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Review: Field Effect in Cancer–An Update Available online at www.annclinlabsci.org Annals of Clinical & Laboratory Science, vol. 39, no. 4, 2009 331 Review: Field Effect in Cancer–An Update Hong Chai and Robert E. Brown Department of Pathology and Laboratory Medicine, University of Texas Health Science Center–Medical School at Houston, Houston, Texas Abstract. The concept “field effect in cancer” originated in 1953 from the histopathological observations of Slaughter and colleagues [1] regarding the occurrence of multiple primary oral squamous cell carcinomas and their local recurrences. The development of modern molecular technologies has extended the field effect concept by exploring the molecular abnormalities in tissues that appear histologically normal. To date, such field effect biomarkers have been reported in several sites and organs, eg, head and neck, colon and rectum, prostate, breast, lung, esophagus, stomach, and skin. Two popular hypotheses have been proposed. One hypothesis implicates genetic alterations that occur in a stepwise fashion (initiation, promotion, and progression); a clone gains growth advantage and acquires more genetic alterations, which eventually result in cancer. A second hypothesis focuses on epigenetic alterations, which include hypermethylation of the DNA promoter of certain tumor suppressor genes, leading to down-regulation of these genes. In this update, we discuss in detail the evidence that supports these two hypotheses. In addition, we attempt to provide a comprehensive overview of the field effect in carcinogenesis and its possible mechanisms in various organs. Moreover, we discuss the potential utilization of field effect biomarkers in cancer prevention, surgical considerations, and clinical prognosis. Keywords: field effect, carcinogenesis, field cancerization, multiple primary cancers, DNA methylation Introduction benign contiguous tissue. Based on these findings, they suggested field cancerization to be an The concept of the field effect in cancer, also known important factor in recurrence of oral cancer after as field defect or field cancerization, was introduced therapy. This interesting concept is considered to by Slaughter et al in 1953 [1]. In this classic paper, underlie the multicentricity of cancer in many, if the authors studied oral squamous cell carcinomas not all, patients who have multiple tumors in the in 783 patients from the gross and microscopic same organ but no apparent familial predisposition standpoint. They found 88 instances of independent to those tumors. In recent years, the development multiple tumors, which was far beyond the of modern molecular technologies has extended the statistical probability of their chance occurrence field effect concept by exploring the molecular [1]. They also observed microscopic abnormalities abnormalities in tissues that appear histologically (hyperplastic or atypical epithelium) in grossly normal. To date, such field effect biomarkers have been reported in various sites and organs, including Address correspondence to Robert E. Brown, M.D., Depart- the head and neck [2], lung [3], colon and rectum ment of Pathology and Laboratory Medicine, University of Texas Medical School-Houston, 6431 Fannin Street MSB [4,5], breast [6], stomach [7], prostate [8,9], and 2.286; Houston, TX 77030, USA; tel 713 500 5332; fax bladder [10]. 713,500 0695; e-mail: [email protected]. 0091-7370/09/0400-0331. $2.45. © 2009 by the Association of Clinical Scientists, Inc. 332 Annals of Clinical & Laboratory Science, vol. 39, no. 4, 2009 Thus far, the exact underlying mechanisms of at the surgical margins [16]. This may partially the field effect in cancer are not fully understood. explain the high frequency of local recurrences and However, growing molecular evidence suggests a second primary tumors in HNSCC patients. Based carcinogenesis model in which the development of on these data, Tabor et al [16] proposed that a field with genetically altered cells plays a central accumulation of genetic alterations forms the basis role [2]. In addition, alterations of DNA methylation for the progression from a normal cell to a cancer patterns may contribute to field effects [11]. In this cell, referred to as the process of multistep review, we attempt to summarize the current carcinogenesis. This process involves at least three evidence regarding the cancer field effect in several steps. In the initial phase, a stem cell acquires well-studied organ systems. We discuss the findings genetic alterations and forms a “patch,” a clonal in each system and consider possible common unit of altered daughter cells. Such patches can be mechanisms for this phenomenon. We also review recognized on the basis of mutations in TP53 [17]. the possible role of field effect as a surrogate Next, a patch is converted into an expanding field. biomarker in cancer prevention and as a predictor Additional genetic alterations are required for this of carcinogenesis and clinical prognosis. step, and by virtue of its growth advantage, a proliferating field gradually replaces the normal Squamous Cell Carcinoma of Head and Neck mucosa. In the mucosa of the head and neck, as well as the esophagus, such fields have been detected Head and neck squamous cell carcinoma (HNSCC) with a diameter of >7 cm using molecular analysis, is one of the common malignancies in humans. whereas they are usually not detected by routine The average 5-yr survival rate is one of the lowest histopathological techniques [2]. Ultimately, clonal among aggressive cancers, and has not been divergence leads to the development of one or more significantly improved during the last two decades tumors within a contiguous field of pre-neoplastic [12]. Advances in surgical and nonsurgical therapy cells. An important clinical implication is that have led to increased local tumor control. However, fields often remain after surgery of the primary overall mortality rates have not improved, mostly tumor and may lead to new cancers, designated due to tumor recurrence at regional and distant presently by clinicians as “second primary tumor” sites [13]. Local recurrences and the development or “local recurrence,” depending on the exact site of second primary tumors occur in cases with and time interval. This hypothesis has also been advanced tumors, even with histopathologically postulated in other organ systems. tumor-free surgical margins [14]. A large proportion of these cases shows a common clonal origin, even Cancers of Colon and Rectum if the lesions are >7 cm apart [15]. Such observations support the hypothesis of a field effect in cancer. Colorectal cancer is currently the fourth most The term “field cancerization,” also known as common malignancy and the third most common “field effect,” was first used by Slaughter et al [1] in cause of death from cancer worldwide (WHO fact 1953. Originally, histological examinations were sheet, February 2009). It is typified by tumor performed on tumor-adjacent “normal tissue” and progression from adenoma to carcinoma, with surgical margins to assess the presence of a field mutations in the Adenomatous Polyposis Coli lesion. With the application of modern molecular (APC) gene believed to be one of the earliest genetic technologies, new findings support a carcinogenesis aberrations. In colorectal cancer, the field effect is model in which the development of a field with usually characterized by the simultaneous genetically altered cells plays a central role. occurrence of multiple but distinct tumors. In the Measuring the loss of heterozygosity (LOH) with multistep carcinogenesis model proposed by Fearon microsatellite analysis shows that a significant and Vogelstein [18], genetic alterations occur in a proportion of samples have tumor-associated stepwise fashion such that a clone with growth genetic alterations in biopsies from the histopath- advantage proliferates, acquires more genetic ologically normal mucosa adjacent to the tumor or alterations, and undergoes another selection for Field effect in cancer–an update 333 survival and growth, eventually resulting in cancer. in recent years suggest that there is synergy between According to this model, precancerous cells that genetic and epigenetic changes and that Knudson’s are in proximity to cancer cells should have some, two-hit hypothesis [23] may need to be revised: but not all, of the genetic alterations that are present instead of two possibilities (loss of heterozygosity in the fully developed cancer. At least three steps or homozygous deletion), a third possibility– are suggested in tumorigenesis: initiation, pro- transcriptional silencing by DNA methylation of motion, and progression [18]. Initiation starts when promoters–can disable tumor-suppressor genes a loss of specific chromosomal regions occurs, [11,24,25]. Shen et al [4] reported methylation of which is frequent in colorectal neoplasia. The the O6-methylguanine-DNA methyltransferase common region of loss on chromosome 17p in (MGMT) gene promoter in normal-appearing colorectal tumors has been identified and contains colorectal mucosa adjacent to colorectal cancer [4]. the p53 gene [19] (the TP53 gene in humans). p53 They demonstrated that normal appearing mucosa encodes a transcription factor that is important in located 1 cm from a colorectal cancer with MGMT multicellular organisms, where it regulates the cell promoter methylation is more likely to have hyper- cycle and functions as a tumor suppressor that is methylation than normal-appearing colorectal involved in preventing cancer [20]. The second
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