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Graf MR, Apte S, Terzo E, Padhye S, Shi S, Cox MK, Clark RB, Modur V, Badarinarayana V. Novel read through agent: ZKN-0013 demonstrates efficacy in APC min model of familial adenomatous polyposis. J Mol Med (Berl) 2023; 101:375-385. [PMID: 36808265 DOI: 10.1007/s00109-023-02291-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 01/20/2023] [Accepted: 01/23/2023] [Indexed: 02/23/2023]
Abstract
Familial adenomatous polyposis (FAP) is a precancerous, colorectal disease characterized by hundreds to thousands of adenomatous polyps caused by mutations in the tumor suppressor gene adenomatous polyposis coli (APC). Approximately 30% of these mutations are premature termination codons (PTC), resulting in the production of a truncated, dysfunctional APC protein. Consequently, the β-catenin degradation complex fails to form in the cytoplasm, leading to elevated nuclear levels of β-catenin and unregulated β-catenin/wnt-pathway signaling. We present in vitro and in vivo data demonstrating that the novel macrolide, ZKN-0013, promotes read through of premature stop codons, leading to functional restoration of full-length APC protein. Human colorectal carcinoma SW403 and SW1417 cells harboring PTC mutations in the APC gene showed reduced levels of nuclear β-catenin and c-myc upon treatment with ZKN-0013, indicating that the macrolide-mediated read through of premature stop codons produced bioactive APC protein and inhibited the β-catenin/wnt-pathway. In a mouse model of adenomatous polyposis coli, treatment of APCmin mice with ZKN-0013 caused a significant decrease in intestinal polyps, adenomas, and associated anemia, resulting in increased survival. Immunohistochemistry revealed decreased nuclear β-catenin staining in the epithelial cells of the polyps in ZKN-0013-treated APCmin mice, confirming the impact on the β-catenin/wnt-pathway. These results indicate that ZKN-0013 may have therapeutic potential for the treatment of FAP caused by nonsense mutations in the APC gene. KEY MESSAGES: • ZKN-0013 inhibited the growth of human colon carcinoma cells with APC nonsense mutations. • ZKN-0013 promoted read through of premature stop codons in the APC gene. • In APCmin mice, ZKN-0013 treatment reduced intestinal polyps and their progression to adenomas. • ZKN-0013 treatment in APCmin mice resulted in reduced anemia and increased survival.
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Affiliation(s)
| | - Shruti Apte
- Eloxx Pharmaceuticals, Watertown, MA, 02472, USA
| | | | | | - Shuhao Shi
- Eloxx Pharmaceuticals, Watertown, MA, 02472, USA
| | - Megan K Cox
- Eloxx Pharmaceuticals, Watertown, MA, 02472, USA
| | | | - Vijay Modur
- Eloxx Pharmaceuticals, Watertown, MA, 02472, USA
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Garza-Rodríguez ML, Treviño V, Pérez-Maya AA, Rodríguez-Gutiérrez HF, González-Escamilla M, Elizondo-Riojas MÁ, Ramírez-Correa GA, Vidal-Gutiérrez O, Burciaga-Flores CH, Pérez-Ibave DC. Identification of a Novel Pathogenic Rearrangement Variant of the APC Gene Associated with a Variable Spectrum of Familial Cancer. Diagnostics (Basel) 2021; 11:diagnostics11030411. [PMID: 33670908 PMCID: PMC7997431 DOI: 10.3390/diagnostics11030411] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 02/05/2021] [Accepted: 02/22/2021] [Indexed: 01/14/2023] Open
Abstract
Familial adenomatous polyposis (FAP) is an autosomal-dominant condition characterized by the presence of multiple colorectal adenomas, caused by germline variants in the adenomatous polyposis coli (APC) gene. More than 300 germline variants have been characterized. The detection of novel variants is important to understand the mechanisms of pathophysiology. We identified a novel pathogenic germline variant using next-generation sequencing (NGS) in a proband patient. The variant is a complex rearrangement (c.422+1123_532-577 del ins 423-1933_423-1687 inv) that generates a complete deletion of exon 5 of the APC gene. To study the variant in other family members, we designed an endpoint PCR method followed by Sanger sequencing. The variant was identified in the proband patient's mother, one daughter, her brother, two cousins, a niece, and a second nephew. In patients where the variant was identified, we found atypical clinical symptoms, including mandibular, ovarian, breast, pancreatic, and gastric cancer. Genetic counseling and cancer prevention strategies were provided for the family. According to the American College of Medical Genetics (ACMG) guidelines, this novel variant is considered a PVS1 variant (very strong evidence of pathogenicity), and it can be useful in association with clinical data for early surveillance and suitable treatment.
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Affiliation(s)
- María Lourdes Garza-Rodríguez
- Centro Universitario Contra el Cáncer (CUCC), Servicio de Oncología, Universidad Autónoma de Nuevo León, Hospital Universitario “Dr. José Eleuterio González”, Nuevo, León 64460, Mexico; (M.L.G.-R.); (H.F.R.-G.); (M.G.-E.); (M.Á.E.-R.); (O.V.-G.)
| | - Víctor Treviño
- Tecnológico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Nuevo, León 64710, Mexico;
| | - Antonio Alí Pérez-Maya
- Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Nuevo, León 64460, Mexico;
| | - Hazyadee Frecia Rodríguez-Gutiérrez
- Centro Universitario Contra el Cáncer (CUCC), Servicio de Oncología, Universidad Autónoma de Nuevo León, Hospital Universitario “Dr. José Eleuterio González”, Nuevo, León 64460, Mexico; (M.L.G.-R.); (H.F.R.-G.); (M.G.-E.); (M.Á.E.-R.); (O.V.-G.)
| | - Moisés González-Escamilla
- Centro Universitario Contra el Cáncer (CUCC), Servicio de Oncología, Universidad Autónoma de Nuevo León, Hospital Universitario “Dr. José Eleuterio González”, Nuevo, León 64460, Mexico; (M.L.G.-R.); (H.F.R.-G.); (M.G.-E.); (M.Á.E.-R.); (O.V.-G.)
| | - Miguel Ángel Elizondo-Riojas
- Centro Universitario Contra el Cáncer (CUCC), Servicio de Oncología, Universidad Autónoma de Nuevo León, Hospital Universitario “Dr. José Eleuterio González”, Nuevo, León 64460, Mexico; (M.L.G.-R.); (H.F.R.-G.); (M.G.-E.); (M.Á.E.-R.); (O.V.-G.)
| | - Genaro A. Ramírez-Correa
- Department of Molecular Science, UT Health Rio Grande Valley, McAllen, TX 78502, USA;
- Department of Pediatrics, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Oscar Vidal-Gutiérrez
- Centro Universitario Contra el Cáncer (CUCC), Servicio de Oncología, Universidad Autónoma de Nuevo León, Hospital Universitario “Dr. José Eleuterio González”, Nuevo, León 64460, Mexico; (M.L.G.-R.); (H.F.R.-G.); (M.G.-E.); (M.Á.E.-R.); (O.V.-G.)
| | - Carlos Horacio Burciaga-Flores
- Centro Universitario Contra el Cáncer (CUCC), Servicio de Oncología, Universidad Autónoma de Nuevo León, Hospital Universitario “Dr. José Eleuterio González”, Nuevo, León 64460, Mexico; (M.L.G.-R.); (H.F.R.-G.); (M.G.-E.); (M.Á.E.-R.); (O.V.-G.)
- Correspondence: (C.H.B.-F.); or (D.C.P.-I.); Tel.: +52-(81)-83338111 (C.H.B.-F. & D.C.P.-I.)
| | - Diana Cristina Pérez-Ibave
- Centro Universitario Contra el Cáncer (CUCC), Servicio de Oncología, Universidad Autónoma de Nuevo León, Hospital Universitario “Dr. José Eleuterio González”, Nuevo, León 64460, Mexico; (M.L.G.-R.); (H.F.R.-G.); (M.G.-E.); (M.Á.E.-R.); (O.V.-G.)
- Correspondence: (C.H.B.-F.); or (D.C.P.-I.); Tel.: +52-(81)-83338111 (C.H.B.-F. & D.C.P.-I.)
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Zhang Y, Liang B, Song X, Wang H, Evert M, Zhou Y, Calvisi DF, Tang L, Chen X. Loss of Apc Cooperates with Activated Oncogenes to Induce Liver Tumor Formation in Mice. THE AMERICAN JOURNAL OF PATHOLOGY 2021; 191:930-946. [PMID: 33545120 DOI: 10.1016/j.ajpath.2021.01.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 01/03/2021] [Accepted: 01/14/2021] [Indexed: 02/08/2023]
Abstract
Hepatocellular carcinoma (HCC) and hepatoblastoma are the major types of primary liver cancer in adulthood and childhood, respectively. Wnt/β-catenin signaling deregulation is one of the most frequent genetic events in hepatocarcinogenesis. APC regulator of WNT signaling pathway (APC) encodes an inhibitor of the Wnt cascade and acts as a tumor suppressor. Germline defects of the APC gene lead to familial adenomatous polyposis, and its somatic mutations occur in multiple tumor types. However, the contribution of APC in hepatocarcinogenesis remains unclear. Therefore, APC mutations and expression patterns were examined in human HCC and hepatoblastoma samples. Whether loss of Apc alone or in cooperation with other oncogenes triggers liver tumor development in vivo was also investigated. sgApc alone could not drive liver tumor formation, but synergized with activated oncogenes (YapS127A, TazS89A, and c-Met) to induce hepatocarcinogenesis. Mechanistically, Apc deletion induced the activation of β-catenin and its downstream targets in mouse liver tumors. Furthermore, Ctnnb1 ablation or TCF4-mediated transcription blockade completely prevented liver tumor formation, indicating the requirement of a functional β-catenin pathway for loss of Apc-driven hepatocarcinogenesis. This study shows that a subset of HCC patients with loss-of-function APC mutations might benefit from therapeutic strategies targeting the Wnt/β-catenin pathway.
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Affiliation(s)
- Yi Zhang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China; Department of Bioengineering University of California, San Francisco, California
| | - Binyong Liang
- Hepatic Surgery Center, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xinhua Song
- Department of Bioengineering University of California, San Francisco, California
| | - Haichuan Wang
- Liver Transplantation Division, Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China; Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Matthias Evert
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Yi Zhou
- Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Diego F Calvisi
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Liling Tang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China.
| | - Xin Chen
- Department of Bioengineering University of California, San Francisco, California; Department of Therapeutic Sciences and Liver Center, University of California, San Francisco, San Francisco, California.
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Milanese JS, Wang E. Germline Genetics in Cancer: The New Frontier. SYSTEMS MEDICINE 2021. [DOI: 10.1016/b978-0-12-801238-3.11667-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022] Open
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Germline genomes have a dominant-heritable contribution to cancer immune evasion and immunotherapy response. QUANTITATIVE BIOLOGY 2020. [DOI: 10.1007/s40484-020-0212-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Molecular-Clinical Correlation in Pediatric Medulloblastoma: A Cohort Series Study of 52 Cases in Taiwan. Cancers (Basel) 2020; 12:cancers12030653. [PMID: 32168907 PMCID: PMC7139704 DOI: 10.3390/cancers12030653] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 03/09/2020] [Accepted: 03/09/2020] [Indexed: 12/27/2022] Open
Abstract
In 2016, a project was initiated in Taiwan to adopt molecular diagnosis of childhood medulloblastoma (MB). In this study, we aimed to identify a molecular-clinical correlation and somatic mutation for exploring risk-adapted treatment, drug targets, and potential genetic predisposition. In total, 52 frozen tumor tissues of childhood MBs were collected. RNA sequencing (RNA-Seq) and DNA methylation array data were generated. Molecular subgrouping and clinical correlation analysis were performed. An adjusted Heidelberg risk stratification scheme was defined for updated clinical risk stratification. We selected 51 genes for somatic variant calling using RNA-Seq data. Relevant clinical findings were defined. Potential drug targets and genetic predispositions were explored. Four core molecular subgroups (WNT, SHH, Group 3, and Group 4) were identified. Genetic backgrounds of metastasis at diagnosis and extent of tumor resection were observed. The adjusted Heidelberg scheme showed its applicability. Potential drug targets were detected in the pathways of DNA damage response. Among the 10 patients with SHH MBs analyzed using whole exome sequencing studies, five patients exhibited potential genetic predispositions and four patients had relevant germline mutations. The findings of this study provide valuable information for updated risk adapted treatment and personalized care of childhood MBs in our cohort series and in Taiwan.
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AlHarthi FS, Qari A, Edress A, Abedalthagafi M. Familial/inherited cancer syndrome: a focus on the highly consanguineous Arab population. NPJ Genom Med 2020; 5:3. [PMID: 32025336 PMCID: PMC6997177 DOI: 10.1038/s41525-019-0110-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 12/11/2019] [Indexed: 12/18/2022] Open
Abstract
The study of hereditary cancer, which accounts for ~10% of cancer cases worldwide is an important subfield of oncology. Our understanding of hereditary cancers has greatly advanced with recent advances in sequencing technology, but as with any genetic trait, gene frequencies of cancer-associated mutations vary across populations, and most studies that have located hereditary cancer genes have been conducted on European or Asian populations. There is an urgent need to trace hereditary cancer genes across the Arab world. Hereditary disease is particularly prevalent among members of consanguineous populations, and consanguineous marriages are particularly common in the Arab world. There are also cultural and educational idiosyncrasies that differentiate Arab populations from other more thoroughly studied groups with respect to cancer awareness and treatment. Therefore, a review of the literature on hereditary cancers in this understudied population was undertaken. We report that BRCA mutations are not as prevalent among Arab breast cancer patients as they are among other ethnic groups, and therefore, other genes may play a more important role. A wide variety of germline inherited mutations that are associated with cancer are discussed, with particular attention to breast, ovarian, colorectal, prostate, and brain cancers. Finally, we describe the state of the profession of familial cancer genetic counselling in the Arab world, and the clinics and societies dedicated to its advances. We describe the complexities of genetic counselling that are specific to the Arab world. Understanding hereditary cancer is heavily dependent on understanding population-specific variations in cancer-associated gene frequencies.
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Affiliation(s)
- Fawz S AlHarthi
- 1Genomics Research Department, Saudi Human Genome Project, King Fahad Medical City and King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.,2Genetics Counselling Division, Saudi Diagnostic Laboratory, King Faisal Specialist Hospital International Company, Riyadh, Saudi Arabia
| | - Alya Qari
- 3Medical Genetic Department, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Alaa Edress
- 1Genomics Research Department, Saudi Human Genome Project, King Fahad Medical City and King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.,2Genetics Counselling Division, Saudi Diagnostic Laboratory, King Faisal Specialist Hospital International Company, Riyadh, Saudi Arabia
| | - Malak Abedalthagafi
- 1Genomics Research Department, Saudi Human Genome Project, King Fahad Medical City and King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia
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Milanese JS, Tibiche C, Zou J, Meng Z, Nantel A, Drouin S, Marcotte R, Wang E. Germline variants associated with leukocyte genes predict tumor recurrence in breast cancer patients. NPJ Precis Oncol 2019; 3:28. [PMID: 31701019 PMCID: PMC6825127 DOI: 10.1038/s41698-019-0100-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2019] [Accepted: 10/10/2019] [Indexed: 12/15/2022] Open
Abstract
Germline variants such as BRCA1/2 play an important role in tumorigenesis and clinical outcomes of cancer patients. However, only a small fraction (i.e., 5-10%) of inherited variants has been associated with clinical outcomes (e.g., BRCA1/2, APC, TP53, PTEN and so on). The challenge remains in using these inherited germline variants to predict clinical outcomes of cancer patient population. In an attempt to solve this issue, we applied our recently developed algorithm, eTumorMetastasis, which constructs predictive models, on exome sequencing data to ER+ breast (n = 755) cancer patients. Gene signatures derived from the genes containing functionally germline variants significantly distinguished recurred and non-recurred patients in two ER+ breast cancer independent cohorts (n = 200 and 295, P = 1.4 × 10-3). Furthermore, we compared our results with the widely known Oncotype DX test (i.e., Oncotype DX breast cancer recurrence score) and outperformed prediction for both high- and low-risk groups. Finally, we found that recurred patients possessed a higher rate of germline variants. In addition, the inherited germline variants from these gene signatures were predominately enriched in T cell function, antigen presentation, and cytokine interactions, likely impairing the adaptive and innate immune response thus favoring a pro-tumorigenic environment. Hence, germline genomic information could be used for developing non-invasive genomic tests for predicting patients' outcomes in breast cancer.
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Affiliation(s)
| | - Chabane Tibiche
- National Research Council Canada, 6100 Royalmount Avenue, Montreal, QC H4P 2R2 Canada
| | - Jinfeng Zou
- National Research Council Canada, 6100 Royalmount Avenue, Montreal, QC H4P 2R2 Canada
| | - Zhigang Meng
- Department of Biochemistry & Molecular Biology, Medical Genetics, and Oncology, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1 Canada
- Chinese Academy of Agricultural Science, No. 12 Zhongguangcun South Street, Haidian District, Beijing, 100086 China
| | - Andre Nantel
- National Research Council Canada, 6100 Royalmount Avenue, Montreal, QC H4P 2R2 Canada
| | - Simon Drouin
- National Research Council Canada, 6100 Royalmount Avenue, Montreal, QC H4P 2R2 Canada
| | - Richard Marcotte
- National Research Council Canada, 6100 Royalmount Avenue, Montreal, QC H4P 2R2 Canada
- Rosalind and Morris Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue W, Montreal, QC H3A 1A3 Canada
| | - Edwin Wang
- Department of Biochemistry & Molecular Biology, Medical Genetics, and Oncology, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1 Canada
- Alberta Children’s Hospital Research Institute and Arnie Charbonneau Cancer Research Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1 Canada
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Daneberga Z, Berzina D, Borosenko V, Krumina Z, Kokaine-Sapovalova L, Gardovskis A, Berga-Svitina E, Gardovskis J, Miklasevics E. Pathogenic APC Variants in Latvian Familial Adenomatous Polyposis Patients. ACTA ACUST UNITED AC 2019; 55:medicina55100612. [PMID: 31547110 PMCID: PMC6843383 DOI: 10.3390/medicina55100612] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 08/16/2019] [Accepted: 09/18/2019] [Indexed: 01/02/2023]
Abstract
Background and objectives: Familial adenomatous polyposis is one of the APC-associated polyposis conditions described as genetically predetermined colorectal polyposis syndrome with a variety of symptoms. The purpose of this study was to determine sequence variants of the APC gene in patients with familial adenomatous polyposis (FAP) phenotype and positive or negative family history. Materials and Methods: Eight families with defined criteria of adenomatous polyposis underwent molecular genetic testing. Coding regions and flanking intron regions of the APC gene were analyzed by Sanger sequencing. Results: Eight allelic variants of the APC gene coding sequence were detected. All allelic variants of the APC gene were predicted to be pathogenic based on criteria according to the “Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology” (2015), four of them c.1586_1587insAT, c.2336delT, c.3066_3067insGA, and c.4303_4304insC, were considered novel. Conclusions: The timely molecular genetic analysis of APC germline variants and standardized interpretation of the pathogenicity of novel allelic variants has a high impact on choice for treatment, cancer prevention, and family genetic counseling.
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Affiliation(s)
- Zanda Daneberga
- Institute of Oncology, Riga Stradiņš University, LV-1007 Riga, Latvia.
| | - Dace Berzina
- Institute of Oncology, Riga Stradiņš University, LV-1007 Riga, Latvia
| | - Viktors Borosenko
- Department of Surgery, Pauls Stradiņš Clinical University Hospital, LV-1002 Riga, Latvia
| | - Zita Krumina
- Department of Biology and Microbiology, Riga Stradiņš University, LV-1007 Riga, Latvia
| | | | - Andris Gardovskis
- Institute of Oncology, Riga Stradiņš University, LV-1007 Riga, Latvia
- Department of Surgery, Pauls Stradiņš Clinical University Hospital, LV-1002 Riga, Latvia
| | | | - Janis Gardovskis
- Department of Surgery, Riga Stradiņš University, LV-1007, Riga, Latvia
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Milanese JS, Wang E. Germline mutations and their clinical applications in cancer. BREAST CANCER MANAGEMENT 2019. [DOI: 10.2217/bmt-2019-0005] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Affiliation(s)
- Jean-Sébastien Milanese
- Human Health Therapeutics, National Research Council Canada, 6100 Royalmount Ave, Montreal, H4P 2R2, Canada
| | - Edwin Wang
- Department of Biochemistry & Molecular Biology, Medical Genetics, & Oncology, University of Calgary, 3330 Hospital Dr NW, Calgary, T2N 4N1, Canada
- Alberta Children's Hospital Research Institute & Arnie Charbonneau Cancer Research Institute, University of Calgary, 3330 Hospital Dr NW, Calgary, T2N 4N1, Canada
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Li H, Zhang L, Jiang Q, Shi Z, Tong H. Identification a nonsense mutation of APC gene in Chinese patients with familial adenomatous polyposis. Exp Ther Med 2017; 13:1495-1499. [PMID: 28413499 DOI: 10.3892/etm.2017.4122] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2015] [Accepted: 12/19/2016] [Indexed: 12/21/2022] Open
Abstract
Familial adenomatous polyposis (FAP; Mendelian of Inherintance in Man ID, 175100) is a rare autosomal dominant disorder characterized by the development of numerous adenomatous polyps throughout the colon and rectum associated with an increased risk of colorectal cancer. FAP is at time accompanied with certain extraintestinal manifestations such as congenital hypertrophy of the retinal pigment epithelium, dental disorders and desmoid tumors. It is caused by mutations in the adenomatous polyposis coli (APC) gene. The present study reported on a Chinese family with FAP. Polymerase chain reaction and direct sequencing of the full coding sequence of the APC gene were performed to identify the mutation in this family. A nonsense mutation of the APC gene was identified in this pedigree. It is a heterozygous G>T substitution at position 2,971 in exon 15 of the APC gene, which formed a premature stop codon at amino acid residue 991 (p.Glu991*). The resulting truncated protein lacked 1,853 amino acids. The present study expanded the database on APC gene mutations in FAP and enriched the spectrum of known germline mutations of the APC gene. Prophylactic proctocolectomy may be considered as a possible treatment for carriers of the mutation.
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Affiliation(s)
- Haishan Li
- Department of Emergency, The Second People's Hospital of Hefei, Hefei, Anhui 230601, P.R. China
| | - Lingling Zhang
- Department of Oncology, Binzhou People's Hospital, Binzhou, Shandong 256600, P.R. China
| | - Quan Jiang
- Department of General Surgery, Zhongshan Hospital, Fu Dan University, Shanghai 200032, P.R. China
| | - Zhenwang Shi
- Department of Gastroenterology, The Second People's Hospital of Hefei, Hefei, Anhui 230601, P.R. China
| | - Hanxing Tong
- Department of General Surgery, Zhongshan Hospital, Fu Dan University, Shanghai 200032, P.R. China
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Moreira-Nunes CA, Alcântara DDF&A, Lima-Júnior SF, Cavalléro SRDA, Rey JA, Pinto GR, Assumpção PPD, Burbano RR. Presence of c.3956delC mutation in familial adenomatous polyposis patients from Brazil. World J Gastroenterol 2015; 21:9413-9419. [PMID: 26309368 PMCID: PMC4541394 DOI: 10.3748/wjg.v21.i31.9413] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2014] [Accepted: 06/16/2015] [Indexed: 02/07/2023] Open
Abstract
AIM: To characterize APC gene mutations and correlate them with patient phenotypes in individuals diagnosed with familial adenomatous polyposis (FAP) in northern Brazil.
METHODS: A total of 15 individuals diagnosed with FAP from 5 different families from the north of Brazil were analyzed in this study. In addition to patients with histopathological diagnosis of FAP, family members who had not developed the disease were also tested in order to identify mutations and for possible genetic counseling. All analyzed patients or their guardians signed a consent form approved by the Research Ethics Committee of the João de Barros Barreto University Hospital (Belem, Brazil). DNA extracted from the peripheral blood of a member of each of the affected families was subjected to direct sequencing. The proband of each family was sequenced to identify germline mutations using the Ion Torrent platform. To validate the detected mutations, Sanger sequencing was also performed. The samples from all patients were also tested for the identification of mutations by real-time quantitative polymerase chain reaction using the amplification refractory mutation system.
RESULTS: Through interviews with relatives and a search of medical records, it was possible to construct genograms for three of the five families included in the study. All 15 patients from the five families with FAP exhibited mutations in the APC gene, and all mutations were detected in exon 15 of the APC gene. In addition to the patients with a histological diagnosis of FAP, family members without disease symptoms showed the mutation in the APC gene. In the present study, we detected two of the three most frequent germline mutations in the literature: the mutation at codon 1309 and the mutation at codon 1061. The presence of c.3956delC mutation was found in all families from this study, and suggests that this mutation was introduced in the population of the State of Pará through ancestor immigration (i.e., a de novo mutation that arose in one member belonging to this state from Brazil).
CONCLUSION: Regardless of its origin, the c.3956delC mutation is a strong candidate biomarker of this hereditary cancer syndrome in families of northern Brazil.
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