The inherited polyposis syndromes are a group of CLINICAL GENOMICS

Transcription

1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2005;3: CLINICAL GENOMICS Inherited Polyposis Syndromes: Molecular Mechanisms, Clinicopathology, and Genetic Testing BRETT W. DOXEY,* SCOTT K. KUWADA,*,, and RANDALL W. BURT*, *Division of Gastroenterology, University of Utah Health Sciences Center, Salt Lake City VA Medical Center, and Huntsman Cancer Institute, Salt Lake City, Utah The inherited polyposis syndromes are a group of conditions in which multiple gastrointestinal polyps occur in the lumen of the gastrointestinal tract, most exhibit an increased risk of colon cancer. Benign and malignant extraintestinal tumors might also be observed. Recent elucidation of the underlying gene mutations has contributed to our understanding of the cell biology and molecular mechanisms associated with gastrointestinal tumorigenesis. Developments have also allowed genetic testing to become an integral component in accurate diagnosis, categorization, and management of inherited polyposis syndromes. In this review, we will focus on familial adenomatous polyposis, muty human homologue associated polyposis, Peutz Jeghers syndrome, juvenile polyposis, and Cowden syndrome. It is essential that both physician and patient understand the benefits and limitations of genetic testing before submission of samples to the laboratory. There are many issues accompanying molecular diagnosis of cancer syndromes, and genetic counseling is an essential prelude to genetic testing. The inherited polyposis syndromes are a group of conditions in which multiple gastrointestinal polyps occur in the lumen of the gastrointestinal tract (Table 1). Most of these syndromes exhibit an increased risk of colon cancer, and benign and malignant extraintestinal tumors might also be observed. Recent elucidation of the underlying gene mutations has contributed to our understanding of the cell biology and molecular mechanisms associated with cancer pathogenesis and allowed refinement of the categorization, phenotypes, and cancer risks of the inherited polyposis syndromes. A review of the molecular genetics and the current role of genetic testing will be discussed with regards to familial adenomatous polyposis (FAP), muty human homologue (MYH) associated polyposis, Peutz Jeghers syndrome (PJS), juvenile polyposis (JP), and Cowden syndrome (CS). Familial Adenomatous Polyposis FAP was first reported in the medical literature in 1861 and The autosomal-dominant inheritance pattern was established by ,2 The condition includes Gardner syndrome, a portion of Turcot syndrome families, and attenuated adenomatous polyposis coli, also called attenuated FAP (AFAP). FAP is a syndrome characterized by hundreds thousands of adenomatous colon polyps beginning at a mean age of 16 years (range, 7 36 years). By age 35 years, 95% of individuals with FAP have polyps. Without colectomy, colon cancer is inevitable, with a mean age of colon cancer in untreated individuals of 39 years (range, years). Extracolonic manifestations are variably present and include fundic gland polyps of the stomach, duodenal adenomas, osteomas, dental anomalies, congenital hypertrophy of the retinal pigment epithelium, soft tissue tumors, and desmoid tumors. Other associated malignancies include duodenal tumors (especially periampullary), thyroid, CNS, adrenal, and hepatoblastoma. Estimates of the prevalence of FAP vary from cases per 100,000 people. Men and women are affected equally, and the frequency is fairly constant worldwide. Approximately.5% of all colon cancer cases historically have arisen in the setting of FAP; however, the figure might now be as low as.07%, possibly as a result of early diagnosis and intervention in identified FAP families. 3,4 Approximately 75% 80% of individuals with FAP have Abbreviations used in this paper: AFAP, attenuated familial adenomatous polyposis; APC, adenomatous polyposis coli; BMPR1A, bone morphogenic protein receptor 1A; BRR, Bannayan-Ruvalcaba-Riley syndrome; CS, Cowden syndrome; EB1, end-binding protein 1; FAP, familial adenomatous polyposis; hd1g, human discs large; JP, juvenile polyposis; LDD, Lhermitte-Duclos disorder; MYH, muty human homologue; PJS, Peutz Jeghers syndrome; PTT, protein truncation testing; SMAD4, mothers against decapentaplegic homolog 4; TGF, transforming growth factor by the American Gastroenterological Association /05/$30.00 PII: /S (05)

2 634 DOXEY ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 3, No. 7 Table 1. Inherited Polyposis Syndromes Familial adenomatous polyposis Gardner syndrome Turcot syndrome (2/3rd characterized by polyposis and APC germline mutation, 1/3rd as nonpolyposis and MMR germline mutations) FAP MYH-associated polyposis Hamartomatous syndromes Familial JP PJS CS LDP BRR Basal cell nevus Neurofibromatosis 1 Multiple endocrine neoplasia 2B Gorlin s Hereditary mixed polyposis Hyperplastic polyposis syndrome (inheritance is questionable) an affected parent. Offspring of an affected individual have a 50% risk of inheriting the altered APC gene, and up to one third of newly diagnosed cases appear to represent de novo mutations. Familial Adenomatous Polyposis: The APC Gene FAP arises from germline mutations of the APC gene on the long arm of chromosome 5 (5q21-q22). 5,6 The APC protein localizes to the nucleus and to the cytoskeleton in human epithelial cells. 7 It also binds to other proteins including glycogen synthase kinase 3, -catenin, -catenin, tubulin, EB1, and hdlg. 8,9 In FAP, one mutated allele is inherited and present in every cell of the colon (and body). Colonic adenoma formation is believed to be initiated when the second allele is damaged or lost by a somatic or acquired mutation, although this is controversial at present. Mutational inactivation of the APC protein also appears to be an early, if not the first, step in the pathogenesis of more than 80% of all colonic adenomas and cancers. 9 APC isaprimeexampleofatumor suppressor gene, requiring loss of both alleles for tumorigenesis. The progression of adenoma to carcinoma after APC inactivation is similar in FAP and the sporadic setting, with accumulation of mutations in additional relevant genes including K-ras and p53 and a gene or genes on chromosome In sporadic adenomas, the APC alleles must be damaged or lost by acquired mutations for adenoma formation to begin, which is why they typically occur at a much later age than in FAP. One of the principal roles of the APC protein is regulation of the Wingless/Wnt signaling pathway. 11 Mutation of the APC gene results in a defective complex of glycogen synthase kinase 3, APC, and axin, which is unable to bind or phosphorylate -catenin, preventing its degradation. The cytoplasmic accumulation of -catenin results in constitutive activation of the Wnt signaling pathway, which favors cell growth and suppression of apoptosis. The APC protein also binds to microtubules and can promote microtubule assembly in vitro. This microtubule assembly might play a part in the normal migration mechanism of the colonocyte up the colonic crypt. Mutated APC may cause disruption of normal cellular positioning in the crypt. 12,13 The APC protein has also been shown to accumulate at the kinetochore during mitosis, contribute to kinetochore-microtubule attachment, and play a role in chromosome segregation in mouse embryonic stem cells. 14,15 This has led some to hypothesize that mutations of APC might play a role in the chromosomal instability often manifested when APC function is lost, although this is controversial. Familial Adenomatous Polyposis: APC Mutations and Genetic Testing Methods More than 825 different germline mutations have been found to date in families with FAP. 16 Greater than 90% of APC germline mutations that cause FAP give rise to a truncated protein product with loss of normal function. To some extent, the location of the APC gene mutation correlates with the number of colonic adenomas and extracolonic manifestations; however, identical mutations can be associated with differing phenotypes Modifying genes and additional mutations of the APC gene are 2 hypotheses that might explain these observations. The laboratory methods used for genetic testing in FAP have included protein truncation testing (PTT), gene sequencing, and linkage testing. 21 PTT examines for truncation of the APC protein in vitro and thus also assures that a mutation actually causes disease. It must be understood, therefore, that PTT infers, but does not specifically identify, the disease-causing mutation. DNA sequencing of the APC gene is more accurate than PTT and has supplanted PTT as the test of choice. The specific disease-causing mutation is identified in greater than 90% of families with known FAP. Once the mutation has been identified in an index case in a family, other family members can be tested for that identical germline mutation. The accuracy for mutation finding in relatives after a germline mutation has been identified in an index case is nearly 100%.

3 July 2005 INHERITED POLYPOSIS SYNDROMES 635 Table 2. Molecular Genetic Testing Available for FAP Method Mutations detected Detection rate Availability, details, and cost Full gene sequencing APC sequence alteration Up to 90% Up-to-date information available through the website: Mutation scanning 80% 90% Southern blot analysis Deletion or duplication of one or more exons May be helpful if large gene deletion is present. Linkage analysis Markers linked to APC gene 95% of families Familial Adenomatous Polyposis: Clinical Process of Genetic Testing Molecular genetic testing of APC detects disease-causing mutations in up to 95% of probands (Table 2). There are 3 settings in which to consider genetic testing for FAP: (1) testing a person with some features of FAP, but where the clinical diagnosis is not certain; (2) testing a person with clinically defined FAP, but where the mutation is not known in the family; and (3) testing relatives in an FAP family once the mutation is known. The first setting is usually defined as a person with 20 or more adenomas but no known family history of FAP. Finding a mutation confirms the diagnosis of FAP and allows relatives to be tested with high accuracy. Successful initial mutation finding is 90% at best, and failure to identify a mutation does not rule out FAP. Genetic testing in the second situation is similar, but the patient has more than 100 adenomas. Possible nonmedical explanations should also be considered, including alternate paternity or undisclosed adoption. Failure to find a mutation means that all close relatives must still be screened as if they have the condition, because it was already clinically defined in one case. In the third setting, relatives of a person with a known germline APC mutation are tested for the presence or absence of that mutation. A positive test result indicates the diagnosis of FAP, whereas a negative test result (absence of mutation) essentially rules it out because a known germline mutation was identified in a family member. Such persons then need only average risk screening for colon cancer. Colon screening begins as early as age 10 years for those at risk for classic FAP and age 18 years for those with AFAP. Therefore, molecular genetic testing is generally offered to an individual age 8 years and older for FAP families and age 18 years or older for AFAP families. Genetic counseling is an essential prelude to genetic testing. 22 A number of important medical and psychosocial issues surround genetic testing. Individuals considering undergoing testing need to understand the ramifications, benefits, and limitations of testing before submitting samples to the laboratory. Informed consent for testing is then required before testing is done. 23 One study demonstrated that for almost one third of individuals assessed for FAP, the physician misinterpreted the test results. 24 It is essential that the physician be familiar with the issues, use trained genetic counselors, or refer to a center at which testing is routinely offered to minimize psychosocial hazards and potentially expensive missteps in testing. More comprehensive descriptions of the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without molecular genetic testing are available through the National Society of Genetic Counselors and the National Cancer Institute. 25 Genetic testing is usually done on DNA obtained from peripheral blood leukocytes. A number of genetic testing laboratories now perform genetic testing for FAP and other inherited conditions. Information about available testing laboratories, test details, and cost of testing is available through the website MYH-Associated Polyposis MYH-associated polyposis is an autosomal-recessive inherited syndrome of multiple colorectal adenomas and carcinoma. It has been reported that MYH mutations might account for 7% 8% of families with the FAP phenotype in whom the APC germline mutation has not been identified. 26,27 Patients present with clinicopathologic features difficult to distinguish from FAP or AFAP, but in the absence of a strong multigenerational family history of polyposis. Patients typically present between the ages of years. The average number of adenomas at presentation is 16, but it might number in the hundreds. 28 Carriers of biallelic and monoallelic germline MYH mutations have an increased risk of colorectal cancer and are more likely to have firstor second-degree relatives with colorectal cancer even in the absence of multiple adenomatous polyps. 29

4 636 DOXEY ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 3, No. 7 Table 3. MYH-Associated Polyposis Syndrome features Suggestive findings Clinicopathologic features of multiple adenoma or FAP Family history compatible with recessive inheritance Absence of germline APC mutation Available genetic tests Y165C, G382D mutations Consider sequence analysis for other MYH mutations, if common mutations not found. MYH-Associated Polyposis: Genetics, Pathophysiology, and Diagnosis MYH is a base excision repair gene on chromosome 1p (1p34.3-p32.1) which encodes the protein MYH (hmyh alpha1) that is involved in repairing oxidative damage to DNA. Oxidation of guanine nucleotides results in the formation of 8-hydroxyguanine, which pairs incorrectly with adenines. In the absence of base excision repair, this results in G:C to T:A conversion mutations. Loss of MYH is associated with G:C to T:A transversions in APC, leading to polyp formation and carcinoma. Studies have identified the 2 most common MYH mutations, G382D and Y165C, which account for approximately 85% of MYH-associated polyposis. 30 Appropriate candidates for MYH mutational analysis testing are patients who exhibit clinicopathologic features of multiple adenomas or FAP, who have a family history compatible with a recessive pattern of inheritance (colon cancers or multiple adenomas in only one generation, or in skipped generations), and in whom testing has failed to show a germline APC mutation. Sequence analysis might be done to identify mutations, or testing might be done by using targeted analysis for Y165C and G382D mutations (Table 3). Juvenile Polyposis Inherited hamartomatous syndromes have been described that account for less than 1% of colorectal cancers in the United States (Table 4). Hamartomatous polyps of JP are characterized by an overgrowth of some constituent of the lamina propria, submucosa, or muscular tissues. JP is an autosomal dominantly inherited condition with an incidence of approximately 1 in 100,000 individuals. At least one third of patients will have a family history of the disease. 31 It is characterized by multiple hamartomatous polyps of the colon and rectum, although polyps might occur throughout the gastrointestinal tract. 32,33 Sporadic juvenile polyps occur in 2% of the general pediatric population. JP is diagnosed when more numerous juvenile polyps are present and is suspected when Table 4. Hamartomatous Syndromes Syndrome Clinical diagnosis Available genetic tests JP Either of the following: (1) 5 juvenile polyps in the colorectum OR juvenile polyps throughout the gastrointestinal tract (2) Any number of juvenile polyps in a person with a known family history of JP SMAD4 (MADH4) mutation BMPR1A mutation PTEN mutation testing considered if SMAD4 and BMPR1A testing is negative PJS Histopathologically confirmed hamartomatous polyp(s). STK11 mutation At least 2 of the 3: (1) Family history of PJS (2) Characteristic hyperpigmentation (3) Small bowel polyposis CS Diagnosis in a person without a family history: PTEN mutation testing (1) Mucocutaneous lesions, and any one of the following: (a) 6 facial papules ( 3 must be trichilemmomas) (b) cutaneous facial papules and oral mucosal papillomatosis (c) oral mucosal papillomatosis and acral keratoses (d) 6 palmoplantar keratoses (2) Two major criteria (one must include macrocephaly or LDD) (3) One major and 3 minor criteria (4) Four minor criteria Diagnosis in a person with a family history: (1) One or more of the pathognomonic criteria a (2) Any one major criterion with or without minor criteria (3) Two minor criteria Up-to-date information available through the website a See Table 5 for pathognomonic, major, and minor features.

5 July 2005 INHERITED POLYPOSIS SYNDROMES 637 polyps occur more proximally in the gastrointestinal tract. Generally accepted clinical criteria for JP include (1) 5 juvenile polyps in the colorectum, (2) juvenile polyps throughout the gastrointestinal tract, or (3) any number of juvenile polyps in a person with a known family history of JP. 34,35 Inherited syndromes that exhibit the gastrointestinal phenotype of JP must also be ruled out, including CS, Bannayan-Ruvalcaba-Riley syndrome (BRR), and Gorlin s syndrome. Polyps begin to appear during the first decade of life, and dozens hundreds of polyps are present in the fully developed syndrome. The average age of diagnosis is 18.5 years. 36 Rectal bleeding with anemia is the most common presenting symptom, followed by abdominal pain, passage of tissue per rectum, and intussusception. A rare form of the disease can be observed in infancy that includes large numbers of juvenile polyps, bleeding, and protein-losing enteropathy with significant morbidity and even mortality. 37 JP has also been associated with hereditary hemorrhagic telangiectasia. 38 Capsule endoscopy represents an emerging tool for diagnosis and surveillance. 39 Endoscopically, polyps have a smooth surface, are often covered by exudates, might be sessile or pedunculated, and range in size from millimeters to centimeters. On cut sections, there are characteristic cysts with nondysplastic epithelial lining and cystic spaces filled with mucin. 40 Estimates of the risk of colon cancer vary from 9% 68%, and the mean age of colon cancer is 34 years with a range of years The cancer risk is believed to arise from the occurrence of adenomatous changes that develop within 50% of the juvenile polyps. Cancers of the stomach, duodenum, pancreas, and biliary tree have been reported in JP. 44 Difficulty exists in phenotypically distinguishing CS and BRR from JP, because each exhibits multiple intestinal juvenile polyps. Now that these syndromes can be defined genetically, a much more accurate classification is evolving. 45 Juvenile Polyposis: Genetics, Pathophysiology, and Diagnosis At least half of the families clinically affected with JP are found to have a disease-causing mutation of either the mothers against decapentaplegic homolog 4 (SMAD4) gene (also called the MADH4 or the DPC4 gene) on chromosome 18q21.1 or the bone morphogenic protein receptor 1A (BMPR1A) gene on chromosome ,47 The SMAD4 gene encodes a cytoplasmic mediator involved in the transforming growth factor beta (TGF- ) signal transduction pathway. Binding of TGF- to the TGF- receptor complex induces SMAD proteins to form complexes that are transported to the nucleus. Within the nucleus, the SMAD complexes mediate transcription of genes that lead to inhibition of cell proliferation. 48 SMAD mutations prevent formation of the complexes, favoring cellular proliferation and dysplastic transformation. 49,50 The BMPR1A is a serine-threonine kinase type 1 receptor that also belongs to the TGF- superfamily. It activates SMAD4 independently of TGF-, but the effector pathway, nuclear control, and transcriptional regulation are similar. It had been suggested that SMAD4 mutations that give rise to JP occur in the stromal cells underlying the epithelial cells that form the polyps. However, biallelic inactivation of the SMAD4 gene has been demonstrated in both the epithelial and stromal cells of JP polyps, suggesting that inactivation of SMAD4 is a primary event in the transformation of epithelial cells into polyps. 51 It was first estimated that SMAD4 mutations accounted for 35% 60% of JP cases; however, subsequent studies have suggested a smaller fraction, and a recent survey from Europe indicated that only 15% of JP families arise from germline mutations of the SMAD4 gene, whereas 38% are from germline mutations of the BMPR1A gene. 52,53 A few families with JP appear to arise from mutations of the PTEN gene, although some maintain that these families are actually CS families. 54 The genetic etiology of JP in up to 50% of cases remains elusive, indicating that other genes might be involved in the etiology of the syndrome. Diagnosis is based on recognition of the disease characteristics and genetic testing. Genetic testing is important to confirm the diagnosis in a proband and to test relatives. Commercial genetic testing is available for JP, and clinical testing is approached as it is in FAP. In individuals meeting the diagnostic criteria for JP, sequencing for all exons and intron-exon boundaries of MADH4 and BMPR1A is performed, with 20% 23% mutation detection rates. 55 If no mutation is found, molecular genetic testing of the PTEN gene might be appropriate. It has been suggested that periodic upper endoscopy and colonoscopy examinations begin in the late teens or earlier, if symptoms occur in those with a clinical or genetic diagnosis. Genetic testing has also been shown to markedly increase screening compliance in relatives of those with JP. 56 Peutz Jeghers Syndrome PJS is an autosomal dominantly inherited syndrome with an incidence estimated at 1 in 120,000 births. 57 It involves histologically distinctive hamartomatous polyps of the gastrointestinal tract and charac-

6 638 DOXEY ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 3, No. 7 teristic mucocutaneous pigmentation. 58 Polyps have a segmental frequency of small bowel, 96%; colon, 27%; stomach, 24%; and rectum, 24%. 59 The mucocutaneous melanin pigment spots are seen in more than 95% of affected individuals, are typically 1 5 mm in diameter, and most commonly occur in the perioral and buccal areas. Characteristic spots on the lips cross the vermilion border and, compared with freckles, are often much darker and more densely clustered. Polyp growth typically begins during the first decade, and the average age of diagnosis is 22 years in men and 26 years in women. The gastrointestinal polyps occur in 88% 100% of persons, range from.1 3 cm, and have a coarsely lobulated surface. Peutz-Jeghers polyps are nondysplastic and have normal overlying epithelium specific to the gastrointestinal site in which they are found. Polyps exhibit an arborizing pattern of growth with muscularis mucosa extending into branching fronds of the polyp, which might result in pseudoinvasion, which may be mistaken for cancer. Adenomatous change and cancer might occur in Peutz-Jeghers polyps. Adenomatous changes are thought to predispose to intestinal cancer in this syndrome through what is sometimes referred to as the hamartomaadenoma-carcinoma sequence. 60,61 The clinical course of PJS is commonly characterized by repeated surgeries for complications from small bowel polyps including intussusception, bleeding, and obstructive symptoms. 62 Both gastrointestinal and extraintestinal cancers are common in PJS, with a combined frequency of all cancers of 93% by age 65 years. 63,64 Extraintestinal cancers include pancreatic, breast, ovarian, testicular, and adenoma malignum of the cervix. 65 Malignant complications become the dominant cause of clinical problems after age 30 years, with an average age of 43 years for cancer diagnosis of any type. Peutz-Jeghers Syndrome: Genetics, Pathophysiology, and Diagnosis In patients with a concordant family history and at least one histopathologically confirmed hamartomatous polyp, a clinical diagnosis is made with the finding of either characteristic melanin pigment spots or small bowel polyposis. In the absence of a family history, diagnosis requires the finding of at least 2 histologically confirmed hamartomatous polyps. 66,67 PJS arises from mutations of the STK11 gene (also called LKB1) on chromosome 19p. 68 Approximately 50% of persons with PJS belong to affected families, whereas 50% are isolated cases and might represent new mutations. Germline mutations of the STK11 gene are found in 60% of those with inherited PJS and 50% of those without a family history, suggesting the possibility of other pathogenic PJS genes. PJS families without STK11 gene mutations exhibit a high incidence of biliary adenocarcinoma compared with families with mutations of STK Loss of the wild-type STK11 allele by mutation or promotor hypermethylation has been found in PJS polyps and cancers, verifying the central role of STK11 as the disease-causing gene of PJS. 70,71 Furthermore, the gene codes for a serine/threonine kinase that associates with the p53 gene and regulates specific p53-dependent apoptosis pathways. 72 Loss of kinase activity has been identified in multiple types of germline STK11 mutations. Mutations of -catenin and p53, but not APC, appear to play a role in neoplasm development after STK11 inactivation. 73 Genetic testing is commercially available for confirmation of clinical diagnosis and identification of at-risk family members. 74 A person known to have the clinical syndrome is first tested. If a relevant mutation can be found in the STK11 gene, other family members can be tested with near 100% accuracy. Cowden Syndrome CS, also called multiple hamartoma syndrome, is an autosomal-dominant condition characterized by multiple hamartomas of the skin, mucous membranes, gastrointestinal tract, and other organs. A high risk for cancer exists including those of the breast, which can be bilateral, thyroid, and perhaps other sites The disease occurs in approximately 1 in 200,000 individuals, but it is believed to be significantly underdiagnosed. An international consortium has developed diagnostic criteria for CS. 78 The hallmark of the syndrome is the presence of multiple facial trichilemmomas (which resemble warts and might be very subtle), oral mucosal fibromas, verrucous and hyperkeratotic skin lesions of the face and limbs, and cobblestone-like hyperkeratotic papules of the gingiva and buccal mucosa. 79 By the third decade of life, 99% of affected persons have developed mucocutaneous stigmata of the disease. Pathognomonic features, major criteria, and minor criteria are listed in Table 5. Possibly related cancers include those of the endometrium, kidney, colon, ovary, lung, melanoma, and retina. Additional benign soft tissue and visceral tumors that have been reported include hemangiomas, lipomas, lymphangiomas, neurofibromas, and meningiomas. Developmental or congenital abnormalities can also occur and include hypoplastic mandible, a prominent forehead, and a high-arched palate.

7 July 2005 INHERITED POLYPOSIS SYNDROMES 639 Table 5. Diagnostic Features of CS Pathognomonic criteria Mucocutaneous lesions Trichilemmomas, facial Acral keratoses Papillomatous papules Mucosal lesions Major criteria Breast carcinoma Thyroid carcinoma (non-medullary), especially follicular Macrocephaly (megalencephaly) LDD Endometrial carcinoma Minor criteria Other thyroid lesions (eg, adenoma or multinodular goiter) Gastrointestinal hamartomas Fibrocystic disease of the breast (male and female) Lipomas Fibromas Genitourinary tumors (renal cell carcinoma, uterine fibroids) or malformation The gastrointestinal hamartomas occur throughout the gastrointestinal tract, but they are most common in the stomach, colon, and esophagus. Lesions of the esophagus are actually glycogenic acanthosis, which appears as whitish flat elevations in the esophagus. 80 Several different types of hamartomas are observed including juvenile polyps, lipomas, inflammatory polyps, ganglioneuromas, and lymphoid hyperplasia. Juvenile-like polyps that contain some neural elements are considered characteristic of this disease. Gastrointestinal cancer risk has not generally been considered elevated, although one study in Japan found 9.6% of 93 CS cases to have colon cancer, indicating that better definition of the gastrointestinal phenotype is needed in other populations. 81 Management of CS involves surveillance and prevention of the associated cancers. Related syndromes include Lhermitte-Duclos disorder (LDD) and BRR. LDD is a rare hamartomatous overgrowth syndrome characterized by focal or diffuse enlargement of cerebellar folia that presents as a slowly growing posterior fossa mass. BRR is a congenital autosomal-dominant disorder characterized by developmental delay, lipomatosis, hamartomatous polyps, megalencephaly, and characteristic pigmented macules of the glans penis. Cowden Syndrome: Genetics, Pathophysiology, and Diagnosis CS, BRR, and LDD have been found to arise from mutations of the PTEN gene, which is located on chromosome 10q Mutations are found in more than 90% of families who exhibit features of both CS and BRR. 85 It has been suggested that CS and BRR be referred to together as the PTEN hamartoma tumor syndromes. Up to 80% of people who meet the diagnostic criteria of CS will be found to have a PTEN mutation, whereas only 10% 50% will have a PTEN mutation when the criteria are not fulfilled Fifty percent 60% of BRR patients exhibit a PTEN mutation. 89 One family with a CS-like phenotype was found to have a disease-causing germline mutation of the BMPR1A gene. 90 Most cases of CS have been diagnosed as the result of either skin or gastrointestinal findings, but commercial genetic testing is now available (Table 4). The protein PTEN is a dual-specificity lipid phosphatase with enzymatic activity that removes phosphate groups from several intracellular signaling molecules. It regulates cellular processes including cell cycling, translation, and apoptosis by blocking activation of elements of the PI3K pathway, including the Akt, and mtor serine/threonine kinases that are involved in cell growth and survival signaling PTEN mutations occur with a wide distribution of frequencies in sporadic primary tumors including colon, breast, thyroid, endometrial carcinomas, and glioblastoma multiforme. 94 In organism model studies, Akt and mtor kinase inhibition has been shown to reverse some of the effects of PTEN protein loss. The possibility arises that drugs that target Akt, mtor, or PI3K itself might have therapeutic activity, and trials of mtor kinase inhibitors are underway as possible therapies for PTEN-associated syndromes and malignancies. 95 References 1. Bussey HJR. Familial polyposis coli: family studies, histopathology, differential diagnosis and results of treatment. Baltimore, MD: Johns Hopkins University Press, Gardner EJ, Burt RW, Freston JW. Gastrointestinal polyposis: syndromes and genetic mechanisms. West J Med 1980;132: Jarvinen HJ. Epidemiology of familial adenomatous polyposis in Finland: impact of family screening on the colorectal cancer rate and survival. Gut 1992;33: Bulow S, Faurschou Nielsen T, Bulow C, et al. The incidence rate of familial adenomatous polyposis: results from the Danish Polyposis Register. Int J Colorectal Dis 1996;11: Groden J, Thliveris A, Samowitz W, et al. Identification and characterization of the familial adenomatous polyposis coli gene. Cell 1991;66: Nishisho I, Nakamura Y, Miyoshi Y, et al. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 1991;253: Neufeld KL, White RL. Nuclear and cytoplasmic localizations of the adenomatous polyposis coli protein. Proc Natl Acad Sci USA 1997;94: Joslyn G, Richardson DS, White R, et al. Dimer formation by an N-terminal coiled coil in the APC protein. Proc Natl Acad Sci U S A 1993;90: Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell 1996;87: Konishi M, Kikuchi-Yanoshita R, Tanaka K, et al. Molecular na-

8 640 DOXEY ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 3, No. 7 ture of colon tumors in hereditary nonpolyposis colon cancer, familial polyposis, and sporadic colon cancer. Gastroenterology 1996;111: Chung DC. The genetic basis of colorectal cancer: insights into critical pathways of tumorigenesis. Gastroenterology 2000; 119: Nathke IS, Adams CL, Polakis P, et al. The adenomatous polyposis coli tumor suppressor protein localizes to plasma membrane sites involved in active cell migration. J Cell Biol 1996; 134: Barth AI, Pollack AL, Altschuler Y, et al. NH2-terminal deletion of beta-catenin results in stable colocalization of mutant beta-catenin with adenomatous polyposis coli protein and altered MDCK cell adhesion. J Cell Biol 1997;136: Fodde R, Kuipers J, Rosenberg C, et al. Mutations in the APC tumour suppressor gene cause chromosomal instability. Nat Cell Biol 2001;3: Kaplan KB, Burds AA, Swedlow JR, et al. A role for the Adenomatous Polyposis Coli protein in chromosome segregation. Nat Cell Biol 2001;3: Beroud C, Collod-Beroud G, Boileau C, et al. UMD (Universal mutation database): a generic software to build and analyze locus-specific databases. Hum Mutat 2000;15: Soravia C, Berk T, Madlensky L, et al. Genotype-phenotype correlations in attenuated adenomatous polyposis coli. Am J Hum Genet 1998;62: Nagase H, Miyoshi Y, Horii A, et al. Correlation between the location of germ-line mutations in the APC gene and the number of colorectal polyps in familial adenomatous polyposis patients. Cancer Res 1992;52: Friedl W, Caspari R, Sengteller M, et al. Can APC mutation analysis contribute to therapeutic decisions in familial adenomatous polyposis? experience from 680 FAP families. Gut 2001; 48: Giardiello FM, Krush AJ, Petersen GM, et al. Phenotypic variability of familial adenomatous polyposis in 11 unrelated families with identical APC gene mutation. Gastroenterology 1994;106: Giardiello FM, Brensinger JD, Petersen GM. AGA technical review on hereditary colorectal cancer and genetic testing. Gastroenterology 2001;121: Petersen GM, Brensinger JD, Johnson KA, et al. Genetic testing and counseling for hereditary forms of colorectal cancer. Cancer 1999;86: Geller G, Botkin JR, Green MJ, et al. Genetic testing for susceptibility to adult-onset cancer: the process and content of informed consent. JAMA 1997;277: Giardiello FM, Brensinger JD, Petersen GM, et al. The use and interpretation of commercial APC gene testing for familial adenomatous polyposis. N Engl J Med 1997;336: Trepanier A, Ahrens M, McKinnon W, et al. Genetic cancer risk assessment and counseling: recommendations of the National Society of Genetic Counselors. J Genet Counseling 2004;13: Al-Tassan N, Chmiel N, Maynard J, et al. Inherited variants of MYH associated with somatic G:C T:A mutations in colorectal tumors. Nat Genet 2002;30: Sampson JR, Dolwani S, Jones S, et al. Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH. Lancet 2003;362: Sieber O, Lipton L, Crabtree M, et al. Mutliple colorectal adenomas, classic adenomatous polyposis, and germline mutations in MYH. N Engl J Med 2004;348: Croitoru M, Cleary S, Di Nicola N, et al. Association between biallelic and monoallelic germline MYH gene mutations and colorectal cancer risk. J Natl Cancer Inst 2004;96: Jones S, Emmerson P, Maynaard J, et al. Biallelic germline mutations in MYH predispose to multiple colorectal adenoma and somatic G:C T:A mutations. Hum Mol Genet 2002;11: Desai DC, Neale KF, Talbot IC, et al. Juvenile polyposis. Br J Surg 1995;82: Hampel H, Peltomäki P. Hereditary colorectal cancer: risk assessment and management. Clin Genet 2000;58: Wirtzfeld DA, Petrelli NJ, Rodriguez-Bigas MA. Hamartomatous polyposis syndromes: molecular genetics, neoplastic risk, and surveillance recommendations. Ann Surg Oncol 2001;8: Jass JR, Williams CB, Bussey HJ, et al. Juvenile polyposis: a precancerous condition. Histopathology 1988;13: Boardman L. Hereditable colon cancer syndromes: recognition and preventative management. Gastroenterol Clin North Am 2002;31: Coburn MC, Pricolo VE, DeLuca FG, et al. Malignant potential in intestinal juvenile polyposis syndromes. Ann Surg Oncol 1995; 2: Nicholls S, Smith V, Davies R, et al. Diffuse juvenile non-adenomatous polyposis: a rare cause of severe hypoalbuminaemia in childhood. Acta Paediatrica 1995;84: Inoue S, Matsumoto T, Iida M, et al. Juvenile polyposis occurring in hereditary hemorrhagic telangiectasia. Am J Med Sci 1999; 317: Heldin C, Miyazono K, Dijke P, et al. TGF-beta signaling from cell membrane to nucleus through SMAD proteins. Nature 1997;390: Haggitt RC, Reid BJ. Hereditary gastrointestinal polyposis syndromes. Am J Surg Pathol 1986;10: Jarvinen H, Franssila KO. Familial juvenile polyposis coli: increased risk of colorectal cancer. Gut 1984;25: Howe JR, Mitros FA, Summers RW. The risk of gastrointestinal carcinoma in familial juvenile polyposis. Ann Surg Oncol 1998; 5: Agnifili A, Verzaro R, Gola P, et al. Juvenile polyposis: case report and assessment of the neoplastic risk in 271 patients reported in the literature. Dig Surg 1999;16: Aaltonen LA, Jass JR, Howe JR. Juvenile polyposis. In: Hamilton SR, Aaltonen LA, eds. World Health Organization classification of tumours: pathology and genetics of tumours of the digestive system. Lyon, France: IARC Press, 2000: Desai DC, Murday V, Phillips RKS, et al. A survey of phenotypic features in juvenile polyposis. J Med Genet 1998;35: Howe JR, Roth S, Ringold JC, et al. Mutations in the SMAD4/ DPC4 gene in juvenile polyposis. Science 1998;280: Howe JR, Bair JL, Sayed MG, et al. Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nat Genet 2001;28: Woodford-Richens KL, Rowan AJ, Poulsom R, et al. Comprehensive analysis of SMAD4 mutations and protein expression in juvenile polyposis: evidence for a distinct genetic pathway and polyp morphology in SMAD4 mutation carriers. Am J Pathol 2001; 159: Roth S, Sistonen P, Salovaara R, et al. SMAD genes in juvenile polyposis. Genes Chromosomes Cancer 1999;26: Bevan S, Woodford-Richens K, Rozen P, et al. Screening SMAD1, SMAD2, SMAD3, and SMAD5 for germline mutations in juvenile polyposis syndrome. Gut 1999;45: Woodford-Richens K, Williamson J, Bevan S, et al. Allelic loss at SMAD4 in polyps from juvenile polyposis patients and use of fluorescence in situ hybridization to demonstrate clonal origin of the epithelium. Cancer Res 2000;60: Woodford-Richens K, Bevan S, Churchman M, et al. Analysis of genetic and phenotypic and heterogeneity in juvenile polyposis. Gut 2000;46: Zhou XP, Woodford-Richens K, Lehtonen R, et al. Germline muta-

9 July 2005 INHERITED POLYPOSIS SYNDROMES 641 tions in BMPR1A/alk3 cause a subset of cases of juvenile polyposis syndrome and of Cowden and Bannayan-Riley-Ruvalcaba syndromes. Am J Hum Genet 2001;69: Huang SC, Chen CR, Lavine JE, et al. Genetic heterogeneity in familial juvenile polyposis. Cancer Res 2000;60: Haidle J, Howe J. Juvenile polyposis syndrome. Accessed May Available: at: Howe JR, Ringold JC, Hughes JH, et al. Direct genetic testing for Smad4 mutations in patients at risk for juvenile polyposis. Surgery 1999;126: Lindor NM, Greene MH. The concise handbook of family cancer syndromes: Mayo Familial Cancer Program. J Natl Cancer Inst 1998;90: Jeghers H, McKusick VA, Katz KH. Generalized intestinal polyposis and melanin spots of the oral mucosa, lips and digits: a syndrome of diagnostic significance. N Engl J Med 1949;241: McGarrity TJ, Kulin HE, Zaino RJ. Peutz-Jeghers syndrome. Am J Gastroenterol 2000;95: Hemminki A. The molecular basis and clinical aspects of Peutz- Jeghers syndrome. Cell Mol Life Sci 1999;55: Wang ZJ, Ellis I, Zauber P, et al. Allelic imbalance at the LKB1 (STK11) locus in tumours from patients with Peutz-Jeghers syndrome provides evidence for a hamartoma- (adenoma)-carcinoma sequence. J Pathol 1999;188: Utsunomiya J, Gocho H, Miyanaga T, et al. Peutz-Jeghers syndrome: its natural course and management. Johns Hopkins Med J 1975;136: Tomlinson IPM, Houlston RS. Peutz-Jeghers syndrome. J Med Genet 1997;34: Giardiello FM, Welsh SB, Hamilton SR, et al. Increased risk of cancer in the Peutz-Jeghers syndrome. N Engl J Med 1987;316: Wirtzfeld DA, Petrelli NJ, Rodriguez-Bigas MA, et al. Hamartomatous polyposis syndromes: molecular genetics, neoplastic risk, and surveillance recommendations. Ann Surg Oncol 2001; 8: Kitaoka F, Shiogama T, Mizutani A, et al. A solitary Peutz-Jegherstype hamartomatous polyp in the duodenum: a case report including results of mutation analysis. Digestion 2004;69: Oncel M, Remzi FH, Church JM, et al. Course and follow-up of solitary Peutz-Jeghers polyps: a case series. Int J Colorectal Dis 2003;18: Nakagawa H, Koyama K, Tanaka T, et al. Localization of the gene responsible for Peutz-Jeghers syndrome within a 6-cM region of chromosome 19p13.3. Hum Genet 1998;102: Olschwang S, Boisson C, Thomas G. Peutz-Jeghers families unlinked to STK11/LKB1 gene mutations are highly predisposed to primitive biliary adenocarcinoma. J Med Genet 2001;38: Miyaki M, Iijima T, Hosono K, et al. Somatic mutations of LKB1 and beta-catenin genes in gastrointestinal polyps from patients with Peutz-Jeghers syndrome. Cancer Res 2000;60: Esteller M, Avizienyte E, Corn PG, et al. Epigenetic inactivation of LKB1 in primary tumors associated with the Peutz-Jeghers syndrome. Oncogene 2000;19: Karuman P, Gozani O, Odze RD, et al. The Peutz-Jegher gene product LKB1 is a mediator of p53-dependent cell death. Mol Cell 2001;7: Mehenni H, Gehrig C, Nezu J, et al. Loss of LKB1 kinase activity in Peutz-Jeghers syndrome, and evidence for allelic and locus heterogeneity. Am J Hum Genet 1998;63: GeneDx, Inc. STK11 testing in Peutz Jeghers syndrome, information sheet. Accessed April Available: at: Lloyd KMI, Dennis M. Cowden s disease: a possible new symptom complex with multiple system involvement. Ann Intern Med 1963;58: Eng C. Cowden syndrome. J Genet Counseling 1997;6: Eng C, Talbot IC, Burt R. Cowden syndrome. In: Hamilton SR, Aaltonen LA, eds. World Health Organization classification of tumours: pathology and genetics of tumours of the digestive system. Lyon, France: IARC Press, 2000: Eng C. Will the real Cowden syndrome please stand up: revised diagnostic criteria. J Med Genet 2000;37: Brownstein MH, Wolf M, Bikowski JB. Cowden s disease: a cutaneous marker of breast cancer. Cancer 1978;41: Kay PS, Soetikno RM, Mindelzun R, et al. Diffuse esophageal glycogenic acanthosis: an endoscopic marker of Cowden s disease. Am J Gastroenterol 1997;92: Kato M, Mizuki A, Hayashi T, et al. Cowden s disease diagnosed through mucocutaneous lesions and gastrointestinal polyposis with recurrent hematochezia, unrevealed by initial diagnosis. Intern Med 2000;39: Nelen MR, Padberg GW, Peeters EA, et al. Localization of the gene for Cowden disease to chromosome 10q Nat Genet 1996;13: Marsh DJ, Dahia PL, Zheng Z, et al. Germline mutations in PTEN are present in Bannayan-Zonana syndrome. Nat Genet 1997;16: Li J, Yen C, Liaw D, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 1997;275: Wanner M, Celebi JT, Peacocke M. Identification of a PTEN mutation in a family with Cowden syndrome and Bannayan-Zonana syndrome. J Am Acad Dermatol 2001;44: Liaw D, Marsh DJ, Li J, et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet 1997;16: Marsh DJ, Dahia PL, Caron S, et al. Germline PTEN mutations in Cowden syndrome-like families. J Med Genet 1998;35: Lynch ED, Ostermeyer EA, Lee MK, et al. Inherited mutations in PTEN that are associated with breast cancer, Cowden disease, and juvenile polyposis. Am J Hum Genet 1997;61: Marsh DJ, Kum JB, Lunetta KL, et al. PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome. Hum Mol Genet 1999;8: Zhou XP, Marsh DJ, Morrison CD, et al. Germline inactivation of PTEN and dysregulation of the phosphoinositol-3-kinase/akt pathway cause human Lhermitte-Duclos disease in adults. Am J Hum Genet 2003;73: Kishimoto H, Hamada K, Saunders M, et al. Physiological functions of Pten in mouse tissues. Cell Struct Funct 2003;28: Li J, Simpson L, Takahashi M, et al. The PTEN/MMAC1 tumor suppressor induces cell death that is rescued by the AKT/protein kinase B oncogene. Cancer Res 1998;58: Simpson L, Parsons R. PTEN: life as a tumor suppressor. Exp Cell Res 2001;264: Eng C. PTEN: one gene, many syndromes. Hum Mutat 2003;22: Sansal I, Sellers WR. The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol 2004;22: Address requests for reprints to: Randall W. Burt, MD, Huntsman Cancer Institute, 2000 Circle of Hope, Room 5260, Salt Lake City, Utah randall.burt@hci.utah.edu; fax: (801)