibition provides an important biomarker for determining the proper dosing of the drug. Also, the chemosensitizer would be predicted to be more efficacious when used in combination with specific classes of DNA damage drugs. For example our laboratory has demonstrated that ovarian cancer cell lines can develop resistance to cisplatin through activation of the Fanconi anemia pathway and increased FANCD2 monoubiquitination.89 This observation suggests that inhibitors of the Fanconi anemia pathway may be chemosensitizers in a subset of tumors. Indeed we have found that small molecule inhibitors of the FANCD2 monoubiquitination sensitize cisplatin resistant ovarian cancer cell lines to cisplatin (D. Chirnomas and A. D'Andrea unpublished observation).
Biomarkers As Predictors of Response to Targeted Monotherapy
This principle has recently been demonstrated by the use of PARP inhibitors in BRCA1 and BRCA2 deficient cells.48,49 As discussed earlier, under normal physiological conditions DNA is being damaged continuously. The result of these stresses is the development of damaged bases or regions of SSBs that are repaired through the BER. Part of the BER pathway requires poly(ADP-ribose) polymerase (PARP), a DNA binding zinc finger protein that catalyzes the transfer of ADP-ribose residues from NAD+ to itself and different chromatin constituents, forming branched ADP-ribose polymers.5 Initially it was observed that PARP deficient (and therefore BER deficient) mice develop normally but have high levels of sister chromatid exchange, a feature of HR.103 This observation suggested that HR could compensate for a loss of PARP-dependent BER. Consequently it was demonstrated in preclinical models that BRCA1/2 deficient human and murine cells were sensitive to PARP inhibiting drugs, whereas cells expressing normal levels of BRCA1 or BRCA2 were unaffected.48,49 PARP1 inhibitors are well tolerated in preclinical murine models104 and in addition to being a potential treatment for BRCA1/2 mutant tumors, may also represent an attractive strategy for chemoprevention of malignancies in mutation carriers. Clearly a biomarker that indicates a failure of BRCA1/2 function in tumor cells may allow the application of PARP inhibitors to a wider spectrum of sporadic human malignancies.
Germline and Acquired Defects in Other DNA Repair Pathways
Biomarkers for Other DNA Repair Pathways: Personalized Medicine Few biomarkers exist at present for evaluating the integrity of the other DNA repair pathways. Several studies have attempted to assay these pathways, using expression biomarkers (ie, the testing of the expression levels of known DNA repair proteins in the pathways.) Better functional biomarkers are needed. Recent studies have indicated that post-translational modifications of DNA repair proteins in these pathways are also required for pathway activity. For instance, polyubiquitination of XPC is required for functional NER,107 and sumoylation of thymine-DNA glycosylase is required for function of BER.108 Antibodies specific for these activated states could potentially be used as functional biomarkers and allow the rapid assessment of drug sensitivity and acquired resistance in clinical samples.
Genomic instability is characteristic of most human malignancies, and this phenotype can arise from acquired defects in any one of six DNA repair pathways. The relevance of these pathways to cancer development and treatment has been ascertained by the systematic study of rare pediatric DNA repair disorders. We have focused on one such pathway, the Fanconi anemia/BRCA pathway, and demonstrated how knowledge of its function may guide cancer management. In the future, the development of biomarkers for the function of other DNA repair pathways may allow the better targeting of conventional agents or the use of monotherapies designed to inhibit specific repair pathways. The biomarkers can also be used as screening tools to find inhibitors of DNA repair that function as chemosensitizers. We predict that these approaches should reduce the toxicity of existing cancer treatments by eliminating the use of noneffective agents and by directing the development of personalized treatment strategies.
The authors indicated no potential conflicts of interest.
We would also like to thank Michelle de la Vega for IH data and Tony Huang, Kanchan Mirchandani, and Allan Gurtan of the D'Andrea laboratory for their advice in preparing this manuscript.
Supported by a grant from the Susan G. Komen Breast Cancer Foundation (R.K.) and by National Institutes of Health Grants No. RO1HL52725, RO1 DK43889, P0150654, P50 CA105009-01, and PO1HL54785 (A.D.). Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
