APC germline mutations in families with familial adenomatous polyposis

Rossanese,Lillian  Barbosa De Queiroz; Marson,Fernando  Augusto De Lima; Ribeiro,José   Dirceu; Coy,Claudio  Saddy Rodrigues; Bertuzzo,Carmen   Silvia

doi:10.3892/or.2013.2681

APC germline mutations in families with familial adenomatous polyposis

Authors:
- Lillian Barbosa De Queiroz Rossanese
- Fernando Augusto De Lima Marson
- José Dirceu Ribeiro
- Claudio Saddy Rodrigues Coy
- Carmen Silvia Bertuzzo
View Affiliations

Affiliations: Department of Medical Genetics, Medical Science Faculty, University of Campinas, Cidade Universitária, Campinas, SP 13081-970, Brazil, Department of Pediatrics, Medical Science Faculty, University of Campinas, Cidade Universitária, Campinas, SP 13081-970, Brazil, Department of Surgery, Medical Science Faculty, University of Campinas, Cidade Universitária, Campinas, SP 13081-970, Brazil
Published online on: August 21, 2013 https://doi.org/10.3892/or.2013.2681
Pages: 2081-2088

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Adenomatous polyposis coli (APC) germline mutations are responsible for the occurrence of familial adenomatous polyposis (FAP). Somatic mutations lead to malignant transformation of adenomas. In this context, considering the significance of APC germline mutations in FAP, we aimed to identify APC germline mutations. In the present study, 20 FAP patients were enrolled. The determination of APC germline mutations was performed using sequencing, and the mutations were compared with clinical markers (gender, age at diagnosis, smoking habits, TNM stage, Astler‑Coller stage, degree of differentiation of adenocarcinoma). The data were compared using the SPSS program, with the Fisher's exact test and χ2 test, considering α=0.05. According to the main results in our sample, 16 alleles with deleterious mutations (80% of the patients) were identified while 7 (35%) patients had no deleterious mutations. There was a predominance of nonsense (45% of the patients) and frameshift (20% of the patients) mutations. There was no statistical significance between the APC germline mutations identified and the clinical variables considered in our study. Only TNM stage was associated with the presence of deleterious mutations. Patients with deleterious mutations had an OR, 0.086 (IC=0.001-0.984); TNM stage I + II in comparison with III + IV, when compared with the patients with no deleterious mutations identified. In this context, as a conclusion, we demonstrated the molecular heterogeneity of APC germline mutations in FAP and the difficulty to perform molecular diagnostics in a Brazilian population, considering the admixed population analyzed.

View Figures

View References

1	National Cancer Institute (INCA). Estimate 2012: Cancer Incidence in Brazil. 2011, http://www.inca.gov.br/estimativa/2012/index.asp?ID=5. Accessed February 25, 2013
2	Leblanc R: Familial adenomatous polyposis and benign intracranial tumors: a new variant of Gardner’s syndrome. Can J Neurol Sci. 27:341–346. 2000.PubMed/NCBI
3	Dundar M, Caglayan AO, Saatci C, et al: How the 11307K adenomatous polyposis coli gene variant contributes in the assessment of risk of colorectal cancer, but not stomach cancer, in a Turkish population. Cancer Genet Cytogenet. 177:95–97. 2007. View Article : Google Scholar : PubMed/NCBI
4	The APC mutations database - UMD. http://www.umd.be/APC/. Accessed February 25, 2013
5	Kerr SE, Thomas CB, Thibodeau SN, et al: APC germline mutations in individuals being evaluated for familial adenomatous polyposis: a review of the Mayo Clinic experience with 1591 consecutive tests. J Mol Diagn. 15:31–43. 2013. View Article : Google Scholar : PubMed/NCBI
6	Zeichner SB, Raj N, Cusnir M, et al: A de novo germline APC mutation (3927del5) in a patient with familial adenomatous polyposis: case report and literature review. Clin Med Insights Oncol. 6:315–323. 2012. View Article : Google Scholar : PubMed/NCBI
7	Astler VB and Coller FA: The prognostic significance of direct extension of carcinoma of the colon and rectum. Ann Surg. 139:846–852. 1954. View Article : Google Scholar : PubMed/NCBI
8	Way LW and Doherty GM: Cirurgia: Diagnóstico e Tratamento. 11th edition. Guanabara Koogan; Rio de Janeiro: 2004, (In Portuguese).
9	Towsend CM, Beauchamp RD, Evers BM and Mattox KL: Sabiston, Tratado de Cirurgia: A Base Biológica da Prática Cirúrgica Moderna. Elsevier; Rio de Janeiro: 2005, (In Portuguese).
10	World Health Organisation. Histological Typing of Intestinal Tumours. International Histological Classification of Tumours. (15)WHO; Geneva: 1976
11	Sambrook J, Fritsch EF and Maniatis T: Molecular Cloning: A Laboratory Manual. Cold Spring Harbor Laboratory Press; New York: 1989
12	Miyoshi Y, Ando H, Nagase H, et al: Germ-line mutations of the APC gene in 53 familial adenomatous polyposis patients. Proc Natl Acad Sci USA. 89:4452–4456. 1992. View Article : Google Scholar
13	Nagase H and Nakamura Y: Mutations of the APC (adenomatous polyposis coli) gene. Hum Mutat. 2:425–434. 1993. View Article : Google Scholar : PubMed/NCBI
14	Gómez-Fernández N, Castellví-Bel S, Fernández-Rozadilla C, et al: Molecular analysis of the APC and MUTYH genes in Galician and Catalonian FAP families: a different spectrum of mutations? BMC Med Genet. 10:572009.PubMed/NCBI
15	Goss KH and Groden J: Biology of the adenomatous polyposis coli tumor suppressor. J Clin Oncol. 18:1967–1979. 2000.PubMed/NCBI
16	Amos-Landgraf JM, Kwong LN, Kendziorski CM, et al: A target-selected Apc-mutant rat kindred enhances the modeling of familial human colon cancer. Proc Natl Acad Sci USA. 104:4036–4041. 2007. View Article : Google Scholar : PubMed/NCBI
17	Half E, Bercovich D and Rozen P: Familial adenomatous polyposis. Orphanet J Rare Dis. 4:222009. View Article : Google Scholar
18	Azzopardi D, Dallosso AR, Eliason K, et al: Multiple rare nonsynonymous variants in the adenomatous polyposis coli gene predispose to colorectal adenomas. Cancer Res. 68:358–363. 2008. View Article : Google Scholar : PubMed/NCBI
19	Gavert N, Yaron Y, Naiman T, et al: Molecular analysis of the APC gene in 71 Israeli families: 17 novel mutations. Hum Mutat. 19:6642002. View Article : Google Scholar : PubMed/NCBI
20	Ruiz-Ponte C, Vega A, Carracedo A and Barros F: Mutation analysis of the adenomatous polyposis coli (APC) gene in northwest Spanish patients with familial adenomatous polyposis (FAP) and sporadic colorectal cancer. Hum Mutat. 18:3552001. View Article : Google Scholar : PubMed/NCBI
21	Schnitzler M, Koorey D, Dwight T, et al: Frequency of codon 1061 and codon 1309 APC mutations in Australian familial adenomatous polyposis patients. Hum Mutat. (Suppl 1): S56–S57. 1998. View Article : Google Scholar : PubMed/NCBI
22	Varesco L, Gismondi V, James R, et al: APC gene mutations in Italian familial polyposis coli patients. Cancer Detect Prev. 17:279–281. 1993.PubMed/NCBI
23	Laken SJ, Petersen GM, Gruber SB, et al: Familial colorectal cancer in Ashkenazim due to a hypermutable tract in APC. Nat Genet. 17:79–83. 1997. View Article : Google Scholar : PubMed/NCBI
24	Lamlum H, Al Tassan N, Jaeger E, et al: Germline APC variants in patients with multiple colorectal adenomas, with evidence for the particular importance of E1317Q. Hum Mol Genet. 9:2215–2221. 2000. View Article : Google Scholar : PubMed/NCBI
25	Frayling IM, Beck Ne, Ilyas M, et al: The APC variants I1307K and E1317Q are associated with colorectal tumors, but not always with a family history. Proc Natl Acad Sci USA. 95:10722–10727. 1998. View Article : Google Scholar : PubMed/NCBI
26	Gryfe R, Di Nicola N, Lal G, et al: Inherited colorectal polyposis and cancer risk of the APC I1307K polymorphism. Am J Hum Genet. 64:378–384. 1999. View Article : Google Scholar : PubMed/NCBI
27	Hahnloser D, Petersen GM, Rabe K, et al: The APC E1317Q variant in adenomatous polyps and colorectal cancers. Cancer Epidemiol Biomarkers Prev. 12:1023–1028. 2003.PubMed/NCBI