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Variant Manifestation of Cowden Disease in Japan: Hamartomatous Polyposis of the Digestive Tract with Mutation of the PTEN Gene

1999; Elsevier BV; Volume: 64; Issue: 1 Linguagem: Inglês

10.1086/302207

1537-6605

Keisuke Kurose, Tsutomu Araki, Tsuyoshi Matsunaka, Yasuharu Takada, Mitsuru Emi,

Fungal Plant Pathogen Control

To the Editor: Because of the clinical heterogeneity and complexity of the group of disorders collectively known as inherited hamartoma syndromes, several attempts have been made to classify them into distinct categories. In the May issue of this Journal, Eng and Ji (Eng and Ji, 1998Eng C Ji H Molecular classification of the inherited hamartoma polyposis syndromes: clearing the muddied waters.Am J Hum Genet. 1998; 62: 1020-1022Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar) reviewed recent progress in molecular characterization of these syndromes and classified them into four clinical entities: Cowden disease (CD [MIM 158350]), Bannayan-Ruvalcaba-Riley syndrome (BRR [MIM 153480]), Peutz-Jeghers syndrome (PJS [MIM 175200]), and juvenile polyposis syndrome (JPS [MIM 174900]). Despite some progress in molecular characterization, specific diagnoses of these disorders remain difficult because their phenotypic spectra overlap and because the penetrance of symptoms is age related. Clinical syndromic diagnosis is also dependent on many factors, such as the nature and type of the first clinical symptoms and the medical discipline of the individual(s) diagnosing the syndrome. PTEN, a gene mapping to 10q23, encodes a dual-specificity phosphatase and is also called MMAC1 or TEP1 (Li and Sun Li and Sun, 1997Li DM Sun H TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor β.Cancer Res. 1997; 57: 2124-2129PubMed Google Scholar; Li et al. Li et al., 1997Li J Yen C Liaw D Podsypanina K Bose S Wang SI Puc J et al.PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer.Science. 1997; 275: 1943-1947Crossref PubMed Scopus (4079) Google Scholar; Steck et al. Steck et al., 1997Steck PA Pershouse MA Jasser SA Yung WK Lin H Ligon AH Langford LA et al.Identification of a candidate tumor suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers.Nat Genet. 1997; 15: 356-362Crossref PubMed Scopus (2442) Google Scholar). PTEN has been identified as the susceptibility gene for CD and BRR (Liaw et al. Liaw et al., 1997Liaw D Marsh DJ Li J Dahia PL Wang SI Zheng Z Bose S et al.Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome.Nat Genet. 1997; 16: 64-67Crossref PubMed Scopus (1617) Google Scholar; Marsh et al. Marsh et al., 1997Marsh DJ Dahia PL Zheng Z Liaw D Parsons R Gorlin RJ Eng C Germline mutations in PTEN are present in Bannayan-Zonana syndrome.Nat Genet. 1997; 16: 333-334Crossref PubMed Scopus (554) Google Scholar), and it appears that PTEN mutations are detected more frequently in CD and BRR patients when strict clinical criteria are applied to the selection of test subjects (Liaw et al. Liaw et al., 1997Liaw D Marsh DJ Li J Dahia PL Wang SI Zheng Z Bose S et al.Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome.Nat Genet. 1997; 16: 64-67Crossref PubMed Scopus (1617) Google Scholar; Marsh et al. Marsh et al., 1997Marsh DJ Dahia PL Zheng Z Liaw D Parsons R Gorlin RJ Eng C Germline mutations in PTEN are present in Bannayan-Zonana syndrome.Nat Genet. 1997; 16: 333-334Crossref PubMed Scopus (554) Google Scholar, Marsh et al., 1998Marsh DJ Coulon V Lunetta KL Rocca-Serra P Dahia PL Zheng Z Liaw D et al.Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation.Hum Mol Genet. 1998; 7: 507-515Crossref PubMed Scopus (521) Google Scholar). LKB1/STK11, a serine threonine kinase gene at 19p13.3, has been identified as a susceptibility gene for PJS (Hemminki et al. Hemminki et al., 1998Hemminki A Markie D Tomlinson I Avizienyte E Roth S Loukola A Bignell G et al.A serine/threonine kinase gene defective in Peutz-Jeghers syndrome.Nature. 1998; 391: 184-187Crossref PubMed Scopus (1264) Google Scholar; Jenne et al. Jenne et al., 1998Jenne DE Reimann H Nezu J Friedel W Loff S Jeschke R Muller O et al.Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase.Nat Genet. 1998; 18: 38-43Crossref PubMed Scopus (926) Google Scholar). As for JPS, however, some controversy exists about its molecular basis. Three possibilities have been raised: (1) germ-line mutations of the SMAD4/DPC4 gene at 18q21.1 are known to be responsible for JPS in some affected families (Howe et al. Howe et al., 1998Howe JR Roth S Ringold JC Summers RW Järvinen HJ Sistonen P Tomlinson IP et al.Mutations in the SMAD4/DPC4 gene in juvenile polyposis.Science. 1998; 280: 1086-1088Crossref PubMed Scopus (719) Google Scholar), (2) PTEN mutations appear to be the predisposing elements for some patients diagnosed with JPS (Lynch et al. Lynch et al., 1997Lynch ED Ostermeyer EA Lee MK Arena JF Ji H Dann J Swisshelm K et al.Inherited mutations in PTEN that are associated with breast cancer, Cowden disease, and juvenile polyposis.Am J Hum Genet. 1997; 61: 1254-1260Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar; Olschwang et al. Olschwang et al., 1998Olschwang S Serova-Sinilnikova OM Lenoir GM Thomas G PTEN germ-line mutations in juvenile polyposis coli.Nat Genet. 1998; 18: 12-14Crossref PubMed Scopus (133) Google Scholar); and (3) yet another putative locus (“JP1”), centromeric to PTEN on chromosome 10q, has been linked to JPS in some affected families (Jacoby et al. Jacoby et al., 1997Jacoby RF Schlack S Cole CE Skarbek M Harris C Meisner LF A juvenile polyposis tumor suppressor locus at 10q22 is deleted from nonepithelial cells in the lamina propria.Gastroenterology. 1997; 112: 1398-1403Abstract Full Text PDF PubMed Scopus (93) Google Scholar). The low penetrance of CD, the sharing of some phenotypic features between CD and JPS, and the possible genetic heterogeneity of JPS make diagnosis complex and confusing. Pathognomonic hallmarks of CD patients are facial trichilemmomas, acral keratoses, and verucoid or papillomatous papules. This triad of skin lesions occurs in 99% of CD patients (Hanssen and Fryns Hanssen and Fryns, 1995Hanssen AM Fryns JP Cowden syndrome.J Med Genet. 1995; 32: 117-119Crossref PubMed Scopus (147) Google Scholar; Longy and Lacombe Longy and Lacombe, 1996Longy M Lacombe D Cowden disease. Report of a family and review.Ann Genet. 1996; 39: 35-42PubMed Google Scholar). Other, less frequent manifestations of CD include thyroid adenomas or goiters (occurring in 40%–60% of CD patients), breast fibroadenomas (70% of affected females), hamartomatous gastrointestinal polyps (35%–40%), and macrocephaly (38%) (Eng Eng, 1998Eng C Genetics of Cowden syndrome: through the looking glass of oncology.Int J Oncol. 1998; 12: 701-710PubMed Google Scholar; Marsh et al. Marsh et al., 1998Marsh DJ Coulon V Lunetta KL Rocca-Serra P Dahia PL Zheng Z Liaw D et al.Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation.Hum Mol Genet. 1998; 7: 507-515Crossref PubMed Scopus (521) Google Scholar). JPS is characterized by gastrointestinal hamartomatous polyps and an increased risk of gastrointestinal cancer (Olschwang et al. Olschwang et al., 1998Olschwang S Serova-Sinilnikova OM Lenoir GM Thomas G PTEN germ-line mutations in juvenile polyposis coli.Nat Genet. 1998; 18: 12-14Crossref PubMed Scopus (133) Google Scholar). We examined a 35-year-old Japanese man who had been followed clinically for JPS because of numerous hamartomatous polypoid lesions throughout the entire digestive tract, from esophagus to rectum. Although he had none of the pathognomonic skin lesions of CD, we extended our clinical examination to the patient's whole body and tested him for mutation of the PTEN gene, in view of Eng's proposal (Eng, 1998Eng C Genetics of Cowden syndrome: through the looking glass of oncology.Int J Oncol. 1998; 12: 701-710PubMed Google Scholar) that PTEN mutation can be a useful diagnostic marker for incompletely expressed CD. After informed consent was obtained, genomic DNAs prepared from blood from the patient and from members of his family were examined by direct sequencing of the entire coding region and exon-intron boundaries of PTEN, according to procedures we have described elsewhere (Kurose et al. Kurose et al., 1998Kurose K Bando K Fukino K Sugisaki Y Araki T Emi M Somatic mutations of the PTEN/MMAC1 gene in fifteen Japanese endometrial cancers: evidence for inactivation of both alleles.Jpn J Cancer Res. 1998; 89: 842-848Crossref PubMed Scopus (36) Google Scholar). The patient's father died of brainstem infarction, a condition unrelated to CD. No other members of his family have been diagnosed as having CD. The patient was found to be heterozygous for a G→A transition at the second nucleotide of codon 130, which would result in a substitution of Gln for Arg (R130Q). The patient's mother and sister did not carry this mutation (fig. 1), nor was it detected in 192 chromosomes from control Japanese individuals. On closer examination, which included ultrasonography and computed tomography, we found a small thyroid adenoma, a few papillomatous papules in his right hand, and a lung tumor, which is now being examined for possible malignancy. Thus, molecular testing of the PTEN gene, as proposed by Eng (Eng, 1998Eng C Genetics of Cowden syndrome: through the looking glass of oncology.Int J Oncol. 1998; 12: 701-710PubMed Google Scholar) in another case of suspected JPS, led us to a diagnosis of CD in a “JPS” patient who manifested atypical symptoms of CD. His germ-line mutation had occurred in the core motif of the phosphatase, at amino acid residue 122–132, encoded by exon 5. Most of the reported germ-line missense mutations of the PTEN gene reported in patients with CD have occurred within this core motif (Marsh et al. Marsh et al., 1998Marsh DJ Coulon V Lunetta KL Rocca-Serra P Dahia PL Zheng Z Liaw D et al.Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation.Hum Mol Genet. 1998; 7: 507-515Crossref PubMed Scopus (521) Google Scholar). Thus, in terms of PTEN mutation, our case is typical of a CD entity, although the phenotype is atypical. Eng and Ji (Eng and Ji, 1998Eng C Ji H Molecular classification of the inherited hamartoma polyposis syndromes: clearing the muddied waters.Am J Hum Genet. 1998; 62: 1020-1022Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar) pointed out that apparent “JPS” patients who carry PTEN germ-line mutations (Lynch et al. Lynch et al., 1997Lynch ED Ostermeyer EA Lee MK Arena JF Ji H Dann J Swisshelm K et al.Inherited mutations in PTEN that are associated with breast cancer, Cowden disease, and juvenile polyposis.Am J Hum Genet. 1997; 61: 1254-1260Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar; Olschwang et al. Olschwang et al., 1998Olschwang S Serova-Sinilnikova OM Lenoir GM Thomas G PTEN germ-line mutations in juvenile polyposis coli.Nat Genet. 1998; 18: 12-14Crossref PubMed Scopus (133) Google Scholar) may in fact belong to a category of CD patients whose phenotypic features are only partially expressed. Eng and Ji (Eng and Ji, 1998Eng C Ji H Molecular classification of the inherited hamartoma polyposis syndromes: clearing the muddied waters.Am J Hum Genet. 1998; 62: 1020-1022Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar) proposed that the presence of a germ-line PTEN mutation could be a good diagnostic sign for CD and BRR. In the future, these inherited hamartoma syndromes should be classified by types of gene mutations, such as the PTEN mutation syndrome. The results described here signal the possibility that a large number of hidden clinical variants of CD may exist among patients who might have escaped correct clinical diagnosis and may have been treated for JPS. Our work underscores the usefulness and importance of molecular methods for achieving differential diagnoses among patients with gastrointestinal polyposis, because JPS and CD predispose to completely different types of cancer. The authors thank the patient and members of his family, for their participation in this study, and Prof. Tetsuro Miki for advice and encouragement. This work was supported by a Grant-in-Aid for priority areas “Cancer Research” and “Genome Science” from the Ministry of Education, Science, Sports and Culture of Japan and by a Research Grant for Cancer Research from the Ministry of Health and Welfare of Japan.