Hereditary gastrointestinal polyposis: Diagnosis, genetic test and risk assessment

Marina De Rosa, Francesca Duraturo, Raffaella Liccardo, Paola Izzo

Dipartimento di Medicina Molecolare e Biotecnologie Mediche and CEINGE Biotecnologie Avanzate, Università di Napoli Federico II, Naples, Italy.

DOI: 10.4236/ojgen.2013.32A3008                

Abstract

Colorectal cancer (CRC) is the second cause of cancer deaths, with over 1 million new cases estimated every year. Familial adenomatous polyposis, MUTYH-associated polyposis and hamartomatous polyposis are inherited syndromes that account for 2%-5% of all colon cancer. The mutated genes responsible for the vast majority of these disorders, are now known (MLH1, MSH2, MSH6, PMS2, APC, MYH, LKB1, SMAD4, BMPR1A, and PTEN) and specific mutations have been identified. Molecular caracterization of inherited CRCs allows pre-symptomatic diagnosis identifying at-risk individuals and improving cancer surveillance. Adenomatous polyposis includes familial adenomatous polyposis (FAP), attenuated FAP (AFAP), and MUTYH-associated polyposis (MAP). Hamartomatous polyposis comprises Peutz-Jeghers syndrome (PJS), juvenile polyposis syndrome (JPS) and “PTEN hamartoma tumour syndrome” (PHTS). MAP is an autosomal recessive condition, while all other disorders are inherited in an autosomal dominant manner. Differential dyagnosis could be very difficult between syndromes because of their phenotypic variability. Attenuated FAP, MAP and Lynch syndrome could be all associated with fewer numbers of adenomas (3-10 polyps), nevertheless, each syndrome has distinct cancer risks, characteristic clinical features, and separate genetic etiologies. Thus, differential diagnosis is essential for correct management of the specific disease. In our laboratory we set up a methodology for genetic tests of the colorectal polyposis syndrome. In these reviews we summarize the literature data and our experience about diagnosis, genetic tests and cancer risk assesment associated with colorectal polyposis. According to literature data, in our experience, there is a portion of analyzing patients that remain without identified mutation, after molecular screening of the specific gene involved in the pathogenesis of the disease. Since the sensibility of used techniques, such as DHPLC, MLPA and sequencing, is now very high, we suggest that a different approach to molecular diagnosis of polyposis syndromes is necessary. In our laboratory, we are now planning to set up analysis of a larger pannel of genes that could be involved in colorectal poliposis syndromes, using a next generation sequencing techniques. In our opinion, a better characterization of molecular basis of the polyposis syndromes will allow a more efficient cancer prevention.

Keywords

Familial Adenomatous Polyposis (FAP); MUTYH-Associated Polyposis (MAP); Peutz-Jeghers Syndrome (PJS); PTEN Hamartoma Tumour Syndrome (PHTS)

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Jasperson, K.W., Tuohy, T.M., Neklason, D.W. and Burt, R.W. (2010) Hereditary and familial colon cancer. Gastroenterology, 138, 2044-2058. doi:10.1053/j.gastro.2010.01.054
[2]	Gallagher, D.J., Smith, J.D., Offit, K. and Stadler, Z.K. (2010) Diagnosing hereditary colorectal cancer. Clinical Colorectal Cancer, 9, 205-211. doi:10.3816/CCC.2010.n.030
[3]	Groden, J., Thliveris, A., Samowitz, W., Carlson, M., Gelbert, L., Albertsen, H., et al. (1991) Identification and characterization of the familial adenomatous polyposis coli gene. Cell, 66, 589-600. doi:10.1016/0092-8674(81)90021-0
[4]	Ritchie, K.J., Walsh, S., Sansom, O.J., Henderson, C.J. and Wolf, C.R. (2009) Markedly enhanced colon tumourigenesis in ApcMin mice lacking glutathione Stransferase Pi. Proceedings of the National Academy of Sciences of the United States of America, 8, 20859-20864.
[5]	Burt, R.W., Leppert, M.F., Slattery, M.L., Samowitz, W.S., Spirio, L.N., Kerber, R.A., Kuwada, S.K., Neklason, D.W., Disario, J.A., Lyon, E., Hughes, J.P., Chey, W.Y. and White, R.L. (2004) Genetic testing and phenotype in a large kindred with attenuated familial adenomatous polyposis. Gastroenterology, 127, 444-451. doi:10.1053/j.gastro.2004.05.003
[6]	Bülow, S., Bjork, J., Christensen, I.J., Fausa, O., Jarvinen, H., Moesgaard, F., et al. (2004) Duodenal adenomatosis in familial adenomatous polyposis. Gut, 53, 381-386. doi:10.1136/gut.2003.027771
[7]	Djureinovic, T., Skoglund, J., Vandrovcova, J., Zhou, X.L., Kalushkova, A., Iselius, L. and Lindblom, A. (2006) A genome wide linkage analysis in Swedish families with hereditary nonfamilial adenomatous polyposis/non-hereditary non-polyposis colorectal cancer. Gut, 55, 362-366. doi:10.1136/gut.2005.075333
[8]	Bianchi, L.K., Burke, C.A., Bennett, A.E., Lopez, R., Hasson, H. and Church, J.M. (2008) Fundic gland polyp dysplasia is common in familial adenomatous polyposis. Clinical Gastroenterology and Hepatology, 6, 180-185. doi:10.1016/j.cgh.2007.11.018
[9]	Aretz, S. (2010) The differential diagnosis and surveillance of hereditary gastrointestinal polyposis syndromes. Deutsches Arzteblatt International, 107, 163-173.
[10]	Aretz, S., Stienen, D., Friedrichs, N., Stemmler, S., Uhlhaas, S., Rahner, N., Propping, P. and Friedl, W. (2007) Somatic APC mosaicism: A frequent cause of familial adenomatous polyposis (FAP). Human Mutation, 28, 985-992. doi:10.1002/humu.20549
[11]	Half, E., Bercovich, D. and Rozen, P. (2009) Familial adenomatous polyposis. Orphanet Journal of Rare Diseases, 12, 4-22.
[12]	Nieuwenhuis, M.H. and Vasen, H.F. (2007) Correlations between mutation site in APC and phenotype of familial adenomatous polyposis (FAP): A review of the literature. Critical Reviews in Oncology/Hematology, 61, 153-161. doi:10.1016/j.critrevonc.2006.07.004
[13]	Wallis, Y.L., Macdonald, F., Hultén, M., Morton, J.E.V., McKeown, C.M., Neoptolemos, J.P., Keighley, M. and Dion, G. (1994) Genotypephenotype correlation between position of constitutional APC gene mutation and CHRPE expression in FAP. Human Genetics, 5, 543-548.
[14]	Bisgaard, M.L. and Bulow, S. (2006) Familial adenomatous polyposis (FAP): Genotype correlation to FAP phenotype with osteomas and sebaceous cysts. American Journal of Medical Genetics, 140, 200-204.
[15]	Sieber, O.M., Lipton, L., Crabtree, M., Heinimann, K., Fidalgo, P., Phillips, R.K., et al. (2003) Multiple colorectal adenomas, classic adenomatous polyposis, and germline mutations in MYH. New England Journal of Medicine, 348, 791-799. doi:10.1056/NEJMoa025283
[16]	Al-Tassan, N., Chmiel, N.H., Maynard, J., Fleming, N., Livingston, A.L., Williams, G.T., et al. (2002) Inherited variants of MYH associated with somatic G:C→T:A mutations in colorectal tumors. Nature Genetics, 30, 227-232. doi:10.1038/ng828
[17]	Vogt, S., Jones, N., Christian, D., Engel, C., Nielsen, M., Kaufmann, A., Steinke, V., Vasen, H.F., Propping, P., Sampson, J.R., Hes, F.J. and Aretz, S. (2009) Expanded extracolonic tumour spectrum in MUTYH-associated polyposis. Gastroenterology, 137, 1976-1985. doi:10.1053/j.gastro.2009.08.052
[18]	De Rosa, M., Scarano, M.I., Panariello, L., Morelli, G., Riegler, G., Rossi, G.B., Tempesta, A., Romano, G., Renda, A., Pettinato, G. and Izzo P. (2003) The mutation spectrum of the APC gene in FAP patients from Southern Italy: Detection of known and four novel mutations. Human Mutation, 21, 655-656. doi:10.1002/humu.9151
[19]	De Rosa, M., Scarano, M.I., Panariello, L., Carlomagno, N., Rossi, G.B., Tempesta, A., Borgheresi, P., Renda, A. and Izzo, P. (1999) Three submicroscopic deletions at the APC locus and their rapid detection by quantitative-PCR analysis. European Journal of Human Genetics, 7, 695-703. doi:10.1038/sj.ejhg.5200344
[20]	Auricchio, R., De Rosa, M., Quaglietta, L., Miele, E., Boccia, G., Staiano, A. and Izzo P. (2005) A dramatic case of early-onset familial adenomatous polyposis. Clinical Genetics, 67, 104-106. doi:10.1111/j.1399-0004.2005.00381.x
[21]	Scarano, M.I., De Rosa, M., Gentile, M., Bucci, L., Ferulano, G.P., Carlomagno, N., Renda, A., Guanti, G., Salvatore, F. and Izzo, P. (1997) Three novel germline mutations in the adenomatous polyposis coli gene. Human Mutation, 9, 191-193. doi:10.1002/(SICI)1098-1004(1997)9:2<191::AID-HUMU16>3.0.CO;2-Y
[22]	De Rosa, M., Galatola, M., Borriello, S., Duraturo, F., Masone, S. and Izzo, P. (2009) Implication of adenomatous polyposis coli and MUTYH mutations in familial colorectal polyposis. Diseases of the Colon & Rectum, 52, 268-274. doi:10.1007/DCR.0b013e318197d15c
[23]	Attard, T.M. and Young, R.J. (2006) Diagnosis and management of gastrointestinal polyps: Pediatric considerations. Gastroenterology Nursing, 29, 16-22. doi:10.1097/00001610-200601000-00003
[24]	Wirtzfeld, D.A., Petrelli, N.J. and Rodriguez-Bigas, M.A. (2001) Hamartomatous polyposis syndromes: Molecular genetics, neoplastic risk, and surveillance recommendations. Annals of Surgical Oncology, 8, 319-327. doi:10.1007/s10434-001-0319-7
[25]	Manfredi, M. (2010) Hereditary hamartomatous polyposis syndromes: understanding the disease risks as children reach adulthood. Gastroenterology & Hepatology, 6, 185-196.
[26]	Giardiello, F.M. and Trimbath, J.D. (2006) Peutz-Jeghers syndrome and management recommendations. Clinical Gastroenterology and Hepatology, 4, 408-415. doi:10.1016/j.cgh.2005.11.005
[27]	Jeghers, H., McKusick, V.A. and Katz, K.H. (1949) Generalized intestinal polyposis and melanin spots of the oral mucosa, lips and digits: A syndrome of diagnostic significance. New England Journal of Medicine, 241, 1031-1036. doi:10.1056/NEJM194912292412601
[28]	Hearle, N., Schumacher, V., Menko, F.H., Olschwang, S., Boardman, L.A., Gille, J.J., et al. (2006) Frequency and spectrum of cancers in the Peutz-Jeghers syndrome. Clinical Cancer Research, 12, 3209-3215. doi:10.1158/1078-0432.CCR-06-0083
[29]	De Rosa, M., Galatola, M., Quaglietta, L., Miele, E., De Palma, G., Rossi, G.B., Staiano, A. and Izzo, P. (2010) Alu-mediated genomic deletion of the serine/threonine protein kinase 11 (STK11) gene in Peutz-Jeghers syndrome. Gastroenterology, 138, 2558-2560. doi:10.1053/j.gastro.2010.03.061
[30]	Marignani, P.A. (2005) LKB1, the multitasking tumour suppressor kinase. Journal of Clinical Pathology, 58, 15-19. doi:10.1136/jcp.2003.015255
[31]	Farooq, A., Walker, L.J., Bowling, J. and Audisio, R.A. (2010) Cowden syndrome. Cancer Treatment Reviews, 36, 577-583. doi:10.1016/j.ctrv.2010.04.002
[32]	Eng, C. (2003) PTEN: One gene, many syndromes. Human Mutation, 22, 183-198.
[33]	Gorlin, R.J., Cohen Jr., M.M., Condon, L.M. and Burke, B.A. (1992) Bannayan-Riley-Ruvalcaba syndrome. American Journal of Medical Genetics, 44, 307-314. doi:10.1002/ajmg.1320440309
[34]	Ruvalcaba, R.H., Myhre, S. and Smith, D.W. (1980) Sotos syndrome with intestinal polyposis and pigmentary changes of the genitalia. Clinical Genetics, 18, 413-416. doi:10.1111/j.1399-0004.1980.tb01785.x
[35]	Liaw, D., Marsh, D.J., Li, J., Dahia, P.L., Wang, S.I., Zheng, Z., et al. (1997) Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nature Genetics, 16, 64-67. doi:10.1038/ng0597-64
[36]	Tan, M.H., Mester, J.L., Ngeow, J., Rybicki, L.A., Orloff, M.S. and Eng, C. (2012) Lifetime cancer risks in individuals with germline PTEN mutations. Clinical Cancer Research, 18, 400-407. doi:10.1158/1078-0432.CCR-11-2283
[37]	Marsh, D.J., Kum, J.B., Lunetta, K.L., Bennett, M.J., Gorlin, R.J., Ahmed, S.F., et al. (1999) PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome. Human Molecular Genetics, 8, 1461-1472. doi:10.1093/hmg/8.8.1461
[38]	Marsh, D.J., Coulon, V., Lunetta, K.L., Rocca-Serra, P., Dahia, P.L., Zheng, Z., et al. (1998) Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation. Human Molecular Genetics, 7, 507-515. doi:10.1093/hmg/7.3.507
[39]	Waite, K.A. and Eng, C. (2002) Protean PTEN: Form and function. American Journal of Human Genetics, 70, 829-844. doi:10.1086/340026
[40]	Eng, C. (2010) Mendelian genetics of rare—and not so rare—cancers. Annals of the New York Academy of Sciences, 1214, 70-82. doi:10.1111/j.1749-6632.2010.05789.x
[41]	Galatola, M., Paparo, L., Duraturo, F., Turano, M., Rossi, G.B., Izzo, P. and De Rosa, M. (2012) Beta catenin and cytokine pathway dysregulation in patients with manifestations of the “PTEN hamartoma tumour syndrome”. BMC Medical Genetics, 13, 28. doi:10.1186/1471-2350-13-28