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Gastrointestinal Tract Cancers: Genetics, Heritability and Germ Line Mutations (Review)

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Gastrointestinal Tract Cancers: Genetics, Heritability and Germ Line Mutations (Review) ONCOLOGY LETTERS 13: 1499-1508, 2017 Gastrointestinal tract cancers: Genetics, heritability and germ line mutations (Review) XIAO-PENG LV Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical College, The Affiliated Xuzhou Hospital of Medical College of Southeast University, Xuzhou, Jiangsu 221009, P.R. China Received October 7, 2016; Accepted November 21, 2016 DOI: 10.3892/ol.2017.5629 Abstract. Gastrointestinal (GI) tract cancers that arise due and DNA repair (1). Although the majority of cases appear to genetic mutations affect a large number of individuals to arise sporadically, a small percentage of GI cancers worldwide. Even though many of the GI tract cancers arise have an apparent hereditary component, as evidenced by sporadically, few of these GI tract cancers harboring a the well-characterized genetic syndromes and the family hereditary predisposition are now recognized and well charac- history associated with the high risk of these syndromes (2). terized. These include Cowden syndrome, MUTYH-associated Nearly 5% of inherited cases are due to highly penetrant polyposis, hereditary pancreatic cancer, Lynch syndrome, mutations with well characterized clinical presentations (3). Peutz-Jeghers syndrome, familial adenomatous polyposis An additional 20-25% of cases are estimated to have an (FAP), attenuated FAP, serrated polyposis syndrome, and associated hereditary component, which has not yet been hereditary gastric cancer. Molecular characterization of the established (4). Many of the GI tract cancers appear to be genes that are involved in these syndromes was useful in the due to mutations in single genes and these types of cancer development of genetic testing for diagnosis and also facili- are less penetrant but occur more frequently as compared tated understanding of the genetic basis of GI cancers. Current to the cancers seen in combination with well-characterized knowledge on the genetics of GI cancers with emphasis on syndromes (1). Examples for single gene mutations include heritability and germ line mutations forms the basis of the common single-nucleotide polymorphisms (SNPs) in genes present review. that are involved in the control of metabolism or which are regulated by environmental factors (4). Mutations in multiple susceptibility loci can also lead to these cancers by inducing Contents additive effects (2). Identification of individuals who are at risk for GI tract cancer, and the development of methods for 1. Introduction better diagnosis and prevention of cancer and therapeutic 2. Hereditary CRC syndromes approaches is dependent on proper understanding of the 3. CRC syndromes with adenomatous polyps molecular basis and genetics of GI tract cancers (3). 4. Hamartomatous polyposis syndromes The present review addresses the genetics of the currently 5. Conclusion well-characterized hereditary cancers of GI tract. In this review we focus on the genetics of hereditary GI cancers, which are primarily that of a type of colorectal cancer (CRC) 1. Introduction syndromes and also briefly discuss some aspects of pancreatic, and stomach cancers. Cancers arising within the gastrointestinal (GI) tract are genetic disorders caused by the sequential accumulation of 2. Hereditary CRC syndromes alterations in genes that control the growth, differentiation, Clinical, pathological, and genetic features form the basis for identifying and classifying the CRC syndromes. Pathophysiological conditions that lead to adenomatous polyps Correspondence to: Dr Xiao-Peng Lv, Xuzhou Central Hospital, include familial adenomatous polyposis (FAP), attenuated Xuzhou Clinical School of Xuzhou Medical College, The Affiliated FAP (AFAP), MUTYH-associated polyposis (MAP) and Xuzhou Hospital of Medical College of Southeast University, Lynch syndrome. Hamartomatous polyps are the primary 199 Jiefang South Road, Xuzhou, Jiangsu 221009, P.R. China lesions in Peutz-Jeghers syndrome (PJS) and juvenile polyp- E-mail: [email protected] osis syndrome (JPS) (5). Serrated polyposis syndrome (SPS) is unique situation as it poses much higher cancer risk and Key words: genetics, heritability, gastrointestinal cancers, therefore this syndrome needs to be identified separately from mutations other conditions. Except for MAP, all these abovementioned conditions are inherited autosomal dominant disorders. MAP 1500 LV: GASTROINTESTINAL TRACT CANCERS: GENETICS, HERITABILITY AND GERM LINE MUTATIONS Table I. Mode of inheritance of non-polyposis syndrome as well as the associated genes, lifetime risk of cancer development and non-malignant features. Syndrome Inheritance Gene Sites Lifetime risk (%) Non-malignant features Lynch Autosomal hMLH1 Colon 50-80 Physical or non-malignant features, with the syndrome dominant hMLH2 Endometrium 40-60 exception of keratoacanthomas and hMLH6 Stomach 11-19 sebaceous adenomas/carcinomas, are rare hPMS2 Ovary 9-12 EpCAM Hepatobiliary tract 2-7 EpCAM Upper urinary tract 4-5 Pancreas 3-4 Small bowel 1-4 CNS 1-3 hMLH, human mutL homolog; hPMS2, human postmeiotic segregation 2; CNS, central nervous system. is autosomal recessive, whereas, SPS is rarely inherited. There occurring simultaneously) and metachronous (multiple cancers are many similarities between the phenotypes of AFAP and occurring at intervals) tumors (22,23). Synchronous and MAP, which are associated with varying numbers of adenomas, metachronous cancers occur to different extents in individuals and these also resemble the phenotypes of Lynch syndrome, with Lynch syndrome (50% incidence) as compared to those sporadic polyps, and other polyposis syndromes, often causing with sporadic CRC (20% incidence) (14,24). Furthermore, the some confusion (6). Despite the clinical similarities between right or proximal colon are frequent sites for CRC in Lynch these syndromes, each of them has unique genetic aetiologies syndrome patients, whereas in individuals with sporadic CRC, and cancer risks, and also specific clinical features. there is relatively higher incidence of sigmoid/distal carci- nomas (9,13,14,25). Crohn's-like reactions, tumor-infiltrating 3. CRC syndromes with adenomatous polyps lymphocytes, signet ring cells and mucinous adenocarcinoma are some of the main pathologic features of CRC associated Conditions that express adenomatous polyps are seen only in a with Lynch syndrome. These pathological features, which few of the inherited GI cancer predisposition syndromes, such are often considered as red flags for Lynch syndrome, are as Lynch syndrome, FAP, AFAP, and MAP. The chances of less common in sporadic CRC (14,21,22,26). A high level developing colon cancer and tumors elsewhere are quite high of microsatellite instability (MSI-H), which is a feature of in these syndromes (7) and non-malignant manifestations carcinogenic process when there is defective DNA mismatch, seen in these syndromes contribute to elevated morbidity and is also a characteristic of Lynch syndrome. Studies show that mortality. MSI-H-bearing colon cancers have better overall prognosis unlike the colon cancers without MSI (27). Lynch syndrome. Lynch syndrome or hereditary non-polyposis Germline mutations in mismatch repair (MMR) genes, colon cancer is one of the main causes for up to 5% of all which are a special class of tumor suppressor genes that are CRC (8-10). Individuals with Lynch syndrome have an 80% responsible for correcting DNA errors that occur during risk for CRC (4). The syndrome is also associated with an replication, lead to the pathogenesis of Lynch syndrome (23). increased risk of developing malignancies at extra-colonic sites Genes recognized to be associated with Lynch syndrome such as endometrium, stomach, ovary, small bowel, pancreas, include human mutL homolog 1 (hMLH1) at 3p21.3, human ureter, renal pelvis, hepatobiliary tract, and brain (11-14). mutS homolog 2 (hMSH2) at 2p21-p22, hMSH3 at 5q11-q12, Among these sites, cancer arising within endometrium is the hMSH6 at 2p16 human postmeiotic segregation 1 (hPMS1) at second most common malignancy in Lynch syndrome with a 2q31-q33, and hPMS2 at 7q22 (22). Almost 90% of the cases lifetime risk between 40 and 60% (Table I), which is similar to with Lynch syndrome arise due to mutations in hMLH1 and or even higher than the estimated risk for CRC in women with hMSH2, whereas a small number of cases (10%) are thought Lynch syndrome. However, endometrial cancer often occurs to be due to mutations in hMSH6 and only on rare occasions before CRC in these women (8,15,16). Approximately 2% of all mutations in hPMS2 are evident (28-31). Mutations in these endometrial cancers likely arise due to Lynch syndrome (17). genes show predominantly autosomal dominant inheritance An important feature of Lynch syndrome is that there is with close to 80% penetrance for CRC and a 25% risk for an early onset of cancer as compared to the general popula- metachronous CRC (14). These numbers are relatively lower tion (13,18). Thus, while in the general population, CRC has for endometrial cancer (60% penetrance) as well as for an onset at 65 years and endometrial cancer at 60 years, these other cancers (<20%). Observed phenotypic variations show onset ages are much lower in people with Lynch syndrome, dependency on the specific gene mutation. Thus, there is a at 44 and 48 years, respectively, for these two types of slightly increased incidence of endometrial cancer in families cancer (14,19-21). Lynch syndrome is also characterized by with hMSH6 mutations who also show a moderately lower the occurrence of synchronous (multiple primary
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