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© 2000 American Society for Clinical Oncology
DNA Repair Defects Inactivate Tumor Suppressor Genes and Induce Hereditary and Sporadic Colon CancersFrom the Howard Hughes Medical Institute Laboratory, University Hospitals of Cleveland, Case Western Reserve University Cancer Center, Cleveland, OH. Address reprint requests to Sanford Markowitz, MD, PhD, Lab I UCRC 2, Case Western Reserve University, 11001 Cedar Ave, Ste 200, Cleveland, OH 44106-3043.
THE BASE-BASE mismatch repair system functions to identify and repair specific classes of errors in the DNA double helix and is remarkably conserved in function and in enzymatic components from bacteria all the way to humans. Genetic defects that inactivate this mechanism have been demonstrated to underlie the inherited cancer syndrome of hereditary nonpolyposis colon cancer (HNPCC) and to also contribute to a substantial percentage of sporadic colon and other solid tumors of humans. Tumors in which mismatch repair has been inactivated can be recognized easily by a molecular test that detects in them the phenomenon of microsatellite instability (MSI), also known as replication errors. Defects in mismatch repair contribute to cancer development in part by increasing global gene mutation rates within cells. Defects in mismatch repair also contribute to colon carcinogenesis by inducing a high rate of mutations in a novel tumor suppressor gene, RII, the type II receptor for the growth inhibitory peptide transforming growth factor beta (TGF-ß). Clinical recognition of cancers with defective mismatch repair may have future importance, considering that these tumors may enjoy a distinct prognosis, respond differently to certain cytotoxic drugs, and, when hereditary, have implications for the medical care required by patients’ families.
The base-base mismatch DNA repair system, or, in short, mismatch repair, demonstrates similar function from bacteria to humans. The system first recognizes and repairs a broad group of errors within the DNA double helix that result from mispairing incorrect bases on opposite strands of the helix (eg, incorrect pairing of adenine with adenine, cytosine, or guanine, as opposed to thymine; reviewed in1-3). Additionally, the system recognizes and repairs the single-stranded DNA loops that occur in the helix when from one to four bases either have been inserted or deleted within one of the DNA strands.1-3 Both such types of errors are most often understood to occur during DNA synthesis as a result of mistakes made by DNA polymerases. In correcting such polymerase errors, mismatch repair is directed toward correcting the sequence of the newly synthesized DNA strand. This is done by incising the strand, digesting away a patch of bases that includes the mispaired region, and then resynthesizing the correct sequence. In bacteria, DNA mismatch repair is initiated when a protein, MutS, recognizes and binds to a DNA mismatch, after which a second protein, MutL, is recruited to bind to the MutS complex.1-3 In humans, genes that are structurally related to bacterial MutS include MutS homolog 2 (hMsh2), hMsh3, and hMsh6 (Table 1). 4-8 Initial data suggest that, in humans, the bacterial MutS function is served by heterodimeric complexes of Msh2 with either Msh6 or Msh3 and that these different heterodimers function to recognize different types of mismatches and loops.6,9 Similarly, in humans, genes related to bacterial MutL include human MutL homolog 1 (hMlh1), hPms1, and hPms2.10-12 Furthermore, it seems that, in humans, a heterodimer of hMlh1 and hPms2 serves as the functional equivalent of the bacterial MutL component.13
HNPCC is a family cancer syndrome first described in 1913 by Aldred Warthin,14 and more recently the object of intensive clinical study by Henry Lynch et al.15 The syndrome is often referred to by the eponym of Lynch Syndrome. In HNPCC kindreds, cancer susceptibility is inherited in autosomal-dominant fashion and is evidenced by the development in affected individuals of cancers, of which the most common is colon cancer of the right colon. A set of clinical criteria for recognizing HNPCC kindreds, known as the Amsterdam criteria, requires the following: the presence within a family of three individuals with colon cancer, that these individuals represent two different generations, that these individuals include one member who is a first-degree relative of the two remaining persons, and that one of the three affected individuals had developed colon cancer before the age of 50 years.16 These criteria, although useful, are highly stringent and certainly, in some cases, fail to identify families with legitimate HNPCC. Despite the term HNPCC, however, current evidence suggests that adenomatous polyps are in fact present as precursors to the colon cancers that develop in this syndrome.17-19 It seems that the rate of malignant transformation of such polyps is dramatically faster than that characteristic of typical sporadic adenomatous polyps.20 Affected individuals in HNPCC kindreds also show a clearly elevated incidence of endometrial and gastric cancers15,21 as well as the occasional development of rare tumors such as those of the sebaceous gland (the Muir-Torre syndrome) (Table 2). 22,23 Work by the laboratories of Bert Vogelstein and Richard Kolodner has established that germline mutations in hMsh2, hMlh1, hPMS1, or hPMS2 are detectable in 70% of HNPCC kindreds.4,5,8,10-12,23,24 In all cases, inheritance of the mutant allele segregates with the inheritance of cancer susceptibility. The great majority of HNPCC kindreds harbor germline mutations either in hMlh1 (33%) or hMsh2 (31%). Studies of the cancers that arise in these individuals typically demonstrate retention by the tumors of the inherited mutant hMlh1 or hMsh2 allele, accompanied by either loss or mutation of the companion wild-type allele. As would thus be expected, cancer cells from such tumors show in functional assays the absence of mismatch repair ability.25,26 With the exception of a few selected kindreds,27 intact mismatch repair function is generally present in the lymphocytes from individuals with HNPCC despite the presence of a germline mutation in a mismatch repair family gene. These mutant genes are thus most commonly recessive at the cellular level, however, and inheritance of the disease phenotype as a dominant trait reflects the high rate of second-hit events during normal living.
Recognition of the role of defective mismatch repair in cancer has been greatly facilitated by recognition that tumors defective in mismatch repair demonstrate the associated phenotype of instability of microsatellite DNA sequences.28 DNA microsatellites are regions of repetitive DNA sequences in which the repeated unit is from one to three DNA bases long. The most common class of such microsatellites are of the form (CA)n. Such microsatellite repeats are scattered throughout the human genome, and although the length of any given microsatellite is highly variable from one individual to another, for a single individual a given microsatellite demonstrates the same fixed length in all of that individual’s different tissues. The laboratory of Bert Vogelstein, MD, first noted the unanticipated finding that, in HNPCC, the pattern of microsatellite lengths in an individual’s colon cancer differed from that of his germline or somatic tissues.28 This observation is now understood to reflect that DNA polymerases are prone to slip while copying long stretches of the repetitive microsatellite DNA sequences and that, in the absence of effective DNA mismatch repair, the resulting insertion or deletion errors go undetected and unrepaired.3 Tumors that demonstrate such MSI are alternatively referred to as tumors that demonstrate replication errors.
The greater importance of mismatch repair defects in human carcinogenesis was demonstrated by the simultaneous observations by the laboratories of Manuel Perucho and Stephen Thibodeau that in unselected series of individuals with colon cancer nearly 15% were found to have MSI.29,30 Moreover, similar to the colon cancers that arise in HNPCC kindreds, MSI cancers that were seemingly sporadic in origin arose predominantly within the right colon. In some rare instances, it has been shown that these MSI colon cancers arose as a result of an isolated somatic mutation in an Msh2 or Msh1 allele.31 Unexpectedly, the most common mechanism underlying MSI in sporadic colon cancers has been shown to be the transcriptional silencing of the hMlh1 gene consequent to methylation of the hMlh1 gene promoter.32-34 Significantly, the chemotherapeutic agent 5-azactytidine can reverse this methylation and has been demonstrated to reactivate hMlh1 gene expression in these sporadic MSI cancers.32,34 The possibility of pharmacologic hMlh1 gene reactivation suggests that we may be able to turn on hMlh1 to aid in sensitizing MSI tumors to chemotherapy or, possibly, as a chemopreventive strategy for interrupting MSI-induced neoplasia. Of note, seemingly sporadic colon cancers in individuals in whom the cancer develops when the individual is 35 years or younger have been shown in 58% of the cases to be the result of germline mutations in a mismatch repair gene35 that were either new mutations or that had inexplicably not induced previous cancer in other immediate family members.35
One insight into the mechanism by which defective mismatch repair accelerates cancer development results from studies that have shown nearly 1,000-fold increases in spontaneous gene mutation rates in cell culture cells from MSI colon cancer.36,37 Because cancer is the end result of accumulated mutations in key cancer oncogenes and tumor suppressor genes, such increased gene mutation rates could in theory translate into a high susceptibility to early development of cancer.38 The next question posed by these observations is whether the genes targeted for mutation in MSI colon cancers are the same or different from those genes whose mutations give increase to sporadic colon cancers. Initial studies have shown that, like non-MSI colon cancers, MSI colon cancers exhibit a high incidence of mutations in the adenomatous polyposis coli gene.39 However, studies have also suggested that MSI colon cancers have a much lower incidence than non-MSI colon cancers of mutations in the K-ras oncogene and the p53 tumor suppressor gene.30,40
Mutations in a novel tumor suppressor gene, the gene encoding the type II component of the TGF-ß receptor (RII), have been demonstrated to be present in greater than 90% of MSI colon cancers. The TGF-ßs (TGF-ß1, ß2, and ß3) are a family of three highly homologous growth regulatory molecules that inhibit the growth of epithelial cells in general and that have been shown to both inhibit the growth of and induce apoptotic cell death in colon epithelial cells.41,42 In contrast to their potent negative regulatory effects on nontransformed epithelial cells, most cancer cells are either relatively or absolutely resistant to the effects of TGF-ß.41,43-53 The TGF-ßs all act by binding to a common cell surface receptor complex that is composed of a heterodimer of a type 1 (RI) and type 2 (RII) subunit.54-57 It is now clear that, in the cases of MSI colon cancers, TGF-ß resistance is a result of mutational inactivation of the RII gene58,59 (reviewed in43 ). The RII gene is uniquely vulnerable to mutation in MSI cancers, as the gene-coding region includes a unique 10–base-pair polyadenine repeat, essentially a mini-microsatellite sequence (Fig 1). Frameshift mutations within this sequence have been demonstrated to be present in more than 90% of MSI colon cancers.58,59 These frameshift mutations encode for a truncated, and potentially secreted, mutant receptor that lacks the wild-type membrane spanning and cytoplasmic domain and, hence, would be inactive in signaling. Reintroducing a wild-type RII gene in cultured MSI colon cancer cells abrogates the ability of the cells to form tumors in immune-deficient mice, which directly demonstrates the tumor suppressor gene activity of RII, specifically, and of the TGF-ß pathway, in general.60 RII gene mutations have also been found in 90% of MSI gastric cancers.61 RII mutations thus provide a novel genetic pathway for the development of MSI gastrointestinal cancers. Unexpectedly, RII mutations are uncommon in MSI endometrial cancers,61 which suggests that tissue-specific or environmental factors also participate in either the generation or the selection of these mutations. In the colon, the timing of RII mutations is essentially coincident with the transition of late colon adenomas to overt carcinomas.62 Most recently, the TGF-ß pathway has been shown to be involved in tumor suppression in microsatellite-stable colon cancers. This is demonstrated first by the finding in these cancers of novel RII mutations that inactivate the receptor.63 Additionally, the entire TGF-ß signal transduction pathway possesses tumor suppressor activity, as shown by the finding in additional microsatellite-stable colon cancers of mutations in the Smad2 and Smad4 postreceptor signaling elements (Fig 2). 64-66
The distinct genetic background of MSI colon cancers suggests that these tumors may have a distinct set of clinical behaviors. Indeed, a number of studies have suggested that individuals with MSI colon cancers enjoy a superior survival when compared with individuals with non-MSI colon cancers.29,67,68 Additionally, some cancers with defects in mismatch repair demonstrate resistance to DNA methylating agents, including laboratory compounds such as MNNG69 and chemotherapeutic agents such as temozolomide, a dacarbazine-related agent currently undergoing clinical trials for treatment of colon cancer.70 Moreover, mismatch repair–deficient tumors also show cross-resistance to the base analog 6-thioguanine.71 These agents all have in common the introduction of false or adducted bases into the DNA that then induce aberrant nucleotide mispairs that are recognized by the mismatch repair system. However, it is presumed that the mismatch repair system is unable to correct these mispairs when the false base resides on the template DNA strand and so instead participates in induction of cell-death pathways.72,73 The resistance of mismatch repair defective colon cancers seems selective for DNA methylating agents, because in culture these cells show no change in resistance to bifunctional alkylators such as nitrosourea compounds.70 MSI cancers thus define a novel molecular pathway of human carcinogenesis. Recognition of these tumors has led to the identification of novel human cancer genes. Recognition of these tumors in the clinic may have implications for the clinical care of certain individuals. With the coming availability of genetic testing, recognition of these tumors is also likely to lead to the identification of and specialized care for whole families who bear an inherited susceptibility to cancer development.
S.M. is an investigator of the Howard Hughes Medical Institute. Additional support for these studies was provided by grants from the National Cancer Institute, Bethesda, MD.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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INTRODUCTION
FUNCTIONS OF THE BASE-BASE...
