- Volume 16 Issue 12
DOI QR Code
Analysis of Small Fragment Deletions of the APC gene in Chinese Patients with Familial Adenomatous Polyposis, a Precancerous Condition
- Chen, Qing-Wei (Department of Medical Oncology, Jiangsu Cancer Hospital affiliated to Nanjing Medical University) ;
- Zhang, Xiao-Mei (Laboratory of Genetics and Molecular Biology, Jiangsu Institute of Cancer Research) ;
- Zhou, Jian-Nong (Department of General Surgery, Jiangsu Cancer Hospital) ;
- Zhou, Xin (Department of General Surgery, Jiangsu Cancer Hospital) ;
- Ma, Guo-Jian (Laboratory of Genetics and Molecular Biology, Jiangsu Institute of Cancer Research) ;
- Zhu, Ming (Laboratory of Genetics and Molecular Biology, Jiangsu Institute of Cancer Research) ;
- Zhang, Yuan-Ying (Laboratory of Genetics and Molecular Biology, Jiangsu Institute of Cancer Research) ;
- Yu, Jun (Laboratory of Genetics and Molecular Biology, Jiangsu Institute of Cancer Research) ;
- Feng, Ji-Feng (Department of Medical Oncology, Jiangsu Cancer Hospital affiliated to Nanjing Medical University) ;
- Chen, Sen-Qing (Laboratory of Genetics and Molecular Biology, Jiangsu Institute of Cancer Research)
- Published : 2015.07.13
Background: : Familial adenomatous polyposis (FAP) is an autosomal dominant inherited disease mainly caused by mutations of the adenomatous polyposis coli (APC) gene with almost complete penetrance. These colorectal polyps are precancerous lesions that will inevitable develop into colorectal cancer at the median age of 40-year old if total proctocolectomy is not performed. So identification of APC germline mutations has great implications for genetic counseling and management of FAP patients. In this study, we screened APC germline mutations in Chinese FAP patients, in order to find novel mutations and the APC gene germline mutation characteristics of Chinese FAP patients. Materials and Methods: The FAP patients were diagnosed by clinical manifestations, family histories, endoscope and biopsy. Then patients peripheral blood samples were collected, afterwards, genomic DNA was extracted. The mutation analysis of the APC gene was conducted by direct polymerase chain reaction (PCR) sequencing for micromutations and multiplex ligation-dependent probe amplification (MLPA) for large duplications and/or deletions. Results: We found 6 micromutations out of 14 FAP pedigrees, while there were no large duplications and/or deletions found. These germline mutations are c.5432C>T(p. Ser1811Leu), two c.3926_3930delAAAAG (p.Glu1309AspfsX4), c.3921_3924delAAAA (p.Ile1307MetfsX13), c3184_3187delCAAA(p.Gln1061AspfsX59) and c4127_4126delAT (p.Tyr1376LysfsX9), respectively, and all deletion mutations resulted in a premature stop codon. At the same time, we found c.3921_3924delAAAA and two c.3926_3930delAAAAG are located in AAAAG short tandem repeats, c3184_3187delCAAA is located in the CAAA interrupted direct repeats, and c4127_4128 del AT is located in the 5'-CCTGAACA-3', 3'-ACAAGTCC-5 palindromes (inverted repeats) of the APC gene. Furthermore, deletion mutations are mostly located at condon 1309. Conclusions: Though there were no novel mutations found as the pathogenic gene of FAP in this study, we found nucleotide sequence containing short tandem repeats and palindromes (inverted repeats), especially the 5 bp base deletion at codon 1309, are mutations in high incidence area in APC gene,.
Familial adenomatous polyposis;APC gene;germline mutation;colorectal cancer
Supported by : Science and Education of Jaingsu Province, Science and Technology Department of Jiangsu Province
- Aoki K, Taketo MM (2007). Adenomatous polyposis coli (APC): a multi-functional tumor suppress'or gene. J Cell Sci, 120, 3327-35. https://doi.org/10.1242/jcs.03485
- Bisgaard ML, Fenger K, Bulow S, et al (1994). Familial adenomatous polyposis (FAP): frequency, penetrance, and mutation rate. Hum Mutat, 3, 121-5. https://doi.org/10.1002/humu.1380030206
- Caspari R, Friedl W, Mandl M, et al (1994). Familial adenomatous polyposis: mutation at codon 1309 and early onset of colon cancer. Lancet, 343, 629-32. https://doi.org/10.1016/S0140-6736(94)92634-4
- Chen YS, Xu SX, Ding YB, et al (2013).Helicobacter pylori Infection and the risk of colorectal adenoma and adenocarcinoma: an updated meta-analysis of different testing methods. Asian Pac J Cancer Prev, 14, 7613-9. https://doi.org/10.7314/APJCP.2013.14.12.7613
- Chen YS, Xu SX, Ding YB, et al (2014).Colorectal cancer screening in high-risk populations: a survey of cognition among m edical professionals in Jiangsu, China. Asian Pac J Cancer Prev, 14, 6487-91.
- Cooper DN and Krawczak M (1990). The mutational spectrum of single base-pair substitutions causing human genetic disease: patterns and predictions. Hum Genet. 85, 55-74.
- Crabtree MD, Tomlinson IP, Hodgson SV, et al (2002). Explaining variation in familial adenomatous polyposis: relationship between genotype and phenotype and evidence for modifier genes. Gut, 51, 420-3. https://doi.org/10.1136/gut.51.3.420
- David NC, Michael K (1991). Mechanisms of insertionai mutagenesis in human genes causing genetic disease. Hum Genet, 87, 409-15.
- den Dunnen JT, Antonarakis SE (2001). Nomenclature for the description of human sequence variations. Hum Genet, 109, 121-4. https://doi.org/10.1007/s004390100505
- den Dunnen JT, Antonarakis SE (2003). Mutation Nomenclature. Curr Protoc Hum Genet. [Epub ahead of print]
- Fearnhead NS, Britton MP, Bodmer WF (2001). The ABC of APC. Hum Mol Genet, 10, 721-33. https://doi.org/10.1093/hmg/10.7.721
- Half E, Bercovich D, Rozen P (2009). Familial adenomatous polyposis. Orphanet J Rare Dis, 4, 22. https://doi.org/10.1186/1750-1172-4-22
- Genevie ve M, Sabine T, Reinhilde T, et al (2005). Large Deletions of the APC Gene in 15% of Mutation-Negative Patients With Classical Polyposis (FAP): A Belgian Study. Hum Mutat, 25, 125-34. https://doi.org/10.1002/humu.20122
- Jaehoon J, Sang JY, Hyojin P (2013). A Novel Germline Mutation in Exon 15 of the APC Gene in Attenuated Familial Adenomatous Polyposis: A Report of Two Cases. Gut and Liver, 7, 120-5. https://doi.org/10.5009/gnl.2013.7.1.120
- Jang YH, Lim SB, Kim MJ, et al (2010). Three novel mutations of the APC gene in Korean patients with familial adenomatous polyposis. Cancer. Genet. Cytogenet, 200, 34-9. https://doi.org/10.1016/j.cancergencyto.2010.03.015
- Johan H, van Es, Rachel H, et al (2001). The Many Faces of the Tumor Suppressor Gene APC. Exp Cell Res, 264, 126-34. https://doi.org/10.1006/excr.2000.5142
- Keiko T, Yasuyoshi S, Yuri S, et al (2014). A Case of a Child with an APC Pathogenic Mutation, Aberrant Expression of Splice Variants and Positive Family History of FAP. Jpn J Clin Oncol, 44, 602-6. https://doi.org/10.1093/jjco/hyu050
- Kerr SE1, Thomas CB, Thibodeau SN, et al (2013). APC Germline Mutations in Individuals Being Evaluated for Familial Adenomatous Polyposis A Review of the Mayo Clinic Experience with 1591Consecutive Tests. J Mol Diagn, 15, 31-43. https://doi.org/10.1016/j.jmoldx.2012.07.005
- Kittiyod P, Sirinporn S, Chucheep S, et al (2012). Colon Cancer Prevention by Detection of APC Gene Mutation in a Family with Attenuated Familial Adenomatous Polyposis. Asian Pac J Cancer Prev, 13, 5101-4. https://doi.org/10.7314/APJCP.2012.13.10.5101
- Krawczak M, Cooper DN (1991). Mechanisms of insertionai mutagenesis in human genes causing genetic disease. Hum Genet, 87, 409-15.
- Liao DX, Li b, Du XM, et al (2014). Two Chinese pedigrees for adenomatous polyposis coli: new mutations at codon 1309 and predisposition to phenotypic variations. Familial Cancer, 13, 361-8. https://doi.org/10.1007/s10689-014-9713-8
- Michael K, and David N. Cooper (1991). Gene deletions causing human genetic disease: mechanisms of mutagenesis and the role of the local D N A sequence environment. Hum Genet, 86, 425-41.
- Miyoshi Y, Ando H, Nagase H, et al (1992). Germ-line mutations of the APC gene in 53 familial adenomatous polyposis patients. Proc Natl Acad Sci U S A, 89, 4452-6. https://doi.org/10.1073/pnas.89.10.4452
- Miyoshi Y, Nagase H, Ando H, et al (1992). Somatic mutations of the APC gene in colorectal tumors: Mutation cluster region in the APC gene. Hum Mol Genet, 1, 229-33. https://doi.org/10.1093/hmg/1.4.229
- Newton KF, Mallinson EK, Bowen J, et al (2012). Genotypephenotype correlation in colorectal polyposis. Clin Genet, 81, 521-31. https://doi.org/10.1111/j.1399-0004.2011.01740.x
- Polakis P. (1997). The adenomatous polyposis coli (APC) tumor suppressor. Biochim Biophys Acta, 1332, 127-47.
- Rustgi AK (2013). The genetics of hereditary colon cancer. Genes Dev, 21, 2525-38.
- Sarah E. Kerr, Cheryl B. Thomas, et al (2013). APC Germline Mutations in Individuals Being Evaluated for Familial Adenomatous Polyposis. J Mol Diagn, 15, 31-43. https://doi.org/10.1016/j.jmoldx.2012.07.005
- Sieber OM, Segditsas S, Knudsen AL, et al (2006). Disease severity and genetic pathways in attenuated familial adenomatous polyposis vary greatly but depend on the site of the germline mutation. Gut, 55, 1440-8. https://doi.org/10.1136/gut.2005.087106
- Song G, Yuan Y, Zheng F, et al(2013). Novel insertion mutation p.Asp610GlyfsX23 in APC gene causes familial adenomatous polyposis in Chinese families. Gene, 516, 204-8. https://doi.org/10.1016/j.gene.2012.12.077
- Stekrova J, Sulova M, Kebrdlova V, et al (2007). Novel APC mutations in Czech and Slovak FAP families: clinical and genetic aspects. BMC Med Genet, 8, 16.
- Stenson PD, Ball EV, et al (2003). Human Gene Mutation Database (HGMD): 2003 update. Hum Mutat, 21, 577-81. https://doi.org/10.1002/humu.10212
- Sun ZQ, Wang GJ, Zhao ZL, et al (2014). Significance of HPV Infection and Genic Mutation of APC and K-ras in Patients with Rectal Cancer. Asian Pac J Cancer Prev, 14, 121-6.
- van der Luijt RB, Khan PM, Mort M, et al (1997). Molecular analysis of the APC gene in 105 Dutch kindreds with familial adenomatous polyposis: 67 germline mutations identified by DGGE, PTT, and southern analysis. Hum Mutat, 9, 7-16. https://doi.org/10.1002/(SICI)1098-1004(1997)9:1<7::AID-HUMU2>3.0.CO;2-8
- van Es JH, Giles RH, Clevers HC (2001). The Many Faces of the Tumor Suppressor Gene APC. Exp Cell Res, 264, 126-34. https://doi.org/10.1006/excr.2000.5142
- Wang TT, Chen SQ, Zhang XM, et al (2008). Germline mutation of adenomatous polyposis coli gene in Chinese patients with adenomatous polyposis. China J Med Genet, 25, 199-202.
- Yang L, Huang XE, Xu L, et al (2013). Role of MYH polymorphisms in sporadic colorectal cancer in China: a case-control, population-based study. Asian Pac J Cancer Prev, 14, 6403-9. https://doi.org/10.7314/APJCP.2013.14.11.6403
- Yeo CJ (1999). Tumor suppressor genes: A short review. Surgery, 125, 363-6. https://doi.org/10.1016/S0039-6060(99)70001-2
- Yousef B, Davood D, Heidar E, et al (2006). Distribution of Cancer and Adenomatous Polyps in the Colorectum: Study in an Iranian Population. Asian Pac J Cancer Prev, 7, 65-8.
- Zhang M, Lan FH (2014). The advances of familial adenomatous polyposis. Int J genet, 37, 82-8.
- Zhang JF, Cao HL, Zhang B, et al (2013). Berberine potently attenuates intestinal polyps growth in ApcMin mice and familial adenomatous polyposis patients through inhibition of Wnt signalling. J Cell Mol Med, 17, 1484-93. https://doi.org/10.1111/jcmm.12119
- Zhang Y, Guanting Lu, Qingtao Hu, et al (2014). A de novo germline mutation of APC for inheritable colon cancer in a Chinese family using multigene next generation sequencing. Biochem Biophys Res Commun, 447, 503-7. https://doi.org/10.1016/j.bbrc.2014.04.014
- Identification a nonsense mutation of APC gene in Chinese patients with familial adenomatous polyposis vol.13, pp.4, 2017, https://doi.org/10.3892/etm.2017.4122
- Detection of a heterozygous germline APC mutation in a three-generation family with familial adenomatous polyposis using targeted massive parallel sequencing in Vietnam vol.19, pp.1, 2018, https://doi.org/10.1186/s12881-018-0701-y