Biopolym. Cell. 2017; 33(2):102-115.
http://dx.doi.org/10.7124/bc.000948
Molecular Biomedicine
Familial adenomatous polyposis: age of onset and association with mutations of the APC gene in patients from West Ukraine
4Lozynska M. R., 1Lozynskyy Y. S., 2Plawski A., 1Pinyazhko R. O., 4Prokopchuk N. M., 3Fedota O. M.
  1. Danylo Halytsky Lviv National Medical University
    69, Pekarska Str., Lviv, Ukraine, 79010
  2. Institute of Human Genetics of PAS
    32, Strzeszynska Str.,Poznan, Poland, 60-479
  3. V. N. Karazin Kharkiv National University
    4, Svobody Sq., Kharkiv, Ukraine, 61077
  4. State Institution "Institute of Hereditary Pathology, NAMS of Ukraine"
    31a, M. Lysenko Str., Lviv, Ukraine, 79008

Abstract

Aim. To evaluate the average age of familial adenomatous polyposis (FAP) onset in both males, females and in their relatives, carriers or not carriers of the APC gene mutations, to estimate the anticipation in successive generations for early identification of the individuals in the risk group. Methods. The medical records, genealogical information were gathered and molecular genetic study of blood was carried out in 25 probands with adenomatous polyposis. FAP was confirmed in 44.0 % of probands. The probands with FAP had 36 affected relatives. The amplified frag-ments of the APC gene were screened for the mutations involving heteroduplex analysis and detection of single-stranded conformational polymorphism. The age of FAP onset was evaluated in probands and their relatives. The anticipation index (A) was calculated. Results. Among patients with FAP 61.7 % were males and 38.3 % were females. The age of FAP onset in males was 36.0 ± 1.4 years, while in females the disease manifested earlier – in 29.5 ± 2.4 years (p<0.01). The APC mutations, including four novel mutations, were found in 63.6 % of probands with FAP. The lowest age of polyposis onset was observed in carriers of the APC mutation c.3927_3931delAAAGA p.Q1309fs. The average age difference between FAP onset in the parents and their offspring was 12.0 ± 1.7 years. In 3 of 4 families with FAP and novel mutations of the APC gene predominance of males (12:4) and anticipation phenomenon were observed.The strongest age correlations of FAP onset were found in mother-offspring pairs and parents-son pairs. The statistically significant difference between the data confirmed more similarities of descendant, especially sons, with parents. Conclusions. There was no statistically significant differ-ence between average age of the disease onset in patients carriers of the APC mutations (33.1 ± 2.1 years) and in patients without the APC mutations studied by the traditional methods (33.7 ± 1.6 years). In offsprings with FAP the reduced age of disease onset compared to the parents was revealed irrespective of the presense of the APC mutations. The anticipation index in FAP was 18.0 %. Accounting anticipation allows estimating the approximate average age at FAP onset during genetic counseling, and therefore timely carries out targeted prevention.
Keywords: , , ,
Full text: (PDF, in English)

References

[1] Urso EDL, Delaini GG, Campi M, Bacchelli C, Pucciarelli S. Colorectal polyposis: clinical presentation and surgical treatment. Colorectal Disease. 2014;17(1):61–6.
[2] Talseth-Palmer BA. The genetic basis of colonic adenomatous polyposis syndromes. Hered Cancer Clin Pract. 2017;15:5. Review.
[3] Valle L. Genetic predisposition to colorectal cancer: where we stand and future perspectives. World J Gastroenterol. 2014;20(29):9828-49.
[4] Bülow S, Faurschou Nielsen T, Bülow C, Bisgaard ML, Karlsen L, Moesgaard F. The incidence rate of familial adenomatous polyposis. Results from the Danish Polyposis Register. Int J Colorectal Dis. 1996;11(2):88-91.
[5] de la Chapelle A. Genetic predisposition to colorectal cancer. Nat Rev Cancer. 2004;4(10):769-80.
[6] Acar T, Kumkumolu Y. Our surgical experience on familial adenomatous polyposis. Surgical Chronicles. 2015; 20(1):217–20.
[7] Groden J, Thliveris A, Samowitz W, Carlson M, Gelbert L, Albertsen H, Joslyn G, Stevens J, Spirio L, Robertson M, Sargeant l, Krapcho K, Wolff E, Burt R, Hughes J.P., Warrington J, McPherson J, Wasmuth J, Le Paslier D, Abderrahim H, Cohen D, Leppert M, White R. Identification and characterization of the familial adenomatous polyposis coli gene. Cell. 1991;66(3):589-600.
[8] Kita K, Wittmann T, Nathke IS, Waterman-Storer CM. Adenomatous Polyposis Coli on microtubule plus ends in cell extensions can promote microtubule net growth with or without EB1. Mol Biol Cell. 2006; 17(5): 2331–45. PMC1446093
[9] Gayther SA, Wells D, SenGupta SB, Chapman P, Neale K, Tsioupra K, Delhanty JD. Regionally clustered APC mutations are associated with a severe phenotype and occur at a high frequency in new mutation cases of adenomatous polyposis coli. Hum Mol Genet. 1994;3(1):53-6.
[10] Zhang Y, Lu G, Hu Q, Wang X, Li C, Mao Y, Cui M. A de novo germline mutation of APC for inheritable colon cancer in a Chinese family using multigene next generation sequencing. Biochem Biophys Res Commun. 2014;447(3):503-7.
[11] Moisio AL, Järvinen H, Peltomäki P. Genetic and clinical characterisation of familial adenomatous polyposis: a population based study. Gut. 2002;50(6):845-50.
[12] Papp J, Kovacs ME, Matrai Z, Orosz E, Kásler M, Børresen-Dale AL, Olah E. Contribution of APC and MUTYH mutations to familial adenomatous polyposis susceptibility in Hungary. Fam Cancer. 2016;15(1):85-97.
[13] Lucci-Cordisco E, Risio M, Venesio T, Genuardi M. The growing complexity of the intestinal polyposis syndromes. Am J Med Genet A. 2013;161A(11):2777-87.
[14] Delaini GG, Skřička T, Colucci G. Intestinal polyps and polyposis. From genetics to treatment and follow up. Italia: Springer-Verlag, 2009: 246 p.
[15] Heinimann K, Müllhaupt B, Weber W, Attenhofer M, Scott RJ, Fried M, Martinoli S, Müller H, Dobbie Z. Phenotypic differences in familial adenomatous polyposis based on APC gene mutation status. Gut. 1998;43(5):675-9.
[16] Young J, Simms LA, Tarish J, Buttenshaw R, Knight N, Anderson GJ, Bell A, Leggett B. A family with attenuated familial adenomatous polyposis due to a mutation in the alternatively spliced region of APC exon 9. Hum Mutat. 1998;11(6):450-5.
[17] Iwama T, Utsunomiya J. Anticipation phenomenon in familial adenomatous polyposis:an analysis of its origin. World J Gastroenterol. 2000; 6(3): 335–8.
[18] McInnis MG. Anticipation: an old idea in new genes. Am J Hum Genet. 1996;59(5):973-9. Review.
[19] Ning XH, Zhang N, Li T, Wu PJ, Wang X, Li XY, Peng SH, Wang JY, Chen JC, Gong K. Telomere shortening is associated with genetic anticipation in Chinese Von Hippel-Lindau disease families. Cancer Res. 2014;74(14):3802-9.
[20] Tabori U, Nanda S, Druker H, Lees J, Malkin D. Younger age of cancer initiation is associated with shorter telomere length in Li-Fraumeni syndrome. Cancer Res. 2007;67(4):1415-8.
[21] Hsu L, Zhao LP, Malone KE, Daling JR. Assessing changes in ages at onset over successive generation: an application to breast cancer. Genet Epidemiol. 2000;18(1):17-32.
[22] McFaul CD, Greenhalf W, Earl J, Howes N, Neoptolemos JP, Kress R, Sina-Frey M, Rieder H, Hahn S, Bartsch DK; European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC); German National Case Collection for Familial Pancreatic Cancer (FaPaCa). Anticipation in familial pancreatic cancer. Gut. 2006;55(2):252-8.
[23] Goldberg JM, Piver MS, Jishi MF, Blumenson L. Age at onset of ovarian cancer in women with a strong family history of ovarian cancer. Gynecol Oncol. 1997;66(1):3-9.
[24] Bertorelle R, Rampazzo E, Pucciarelli S, Nitti D, De Rossi A. Telomeres, telomerase and colorectal cancer. World J Gastroenterol. 2014;20(8):1940-10. PMC3934464
[25] Horwitz M, Goode EL, Jarvik GP. Anticipation in familial leukemia. Am J Hum Genet. 1996; 59(5): 990–998.
[26] Wiernik PH, Wang SQ, Hu XP, Marino P, Paietta E. Age of onset evidence for anticipation in familial non-Hodgkin's lymphoma. Br J Haematol. 2000;108(1):72-9.
[27] Goldstein AM, Clark WH Jr, Fraser MC, Tucker MA. Apparent anticipation in familial melanoma. Melanoma Res. 1996;6(6):441-6.
[28] Shibata D, Peinado MA, Ionov Y, Malkhosyan S, Perucho M. Genomic instability in repeated sequences is an early somatic event in colorectal tumorigenesis that persists after transformation. Nat Genet. 1994;6(3):273-81.
[29] Bozzao C, Lastella P, Stella A. Anticipation in lynch syndrome: where we are where we go. Curr Genomics. 2011;12(7):451-65.
[30] Seguí N, Pineda M, Guinó E, Borràs E, Navarro M, Bellido F, Moreno V, Lázaro C, Blanco I, Capellá G, Valle L. Telomere length and genetic anticipation in Lynch syndrome. PLoS One. 2013;8(4):e61286.
[31] Makuch GW, Zastavna DV, Tyrkus MN, et al. Pat. 32044 Ukraine, IPC G01N33/49 (2006.01) Method of DNA isolation from peripheral blood leukocytes. patent owner SI "Institute of Hereditary Pathology of National Academy of Medical Sciences." N u200801896; appl. 14.02.2008; publ.25.04.2008, Bull. N8/2008.
[32] Plawski A, Jura J, Slomski R. Wykrywanie mutacji punktowych w genie supresorowym APC czlowieka metod heterodupleksów. Przyklady analiz DNA, 2001: 80–9.
[33] Plawski A, Lubinski J, Banasiewicz T, et al. Mutations in the APC gene were found in 42 (35 %) Polish families with FAP, and 22 types of mutation in the APC gene were identified. J Med Genet. 2004; 41: e11.
[34] Atramentova LA, Belyaeva LV. Correlation between family and age of manifestation of lung and colon cancer. Genetika. 2003; 39(12):1702–9.
[35] Sieber OM, Tomlinson IP, Lamlum H. The adenomatous polyposis coli (APC) tumour suppressor--genetics, function and disease. Mol Med Today. 2000;6(12):462-9. Review. Erratum in: Mol Med Today 2001 Jan;7(1):40.
[36] Aretz S, Uhlhaas S, Caspari R, Mangold E, Pagenstecher C, Propping P, Friedl W. Frequency and parental origin of de novo APC mutations in familial adenomatous polyposis. Eur J Hum Genet. 2004;12(1):52-8.
[37] Castellsagué E, González S, Guinó E, Stevens KN, Borràs E, Raymond VM, Lázaro C, Blanco I, Gruber SB, Capellá G. Allele-specific expression of APC in adenomatous polyposis families. Gastroenterology. 2010;139(2):439-47, 447.e1.
[38] Spier I, Horpaopan S, Vogt S, Uhlhaas S, Morak M, Stienen D, Draaken M, Ludwig M, Holinski-Feder E, Nöthen MM, Hoffmann P, Aretz S. Deep intronic APC mutations explain a substantial proportion of patients with familial or early-onset adenomatous polyposis. Hum Mutat. 2012;33(7):1045-50.
[39] Kadiyska TK, Todorov TP, Bichev SN, Vazharova RV, Nossikoff AV, Savov AS, Mitev VI. APC promoter 1B deletion in familial polyposis--implications for mutation-negative families. Clin Genet. 2014;85(5):452-7.
[40] Roger L, Jones RE, Heppel NH, Williams GT, Sampson JR, Baird DM. Extensive telomere erosion in the initiation of colorectal adenomas and its association with chromosomal instability. J Natl Cancer Inst. 2013;105(16):1202-11.
[41] Hoffmeyer K, Raggioli A, Rudloff S, Anton R, Hierholzer A, Del Valle I, Hein K, Vogt R, Kemler R. Wnt/β-catenin signaling regulates telomerase in stem cells and cancer cells. Science. 2012;336(6088):1549-54.
[42] Calado RT, Yewdell WT, Wilkerson KL, Regal JA, Kajigaya S, Stratakis CA, Young NS. Sex hormones, acting on the TERT gene, increase telomerase activity in human primary hematopoietic cells. Blood. 2009;114(11):2236-43.
[43] Nanni S, Narducci M, Della Pietra L, Moretti F, Grasselli A, De Carli P, Sacchi A, Pontecorvi A, Farsetti A. Signaling through estrogen receptors modulates telomerase activity in human prostate cancer. J Clin Invest. 2002;110(2):219-27.
[44] Wu KJ, Grandori C, Amacker M, Simon-Vermot N, Polack A, Lingner J, Dalla-Favera R. Direct activation of TERT transcription by c-MYC. Nat Genet. 1999;21(2):220-4.
[45] Newbold RF. The significance of telomerase activation and cellular immortalization in human cancer. Mutagenesis. 2002;17(6):539-50.
[46] Kyo S, Takakura M, Kanaya T, Zhuo W, Fujimoto K, Nishio Y, Orimo A, Inoue M. Estrogen activates telomerase. Cancer Res. 1999;59(23):5917-21.