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Andour H, Mamouch A, Hassar S, Fikri M, Kettani NEC, Jiddane M, Touarsa F. Gardner syndrome: When cervical-facial osteomas reveal the tip of the iceberg: A case report and literature review. Radiol Case Rep 2025; 20:1967-1971. [PMID: 39911622 PMCID: PMC11795357 DOI: 10.1016/j.radcr.2024.12.043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 12/13/2024] [Accepted: 12/14/2024] [Indexed: 02/07/2025] Open
Abstract
Gardner syndrome is a subtype of familial adenomatous polyposis (FAP) characterized by colonic manifestations, multiple skull osteomas, dental abnormalities, benign soft tissue tumors, and a high risk of development of both colorectal cancer and papillary thyroid carcinoma. Many patients are incidentally diagnosed when presenting with craniofacial tumefactions related to osteomas. In such cases, further exploration of family history and other clinical manifestations often reveals positive findings. We report the case of a 34-year-old woman who presented with craniofacial tumefactions and recurrent orbital discomfort. A cranio-facial CT-scan revealed multiple osteomas, including one affecting the orbital region. Investigation of her family history, along with her clinical history, confirmed the presence of Gardner syndrome in her father and siblings, with colonic polyposis- under ongoing surveillance.
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Affiliation(s)
- Hajar Andour
- Neuroradiology Department, Ibn-Sina Hospital, Rabat, Morocco
| | - Amine Mamouch
- Neuroradiology Department, Ibn-Sina Hospital, Rabat, Morocco
| | - Soufiane Hassar
- Neuroradiology Department, Ibn-Sina Hospital, Rabat, Morocco
| | - Meriem Fikri
- Neuroradiology Department, Ibn-Sina Hospital, Rabat, Morocco
| | | | - Mohamed Jiddane
- Neuroradiology Department, Ibn-Sina Hospital, Rabat, Morocco
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2
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Schuch LF, Silveira FM, Pereira-Prado V, Sicco E, Pandiar D, Villarroel-Dorrego M, Bologna-Molina R. Clinicopathological and molecular insights into odontogenic tumors associated with syndromes: A comprehensive review. World J Exp Med 2024; 14:98005. [PMID: 39713074 PMCID: PMC11551705 DOI: 10.5493/wjem.v14.i4.98005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 08/19/2024] [Accepted: 08/26/2024] [Indexed: 10/31/2024] Open
Abstract
The association between genetic syndromes and odontogenic tumors encompasses several entities, reflecting the intricate interplay between genetic factors and the development of these lesions. The present study aimed to comprehensively investigate the associations between genetic syndromes and odontogenic tumors. We delineated the diverse spectrum of syndromic connections, including key syndromes such as Gardner syndrome, Gorlin syndrome, Schimmelpenning syndrome, and others. Our findings underscore the clinical significance of recognizing odontogenic tumors associated with genetic syndromes as diagnostic indicators for early intervention. We advocate for multidisciplinary collaboration among clinicians, geneticists, and researchers to deepen our understanding of the underlying mechanisms driving these syndromic associations. In light of this, our study contributes to the growing body of knowledge in dentistry and medical genetics, offering insights that may inform clinical practice and enhance patient care for individuals affected by genetic syndromes and odontogenic tumors.
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Affiliation(s)
- Lauren Frenzel Schuch
- Department of Diagnosis in Pathology and Oral Medicine, Faculty of Dentistry, Universidad de la República, Montevideo 1600, Uruguay
| | - Felipe Martins Silveira
- Department of Diagnosis in Pathology and Oral Medicine, Faculty of Dentistry, Universidad de la República, Montevideo 1600, Uruguay
| | - Vanesa Pereira-Prado
- Department of Diagnosis in Pathology and Oral Medicine, Faculty of Dentistry, Universidad de la República, Montevideo 1600, Uruguay
| | - Estefania Sicco
- Department of Diagnosis in Pathology and Oral Medicine, Faculty of Dentistry, Universidad de la República, Montevideo 1600, Uruguay
| | - Deepak Pandiar
- Department of Oral Pathology and Microbiology, Saveetha Dental College and Hospitals Chennai, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Chennai 600077, Tamil Nādu, India
| | - Mariana Villarroel-Dorrego
- Department of Oral Pathology, Oral Medicine, School of Dentistry, Universidad Central de Venezuela, Venezuela, Caracas 1051, Distrito Capital, Venezuela
| | - Ronell Bologna-Molina
- Department of Diagnosis in Pathology and Oral Medicine, Faculty of Dentistry, Universidad de la República, Montevideo 1600, Uruguay
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Oliveira D, Maia S, Balacó I, Coelho P, Almeida S, Venâncio M, Saraiva J, Nishimura G, Sousa SB. Pachydysostosis of the fibula in a case of familial adenomatous polyposis. Eur J Med Genet 2024; 68:104913. [PMID: 38286305 DOI: 10.1016/j.ejmg.2024.104913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 10/09/2023] [Accepted: 01/20/2024] [Indexed: 01/31/2024]
Abstract
BACKGROUND Familial Adenomatous Polyposis (FAP) is a colorectal cancer (CRC) predisposition syndrome caused by germline APC mutations and characterised by an increased risk of CRC and colonic polyps and, in certain forms, of specific prominent extraintestinal manifestations, namely osteomas, soft tissue tumours and dental anomalies. Pachydysostosis of the fibula is a rare clinical entity defined by unilateral bowing of the distal portion of the fibula and elongation of the entire bone, without affectation of the tibia. CLINICAL REPORT We report a 17-year-old male, who presented with a non-progressive bowing of the right leg detected at 18 months of age caused by a fibula malformation (later characterized as pachydysostosis) and a large exophytic osteoma of the left radius, noticed at the age of 15 years, without gastrointestinal symptoms. There was no relevant family history. Detailed characterisation revealed multiple osteomas, skin lesions and dental abnormalities, raising the hypothesis of FAP. This diagnosis was confirmed by genetic testing [c.4406_4409dup p.(Ala1471Serfs*17) de novo mutation in the APC gene] and endoscopic investigation (multiple adenomas throughout the colon, ileum and stomach). DISCUSSION This case report draws attention to the phenotypic spectrum of skeletal manifestations of FAP: this patient has a congenital fibula malformation, not previously associated with this syndrome, but which is likely to have been its first manifestation in this patient. This clinical case also illustrates the challenges in the early diagnosis of FAP, especially without family history, and highlights the importance of a multidisciplinary approach and the adequate study of rare skeletal abnormalities.
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Affiliation(s)
- Daniela Oliveira
- Medical Genetics Unit, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal; University Clinic of Genetics, Faculty of Medicine, Universidade de Coimbra, Coimbra, Portugal; Clinical Academic Center of Coimbra, Coimbra, Portugal.
| | - Sofia Maia
- Medical Genetics Unit, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal; University Clinic of Genetics, Faculty of Medicine, Universidade de Coimbra, Coimbra, Portugal; Clinical Academic Center of Coimbra, Coimbra, Portugal
| | - Inês Balacó
- Paediatric Ortopedic Unit, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Paulo Coelho
- Radiology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Susana Almeida
- Paediatric Gastroenterology Unit, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Margarida Venâncio
- Medical Genetics Unit, Hospital Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal
| | - Jorge Saraiva
- Medical Genetics Unit, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal; Clinical Academic Center of Coimbra, Coimbra, Portugal; University Clinic of Pediatrics, Faculty of Medicine, Universidade de Coimbra, Coimbra, Portugal
| | - Gen Nishimura
- Intractable Disease Center, Saitama Medical University Moroyama Campus, Japan
| | - Sérgio B Sousa
- Medical Genetics Unit, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal; University Clinic of Genetics, Faculty of Medicine, Universidade de Coimbra, Coimbra, Portugal; Clinical Academic Center of Coimbra, Coimbra, Portugal.
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Siegmund S, Ricci C, Kao CS, Sangoi AR, Mohanty S, Fletcher CDM, Colecchia M, Acosta AM. Germline APC Alterations May Predispose to Testicular Sex Cord-Stromal Tumors. Am J Surg Pathol 2023; 47:1432-1437. [PMID: 37811860 DOI: 10.1097/pas.0000000000002132] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/10/2023]
Abstract
Sertoli cell tumor is a type of testicular sex cord-stromal tumor (TSCST) typically driven by gain-of-function CTNNB1 variants. Recently, molecular studies have identified TSCSTs (including Sertoli cell tumors) with loss-of-function APC variants, raising the possibility that germline APC alterations may predispose to TSCSTs. In this study, we evaluated 4 TSCSTs from 4 individual patients, including 3 APC -mutant neoplasms identified in prior studies (1 in a patient with familial adenomatous polyposis [FAP] and 2 in patients with unknown syndromic status) and 1 tumor of unknown mutational status diagnosed in a patient with known FAP. Three neoplasms were typical Sertoli cell tumors, and 1 was a malignant unclassified TSCT. All neoplasms exhibited diffuse nuclear beta-catenin expression. Non-neoplastic tissue could be obtained for DNA sequencing in the 3 Sertoli cell tumors. Comparative assessment of non-neoplastic and lesional tissue in these cases suggested that germline APC variants with subsequent inactivation of the gene (loss of heterozygosity) were the likely oncogenic driver of these Sertoli cell tumors. In the malignant unclassified TSCSTs, APC inactivation was also interpreted as the most likely driver event, and the germline origin of the variant was inferred using a recently published method. The results of this study suggest that pathogenic germline APC alterations (eg, FAP and variants thereof) may predispose to TSCSTs.
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Affiliation(s)
- Stephanie Siegmund
- Department of Pathology of Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Costantino Ricci
- Department of Medical and Surgical Sciences (DIMEC), Maggiore Hospital-AUSL Bologna, University of Bologna, Bologna
| | - Chia-Sui Kao
- Department of Pathology, Stanford University, Stanford, CA
| | - Ankur R Sangoi
- Department of Pathology, Stanford University, Stanford, CA
| | - Sambit Mohanty
- Department of Pathology, CORE Diagnostics and Advanced Medical Research Institute, Gurgaon, Haryana, India
| | | | - Maurizio Colecchia
- Department of Pathology, Vita-Salute San Raffaele University, Milan, Lombardy, Italy
| | - Andres M Acosta
- Department of Pathology of Brigham and Women's Hospital, Harvard Medical School, Boston, MA
- Department of Pathology, Indiana University, Indianapolis, IN
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5
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Yang L, Wang Y, Hu S, Wang X. Eflornithine for chemoprevention in the high-risk population of colorectal cancer: a systematic review and meta-analysis with trial sequential analysis. Front Oncol 2023; 13:1281844. [PMID: 38033490 PMCID: PMC10686413 DOI: 10.3389/fonc.2023.1281844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 10/31/2023] [Indexed: 12/02/2023] Open
Abstract
Objectives To evaluate the efficacy of Difluoromethylornithine (DFMO) chemoprevention in the high-risk population for colorectal cancer (CRC). Methods Meta-analysis was conducted to assess the caliber of the included literature by searching five databases for randomized controlled trials of DFMO chemoprevention in the high-risk population of CRC, with RevMan 5.4, Stata 15.0 and TSA 0.9.5.10 employed to statistically analyze the extracted data. Grade profiler 3.6 was employed for grading the evidence for the outcome indicators (disease progression and adenoma incidence). Results Six trials were finally included in this research, with the collective data indicating that the DFMO combination therapy was efficacious in lowering the incidence of recurrent adenomas in patients who had experienced advanced CRC [RR 0.34, 95% CI 0.14 - 0.83, P < 0.05]. Meta-analysis showed that DFMO combined therapy had no statistical difference in disease progression in patients with familial adenomatous polyposis[RR 0.52, 95% CI 0.14 - 1.86, P > 0.05]; Trial Sequential Analysis reveals that the combination therapy of DFMO effectively diminishes the occurrence of recurrent adenomas in patients with a history of advanced colorectal tumors, displaying a Risk Ratio (RR) of 0.33 with a 95% Confidence Interval (CI) of 0.12 - 0.90 and a significance level of P < 0.05. This combination exhibits a statistically significant difference. Subgroup analysis demonstrates that, depending on the drug treatment regimen (DFMO+ Aspirin/DFMO+ Sulindac), the combination of DFMO and aspirin exhibits an effect comparable to a placebo in diminishing the occurrence of new adenomas in patients with a history of advanced colorectal tumors. However, the combination of DFMO and sulindac significantly mitigates the incidence of recurrent adenomas in this patient population. Conclusion This meta-analysis indicates that the existing randomized controlled trials are adequate to ascertain the efficacy of DFMO combination therapy in diminishing the incidence of recurrent adenomas in patients who have previously encountered advanced colorectal tumors. However, further clinical trials need to be conducted to evaluate the optimum dosage and treatment course of prophylactic implementation of DFMO combination therapy in high-risk populations.
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Affiliation(s)
- Lifeng Yang
- School of Nursing, Hexi University, Zhangye, China
| | - Yan Wang
- Peking University First Hospital Ningxia Women and Children’s Hospital (Ningxia Hui Autonomous Region Maternal and Child Health Hospital), Nursing Department, Yinchuan, Ningxia Hui Autonomous Region, China
| | - Shasha Hu
- The First Ward of the Department of Gynecology, The First Hospital of Lanzhou University, Lanzhou, China
| | - Xiaoyan Wang
- School of Nursing, Hexi University, Zhangye, China
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Ranasinghe P, Addison ML, Dear JW, Webb DJ. Small interfering RNA: Discovery, pharmacology and clinical development-An introductory review. Br J Pharmacol 2023; 180:2697-2720. [PMID: 36250252 DOI: 10.1111/bph.15972] [Citation(s) in RCA: 63] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 08/23/2022] [Accepted: 09/29/2022] [Indexed: 11/28/2022] Open
Abstract
Post-transcriptional gene silencing targets and degrades mRNA transcripts, silencing the expression of specific genes. RNA interference technology, using synthetic structurally well-defined short double-stranded RNA (small interfering RNA [siRNA]), has advanced rapidly in recent years. This introductory review describes the utility of siRNA, by exploring the underpinning biology, pharmacology, recent advances and clinical developments, alongside potential limitations and ongoing challenges. Mediated by the RNA-induced silencing complex, siRNAs bind to specific complementary mRNAs, which are subsequently degraded. siRNA therapy offers advantages over other therapeutic approaches, including ability of specifically designed siRNAs to potentially target any mRNA and improved patient adherence through infrequent administration associated with a very long duration of action. Key pharmacokinetic and pharmacodynamic challenges include targeted administration, poor tissue penetration, nuclease inactivation, rapid renal elimination, immune activation and off-target effects. These have been overcome by chemical modification of siRNA and/or by utilising a range of delivery systems, increasing bioavailability and stability to allow successful clinical translation. Patisiran (hereditary transthyretin-mediated amyloidosis) was the first licensed siRNA, followed by givosiran (acute hepatic porphyria), lumasiran (primary hyperoxaluria type 1) and inclisiran (familial hypercholesterolaemia), which all use N-acetylgalactosamine (GalNAc) linkage for effective liver-directed delivery. Others are currently under development for indications varying from rare genetic diseases to common chronic non-communicable diseases (hypertension, cancer). Technological advances are paving the way for broader clinical use. Ongoing challenges remain in targeting organs beyond the liver and reaching special sites (e.g., brain). By overcoming these barriers, siRNA therapy has the potential to substantially widen its therapeutic impact.
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Affiliation(s)
- Priyanga Ranasinghe
- Department of Pharmacology, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
- University/British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, UK
| | - Melisande L Addison
- University/British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, UK
| | - James W Dear
- University/British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, UK
| | - David J Webb
- University/British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, UK
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7
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Ditonno I, Novielli D, Celiberto F, Rizzi S, Rendina M, Ierardi E, Di Leo A, Losurdo G. Molecular Pathways of Carcinogenesis in Familial Adenomatous Polyposis. Int J Mol Sci 2023; 24:5687. [PMID: 36982759 PMCID: PMC10056005 DOI: 10.3390/ijms24065687] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 03/11/2023] [Accepted: 03/15/2023] [Indexed: 03/19/2023] Open
Abstract
Familial adenomatous polyposis (FAP) is a genetic syndrome characterized by the presence of multiple polyps in the gastrointestinal tract and a wide range of systemic extra-intestinal manifestations. Patients affected will inevitably undergo abdominal surgery due to the malignant transformation of one or more adenomas. The pathogenesis of the disease is based on a loss of function mutation in adenomatous polyposis coli (APC), a tumor-suppressor gene, inherited following a Mendelian pattern. This gene is a key component of multiple cell functions that cooperate for homeostasis; when mutated, it contributes to the progression of colorectal adenoma into cancer. Recent studies have demonstrated that several additional mechanisms may influence this process, such as alterations in gut microbiota composition and mucosal barrier immunity, interaction with the immune microenvironment and inflammation, the hormone estrogen, and other signaling pathways. These factors represent promising targets of future therapies and chemoprevention, aiming to alter the progressive nature of the disease and improve the quality of life of families affected. Therefore, we performed a narrative review about the current knowledge of the aforementioned pathways involved in colorectal cancer pathogenesis in FAP, exploring the genetic and environmental factors that may contribute to the development of CRC in FAP.
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Affiliation(s)
- Ilaria Ditonno
- Section of Gastroenterology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, 70124 Bari, Italy
| | - Domenico Novielli
- Section of Gastroenterology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, 70124 Bari, Italy
| | - Francesca Celiberto
- Section of Gastroenterology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, 70124 Bari, Italy
- Course in Organs and Tissues Transplantation and Cellular Therapies, Department of Precision Medicine Jonic Area, University “Aldo Moro” of Bari, 70124 Bari, Italy
| | - Salvatore Rizzi
- Section of Gastroenterology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, 70124 Bari, Italy
| | - Maria Rendina
- Section of Gastroenterology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, 70124 Bari, Italy
| | - Enzo Ierardi
- Section of Gastroenterology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, 70124 Bari, Italy
| | - Alfredo Di Leo
- Section of Gastroenterology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, 70124 Bari, Italy
| | - Giuseppe Losurdo
- Section of Gastroenterology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, 70124 Bari, Italy
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Gagliardi F, Baldini E, Lori E, Cardarelli S, Pironi D, Lauro A, Tripodi D, Palumbo P, D’Armiento E, Cavallaro G, Polistena A, D’Orazi V, Sibio S, Fallahi P, Antonelli A, D’Andrea V, Ulisse S, Sorrenti S. Insights on the Association between Thyroid Diseases and Colorectal Cancer. J Clin Med 2023; 12:2234. [PMID: 36983233 PMCID: PMC10056144 DOI: 10.3390/jcm12062234] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 02/22/2023] [Accepted: 03/11/2023] [Indexed: 03/15/2023] Open
Abstract
Benign and malignant thyroid diseases (TDs) have been associated with the occurrence of extrathyroidal malignancies (EMs), including colorectal cancers (CRCs). Such associations have generated a major interest, as their characterization may provide useful clues regarding diseases' etiology and/or progression, with the possible identification of shared congenital and environmental elements. On the other hand, elucidation of the underlying molecular mechanism(s) could lead to an improved and tailored clinical management of these patients and stimulate an increased surveillance of TD patients at higher threat of developing EMs. Here, we will examine the epidemiological, clinical, and molecular findings connecting TD and CRC, with the aim to identify possible molecular mechanism(s) responsible for such diseases' relationship.
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Affiliation(s)
| | - Enke Baldini
- Department of Surgery, “Sapienza” University of Rome, 00161 Rome, Italy
| | - Eleonora Lori
- Department of Surgery, “Sapienza” University of Rome, 00161 Rome, Italy
| | - Silvia Cardarelli
- Department of Surgery, “Sapienza” University of Rome, 00161 Rome, Italy
| | - Daniele Pironi
- Department of Surgery, “Sapienza” University of Rome, 00161 Rome, Italy
| | - Augusto Lauro
- Department of Surgery, “Sapienza” University of Rome, 00161 Rome, Italy
| | - Domenico Tripodi
- Department of Surgery, “Sapienza” University of Rome, 00161 Rome, Italy
| | | | - Eleonora D’Armiento
- Department of Internal Medicine and Medical Specialties, “Sapienza” University of Rome, 00161 Rome, Italy
| | | | - Andrea Polistena
- Department of Surgery, “Sapienza” University of Rome, 00161 Rome, Italy
| | - Valerio D’Orazi
- Department of Surgery, “Sapienza” University of Rome, 00161 Rome, Italy
| | - Simone Sibio
- Department of Surgery, “Sapienza” University of Rome, 00161 Rome, Italy
| | - Poupak Fallahi
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy
| | - Alessandro Antonelli
- Department of Surgical, Medical and Molecular Pathology and of Critical Area, University of Pisa, 56126 Pisa, Italy
| | - Vito D’Andrea
- Department of Surgery, “Sapienza” University of Rome, 00161 Rome, Italy
| | - Salvatore Ulisse
- Department of Surgery, “Sapienza” University of Rome, 00161 Rome, Italy
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Liu J, Mroczek M, Mach A, Stępień M, Aplas A, Pronobis-Szczylik B, Bukowski S, Mielczarek M, Gajewska E, Topolski P, Król ZJ, Szyda J, Dobosz P. Genetics, Genomics and Emerging Molecular Therapies of Pancreatic Cancer. Cancers (Basel) 2023; 15:779. [PMID: 36765737 PMCID: PMC9913594 DOI: 10.3390/cancers15030779] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 01/14/2023] [Accepted: 01/18/2023] [Indexed: 02/01/2023] Open
Abstract
The number of cases of pancreatic cancers in 2019 in Poland was 3852 (approx. 2% of all cancers). The course of the disease is very fast, and the average survival time from the diagnosis is 6 months. Only <2% of patients live for 5 years from the diagnosis, 8% live for 2 years, and almost half live for only about 3 months. A family predisposition to pancreatic cancer occurs in about 10% of cases. Several oncogenes in which somatic changes lead to the development of tumours, including genes BRCA1/2 and PALB2, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1, are involved in pancreatic cancer. Between 4% and 10% of individuals with pancreatic cancer will have a mutation in one of these genes. Six percent of patients with pancreatic cancer have NTRK pathogenic fusion. The pathogenesis of pancreatic cancer can in many cases be characterised by homologous recombination deficiency (HRD)-cell inability to effectively repair DNA. It is estimated that from 24% to as many as 44% of pancreatic cancers show HRD. The most common cause of HRD are inactivating mutations in the genes regulating this DNA repair system, mainly BRCA1 and BRCA2, but also PALB2, RAD51C and several dozen others.
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Affiliation(s)
- Jakub Liu
- Biostatistics Group, Wroclaw University of Environmental and Life Sciences, 51-631 Wroclaw, Poland
| | - Magdalena Mroczek
- Centre for Cardiovascular Genetics and Gene Diagnostics, Foundation for People with Rare Diseases, Wagistrasse 25, 8952 Schlieren, Switzerland
| | - Anna Mach
- Department of Psychiatry, Medical University of Warsaw, 00-665 Warsaw, Poland
- Central Clinical Hospital of Ministry of the Interior and Administration in Warsaw, 02-507 Warsaw, Poland
| | - Maria Stępień
- Department of Infectious Diseases, Doctoral School, Medical University of Lublin, 20-059 Lublin, Poland
| | - Angelika Aplas
- Central Clinical Hospital of Ministry of the Interior and Administration in Warsaw, 02-507 Warsaw, Poland
| | - Bartosz Pronobis-Szczylik
- Central Clinical Hospital of Ministry of the Interior and Administration in Warsaw, 02-507 Warsaw, Poland
| | - Szymon Bukowski
- Central Clinical Hospital of Ministry of the Interior and Administration in Warsaw, 02-507 Warsaw, Poland
| | - Magda Mielczarek
- Biostatistics Group, Wroclaw University of Environmental and Life Sciences, 51-631 Wroclaw, Poland
- National Research Institute of Animal Production, Krakowska 1, 32-083 Balice, Poland
| | - Ewelina Gajewska
- Central Clinical Hospital of Ministry of the Interior and Administration in Warsaw, 02-507 Warsaw, Poland
| | - Piotr Topolski
- Central Clinical Hospital of Ministry of the Interior and Administration in Warsaw, 02-507 Warsaw, Poland
| | - Zbigniew J. Król
- Central Clinical Hospital of Ministry of the Interior and Administration in Warsaw, 02-507 Warsaw, Poland
| | - Joanna Szyda
- Biostatistics Group, Wroclaw University of Environmental and Life Sciences, 51-631 Wroclaw, Poland
- National Research Institute of Animal Production, Krakowska 1, 32-083 Balice, Poland
| | - Paula Dobosz
- Central Clinical Hospital of Ministry of the Interior and Administration in Warsaw, 02-507 Warsaw, Poland
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10
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Tomaz LB, Liu BA, Meroshini M, Ong SLM, Tan EK, Tolwinski NS, Williams CS, Gingras AC, Leushacke M, Dunn NR. MCC is a centrosomal protein that relocalizes to non-centrosomal apical sites during intestinal cell differentiation. J Cell Sci 2022; 135:jcs259272. [PMID: 36217793 PMCID: PMC10658790 DOI: 10.1242/jcs.259272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 09/27/2022] [Indexed: 11/20/2022] Open
Abstract
The gene mutated in colorectal cancer (MCC) encodes a coiled-coil protein implicated, as its name suggests, in the pathogenesis of hereditary human colon cancer. To date, however, the contributions of MCC to intestinal homeostasis and disease remain unclear. Here, we examine the subcellular localization of MCC, both at the mRNA and protein levels, in the adult intestinal epithelium. Our findings reveal that Mcc transcripts are restricted to proliferating crypt cells, including Lgr5+ stem cells, where the Mcc protein is distinctly associated with the centrosome. Upon intestinal cellular differentiation, Mcc is redeployed to the apical domain of polarized villus cells where non-centrosomal microtubule organizing centers (ncMTOCs) are positioned. Using intestinal organoids, we show that the shuttling of the Mcc protein depends on phosphorylation by casein kinases 1δ and ε, which are critical modulators of WNT signaling. Together, our findings support a role for MCC in establishing and maintaining the cellular architecture of the intestinal epithelium as a component of both the centrosome and ncMTOC.
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Affiliation(s)
- Lucian B. Tomaz
- Lee Kong Chian School of Medicine, Nanyang Technological University, 308232, Singapore
- School of Biological Sciences, Nanyang Technological University, 637551, Singapore
- Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), 138648, Singapore
| | - Bernard A. Liu
- Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health, Toronto, ON M5G 1X5, Canada
| | - Meroshini M
- Lee Kong Chian School of Medicine, Nanyang Technological University, 308232, Singapore
| | - Sheena L. M. Ong
- Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), 138648, Singapore
| | - Ee Kim Tan
- Lee Kong Chian School of Medicine, Nanyang Technological University, 308232, Singapore
- Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), 138648, Singapore
| | | | | | - Anne-Claude Gingras
- Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health, Toronto, ON M5G 1X5, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Marc Leushacke
- Skin Research Institute of Singapore, Agency for Science, Technology and Research (A*STAR), 308232, Singapore
| | - N. Ray Dunn
- Lee Kong Chian School of Medicine, Nanyang Technological University, 308232, Singapore
- School of Biological Sciences, Nanyang Technological University, 637551, Singapore
- Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), 138648, Singapore
- Skin Research Institute of Singapore, Agency for Science, Technology and Research (A*STAR), 308232, Singapore
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11
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Ali A, Ahmad A, Taj S, Qaudeer SA, Ahmed SE. Familial Adenomatous Polyposis (FAP) Presenting as Iron Deficiency Anemia in a 33-Year-Old Female: A Case Report. Cureus 2022; 14:e24603. [PMID: 35651449 PMCID: PMC9138202 DOI: 10.7759/cureus.24603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/29/2022] [Indexed: 11/05/2022] Open
Abstract
Iron deficiency anemia is a common clinical concern in women of reproductive age. It presents as microcytic anemia and can be due to a limited number of causes including bleeding, malabsorption, intravascular hemolysis, or a mechanical heart valve. Familial adenomatous polyposis (FAP) is an inherited autosomal dominant disorder due to mutation in the adenomatous polyposis coli (APC) gene that can cause iron deficiency anemia due to GI malignancy, most notably colon cancer. Variation of mutations within the APC gene can cause different forms of FAP, such as Gardner syndrome. This syndrome presents with epidermoid cysts typically in unconventional locations such as the face, scalp, and extremities, as seen in our patient. We report a presentation of FAP in a 33-year-old Caucasian female who initially presented with iron deficiency anemia, hematochezia, and weight loss. Colonoscopy revealed hundreds of polyps within the colon, with two that were biopsied and reported as tubulovillous adenoma. The patient underwent a robotically assisted laparoscopic total proctocolectomy with ileal pouch-anal anastomosis, as well as a diverting loop ileostomy, and was given pain medication. She was referred to genetic counseling for her daughters and herself, which revealed a pathogenic variance in the APC gene.
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Affiliation(s)
- Afrah Ali
- Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, USA
| | - Areesha Ahmad
- Oncology, Lake Erie College of Osteopathic Medicine, Bradenton, USA
| | - Shah Taj
- Oncology, Lake Erie College of Osteopathic Medicine, Bradenton, USA
| | - Shahid A Qaudeer
- Oncology, Lake Erie College of Osteopathic Medicine, Bradenton, USA
| | - Syed E Ahmed
- Hematology/Oncology, Florida Cancer Specialists & Research Institute, Sebring, USA
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12
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Balaguer F, Stoffel EM, Burke CA, Dekker E, Samadder NJ, Van Cutsem E, Lynch PM, Wise PE, Hüneburg R, Lim RM, Boytim ML, Du W, Bruckheimer EM, Cohen A, Church J. Combination of Sulindac and Eflornithine Delays the Need for Lower Gastrointestinal Surgery in Patients With Familial Adenomatous Polyposis: Post Hoc Analysis of a Randomized Clinical Trial. Dis Colon Rectum 2022; 65:536-545. [PMID: 34261858 DOI: 10.1097/dcr.0000000000002095] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Colectomy and proctocolectomy are the initial standard of care for patients with familial adenomatous polyposis. Pharmacotherapy to prevent the progression of polyposis and surgeries in the lower GI tract would be beneficial to patients with this disease. OBJECTIVE This analysis aimed to evaluate the impact of eflornithine-sulindac combination versus monotherapy in delaying time to disease progression in the lower GI tract of patients with familial adenomatous polyposis. DESIGN This is a post hoc analysis of a randomized phase 3 trial. SETTING This study was conducted in 21 hospitals in 7 countries treating patients with familial adenomatous polyposis. PATIENTS Adults with familial adenomatous polyposis were randomly assigned 1:1:1 into 3 arms. INTERVENTIONS Patients received either eflornithine (750 mg), sulindac (150 mg), or both once daily for up to 48 months. MAIN OUTCOME MEASURES Efficacy was evaluated as the time from randomization to predefined primary disease progression end points. RESULTS A total of 158 patients were included in the study. Disease progression was observed in 2 of 54 (3.7%), 9 of 53 (17.0%), and 10 of 51 (19.6%) patients with at least partial lower GI tract in the combination, sulindac, and eflornithine arms, corresponding to risk reductions of 80% (p = 0.02) and 83% (p = 0.01) between combination and sulindac or eflornithine. When endoscopic excision of adenomas ≥10 mm in size was censored, the need for major surgery was observed in 0 of 54, 7 of 53 (13.2%), and 8 of 51 (15.7%) patients in the combination, sulindac, and eflornithine arms, corresponding to risk reductions approaching 100% between combination and sulindac (p = 0.005) or combination and eflornithine (p = 0.003). LIMITATIONS This was a post hoc analysis, the sample size was small, and there were fewer than expected events. CONCLUSIONS Eflornithine-sulindac combination therapy was superior to either drug alone in delaying or preventing the need for lower GI tract surgery in patients with familial adenomatous polyposis. See Video Abstract at http://links.lww.com/DCR/B658. REGISTRATION ClinicalTrials.gov, NCT01483144; EU Clinical Trials Register, EudraCT 2012-000427-41. LA COMBINACIN DE SULINDAC Y EFLORNITINA RETRASA LA NECESIDAD DE CIRUGA DEL TUBO DIGESTIVO BAJO EN PACIENTES CON PAF ANLISIS POSTHOC DE UN ENSAYO CLNICO ALEATORIZADO ANTECEDENTES:La colectomía y la proctocolectomía son el estándar inicial de atención para los pacientes con poliposis adenomatosa familiar. La farmacoterapia para prevenir la progresión de la poliposis y las cirugías en el tracto gastrointestinal inferior sería beneficiosa para los pacientes con esta enfermedad.OBJETIVO:Este análisis tuvo como objetivo evaluar el impacto de la combinación de eflornitina-sulindac versus la monoterapia en el retraso del tiempo hasta la progresión de la enfermedad en el tracto gastrointestinal inferior de pacientes con poliposis adenomatosa familiar.DISEÑO:Este es un análisis posthoc de un ensayo de fase 3 aleatorizado.ENTORNO CLINICO:Veintiún hospitales en 7 países que tratan a pacientes con poliposis adenomatosa familiar.PACIENTES:Adultos con poliposis adenomatosa familiar fueron aleatorizados 1: 1: 1 en 3 brazos.INTERVENCIONES:Los pacientes recibieron eflornitina (750 mg), sulindac (150 mg) o ambos una vez al día durante un máximo de 48 meses.PRINCIPALES MEDIDAS DE VALORACION:La eficacia se evaluó como el tiempo desde la aleatorización hasta los criterios de valoración primarios predefinidos de progresión de la enfermedad.RESULTADOS:Los resultados se informan para la población de estudio excluyendo a los pacientes que se habían sometido a ileostomías permanentes (n = 158). Se observó progresión de la enfermedad en 2/54 (3,7%), 9/53 (17,0%) y 10/51 (19,6%) pacientes con al menos tracto gastrointestinal inferior parcial en los brazos de combinación, sulindac y eflornitina, respectivamente, correspondientes al riesgo de reducciones del 80% (p = 0,02) y del 83% (p = 0,01) entre la combinación y el sulindaco o la eflornitina, respectivamente. Cuando se censuró la escisión endoscópica de adenomas ≥10 mm de tamaño, se observó la necesidad de cirugía mayor en 0/54, 7/53 (13,2%) y 8/51 (15,7%) pacientes en la combinación, sulindac y eflornitina, respectivamente, correspondientes a reducciones de riesgo cercanas al 100% entre combinación y sulindac (p = 0,005) o combinación y eflornitina (p = 0,003).LIMITACIONES:Este fue un análisis posthoc, el tamaño de la muestra fue pequeño y hubo menos eventos de los esperados.CONCLUSIONES:La terapia de combinación de eflornitina-sulindac fue superior a cualquier fármaco solo para retrasar o prevenir la necesidad de cirugía del tracto gastrointestinal inferior en pacientes con poliposis adenomatosa familiar. Consulte Video Resumen en http://links.lww.com/DCR/B658.
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Affiliation(s)
- Francesc Balaguer
- Department of Gastroenterology, Hospital Clinic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain
| | - Elena M Stoffel
- Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan
| | - Carol Ann Burke
- Department of Gastroenterology, Hepatology & Nutrition, Cleveland Clinic, Cleveland, Ohio
| | - Evelien Dekker
- Department of Gastroenterology & Hepatology, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Amsterdam, The Netherlands
| | - N Jewel Samadder
- Division of Gastroenterology & Hepatology, Mayo Clinic, Phoenix, Arizona
| | | | - Patrick M Lynch
- Department of Gastroenterology, Hepatology and Nutrition, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Paul E Wise
- Department of Surgery, Washington University School of Medicine, St. Louis, Missouri
| | - Robert Hüneburg
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
- National Center for Hereditary Tumor Syndromes, Bonn, Germany
| | - Ramona M Lim
- Division of Population Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
| | | | - Wei Du
- Clinical Statistics Consulting, Blue Bell, Pennsylvania
| | | | - Alfred Cohen
- Cancer Prevention Pharmaceuticals, Inc, Tucson, Arizona
| | - James Church
- Department of Gastroenterology, Hepatology & Nutrition, Cleveland Clinic, Cleveland, Ohio
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13
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Mitra S, Paramaguru R, Das P, Katti SV. Preneoplastic Lesions and Polyps of the Gastrointestinal Tract. SURGICAL PATHOLOGY OF THE GASTROINTESTINAL SYSTEM 2022:593-698. [DOI: 10.1007/978-981-16-6395-6_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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14
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Symptomatic familial adenomatous polyposis in an adolescent: A case report. Int J Surg Case Rep 2021; 84:106118. [PMID: 34186461 PMCID: PMC8254105 DOI: 10.1016/j.ijscr.2021.106118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 06/09/2021] [Accepted: 06/15/2021] [Indexed: 11/24/2022] Open
Abstract
INTRODUCTION Familial adenomatous polyposis (FAP) is an inherited colorectal cancer syndrome characterized by several adenomatous polyps of the gastrointestinal mucosa with a universal risk of colorectal cancer in a lifetime. FAP is usually asymptomatic in the first decade of life. CASE PRESENTATION We report a case of a 13-year-old girl diagnosed with FAP who presented in our center with symptoms of hematochezia along with a positive history of the untimely demise of her father and elder sister with similar symptoms. DISCUSSION FAP is an autosomal dominant disease affecting both male and female equally with variable penetrance. Diagnosis is made by finding hundreds to thousands of adenomatous polyps in the colon and rectum, and molecular analysis of the APC gene which forms the definitive diagnosis. Prophylactic laparoscopic total proctocolectomy with ileorectal anastomosis is a safe and feasible surgical option with a low risk of complications among adolescents. An endoscopic/colonoscopic procedure is recommended every 6 to 12 months after surgery to assess the anastomosis site, pouch, and residual rectum. CONCLUSION FAP, a rare disease entity in adolescents should be managed by appropriate diagnostic procedures, early prophylactic surgery, and regular lifelong follow-up.
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15
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Zhou J, Singh P, Yin K, Wang J, Bao Y, Wu M, Pathak K, McKinley SK, Braun D, Lubitz CC, Hughes KS. Non-medullary Thyroid Cancer Susceptibility Genes: Evidence and Disease Spectrum. Ann Surg Oncol 2021; 28:6590-6600. [PMID: 33660127 DOI: 10.1245/s10434-021-09745-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 01/31/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND The prevalence of non-medullary thyroid cancer (NMTC) is increasing worldwide. Although most NMTCs grow slowly, conventional therapies are less effective in advanced tumors. Approximately 5-15% of NMTCs have a significant germline genetic component. Awareness of the NMTC susceptibility genes may lead to earlier diagnosis and better cancer prevention. OBJECTIVE The aim of this study was to provide the current panorama of susceptibility genes associated with NMTC and the spectrum of diseases associated with these genes. METHODS Twenty-five candidate genes were identified by searching for relevant studies in PubMed. Each candidate gene was carefully checked using six authoritative genetic resources: ClinGen, National Comprehensive Cancer Network guidelines, Online Mendelian Inheritance in Man, Genetics Home Reference, GeneCards, and Gene-NCBI, and a validated natural language processing (NLP)-based literature review protocol was used to further assess gene-disease associations where there was ambiguity. RESULTS Among 25 candidate genes, 10 (APC, DICER1, FOXE1, HABP2, NKX2-1, PRKAR1A, PTEN, SDHB, SDHD, and SRGAP1) were verified among the six genetic resources. Two additional genes, CHEK2 and SEC23B, were verified using the NLP protocol. Seventy-nine diseases were found to be associated with these 12 NMTC susceptibility genes. The following diseases were associated with more than one NMTC susceptibility gene: colorectal cancer, breast cancer, gastric cancer, kidney cancer, gastrointestinal stromal tumor, paraganglioma, pheochromocytoma, and benign skin conditions. CONCLUSION Twelve genes predisposing to NMTC and their associated disease spectra were identified and verified. Clinicians should be aware that patients with certain pathogenic variants may require more aggressive surveillance beyond their thyroid cancer risk.
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Affiliation(s)
- Jingan Zhou
- Department of General Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.,Division of Surgical Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Preeti Singh
- Division of Surgical Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Kanhua Yin
- Division of Surgical Oncology, Massachusetts General Hospital, Boston, MA, USA.,Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Jin Wang
- Division of Surgical Oncology, Massachusetts General Hospital, Boston, MA, USA.,Department of Breast Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Yujia Bao
- Computer Science and Artificial Intelligence, Massachusetts Institute of Technology, Boston, MA, USA
| | - Menghua Wu
- Computer Science and Artificial Intelligence, Massachusetts Institute of Technology, Boston, MA, USA
| | - Kush Pathak
- Department of Surgical Oncology, P. D Hinduja Hospital, Mumbai, India
| | - Sophia K McKinley
- Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Danielle Braun
- Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA.,Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Carrie C Lubitz
- Division of Surgical Oncology, Massachusetts General Hospital, Boston, MA, USA.,Institute for Technology Assessment, Massachusetts General Hospital, Boston, MA, USA
| | - Kevin S Hughes
- Division of Surgical Oncology, Massachusetts General Hospital, Boston, MA, USA.
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16
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Barcellini A, Peloso A, Pugliese L, Vitolo V, Cobianchi L. Locally Advanced Pancreatic Ductal Adenocarcinoma: Challenges and Progress. Onco Targets Ther 2020; 13:12705-12720. [PMID: 33335406 PMCID: PMC7737010 DOI: 10.2147/ott.s220971] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 11/30/2020] [Indexed: 12/24/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the major causes of death in the Western world, and it is estimated to become the second leading cause of tumour-related mortality in the next 10 years. Among pancreatic cancers, ductal adenocarcinomas are by far the most common, characterised by a challenging diagnosis due to the lack of initial and pathognomonic clinical signs. In this scenario, non-metastatic locally advanced pancreatic cancer (LAPC) accounts for a large proportion of all new pancreatic ductal adenocarcinoma diagnoses. There is no consensus on a common definition of LAPC. Still, it usually includes tumours that are not resectable due to vascular involvement. As of today, treatment is limited, and the prognosis is very unfavourable. Curative-intent surgery remains the gold-standard even if often jeopardized by vascular involvement. Continuing progress in our understanding of LAPC genetics and immunology will permit the development of different treatments, targeted or combined, including radiation therapy, hadrontherapy, targeted immunotherapies or new chemotherapies. A multidisciplinary approach combining various fields of expertise is essential in aiming to limit disease progression as well as patient outcome. Using a narrative literature review approach, the manuscript explores the most up-to-date knowledge concerning locally advanced pancreatic ductal adenocarcinoma management.
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Affiliation(s)
- Amelia Barcellini
- National Center of Oncological Hadrontherapy (Fondazione CNAO), Pavia, Italy
| | - Andrea Peloso
- Divisions of Transplantation and Visceral Surgery, Department of Surgery, University of Geneva, Geneva, Switzerland
| | - Luigi Pugliese
- General Surgery, Foundation IRCCS San Matteo Hospital, Pavia, Italy
| | - Viviana Vitolo
- National Center of Oncological Hadrontherapy (Fondazione CNAO), Pavia, Italy
| | - Lorenzo Cobianchi
- General Surgery, Foundation IRCCS San Matteo Hospital, Pavia, Italy.,Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, Foundation IRCCS San Matteo Hospital, University of Pavia, Pavia, Italy
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17
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Zhang Z, Wang D, Xu C, Li Y, Yu Y, Chen C, Li M, Zhang X. Analysis of expression levels of markers associated with tumor proliferation and angiogenesis in familial adenomatous polyposis. Mol Genet Genomic Med 2020; 8:e1534. [PMID: 33108070 PMCID: PMC7767556 DOI: 10.1002/mgg3.1534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 09/30/2020] [Accepted: 10/02/2020] [Indexed: 11/11/2022] Open
Abstract
Background Familial adenomatous polyposis (FAP) is an autosomal dominant hereditary disease with colorectal adenomatous polyps as the main clinical manifestations. The objective of this study was to analyze and compare the expression levels of tumor proliferation and angiogenesis‐related genes in different tissue sections of FAP patients through qPCR, western blot, and immunohistochemistry (IHC) analysis. Methods Seventeen patients with FAP admitted to Tianjin Union Medical Center from January 2010 to June 2015 were selected, and then, normal intestinal mucosa, polyp tissue, or cancerous polyp tissue were collected. QPCR, western blot, and IHC were used to detect the expression level of genes or proteins correlated with tumor proliferation. Results The mRNA expression of CD31 in large polyp tissue was significantly higher than that in normal tissue and small polyp tissue. Compared with normal tissue and polyp tissue, the expression level of KI67 mRNA in cancer tissue was remarkably increased. The VEGFA mRNA and CDH5 mRNA expression in both polyp and cancer tissues were prominently lower than those in normal tissue. The expression of CD31 protein in cancer tissue was lower than that in normal tissue and polyp tissue, whereas the expression levels of VEGF, CDH5, and KI67 protein were widely higher than that in normal tissue and polyp tissue. Conclusion Abnormal expressions of CD31, KI67, VEGF(A), and CDH5 were associated with the carcinogenesis of FAP.
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Affiliation(s)
- Zhao Zhang
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, China
| | - Dan Wang
- Department of pathology, Tianjin Medical University General Hospital, Tianjin, China
| | - Chen Xu
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, China
| | - Yuwei Li
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, China
| | - Yongjun Yu
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, China
| | - Chao Chen
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, China
| | - Mingsen Li
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, China
| | - Xipeng Zhang
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, China
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18
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Stefanski CD, Prosperi JR. Wnt-Independent and Wnt-Dependent Effects of APC Loss on the Chemotherapeutic Response. Int J Mol Sci 2020; 21:E7844. [PMID: 33105836 PMCID: PMC7660076 DOI: 10.3390/ijms21217844] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 10/20/2020] [Accepted: 10/20/2020] [Indexed: 12/12/2022] Open
Abstract
Resistance to chemotherapy occurs through mechanisms within the epithelial tumor cells or through interactions with components of the tumor microenvironment (TME). Chemoresistance and the development of recurrent tumors are two of the leading factors of cancer-related deaths. The Adenomatous Polyposis Coli (APC) tumor suppressor is lost in many different cancers, including colorectal, breast, and prostate cancer, and its loss correlates with a decreased overall survival in cancer patients. While APC is commonly known for its role as a negative regulator of the WNT pathway, APC has numerous binding partners and functional roles. Through APC's interactions with DNA repair proteins, DNA replication proteins, tubulin, and other components, recent evidence has shown that APC regulates the chemotherapy response in cancer cells. In this review article, we provide an overview of some of the cellular processes in which APC participates and how they impact chemoresistance through both epithelial- and TME-derived mechanisms.
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Affiliation(s)
- Casey D. Stefanski
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46617, USA;
- Mike and Josie Harper Cancer Research Institute, South Bend, IN 46617, USA
| | - Jenifer R. Prosperi
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46617, USA;
- Mike and Josie Harper Cancer Research Institute, South Bend, IN 46617, USA
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine-South Bend, South Bend, IN 46617, USA
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19
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Limited Proteolysis of Cyclooxygenase-2 Enhances Cell Proliferation. Int J Mol Sci 2020; 21:ijms21093195. [PMID: 32366045 PMCID: PMC7246915 DOI: 10.3390/ijms21093195] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Revised: 04/22/2020] [Accepted: 04/28/2020] [Indexed: 01/28/2023] Open
Abstract
Accumulating evidence suggests that the cyclooxygenase-2 (COX-2) enzyme has additional catalytic-independent functions. Here we show that COX-2 appears to be cleaved in mouse and human tumors, which led us to hypothesize that COX-2 proteolysis may play a role in cell proliferation. The data presented herein show that a K598R point mutation at the carboxyl-terminus of COX-2 causes the appearance of several COX-2 immunoreactive fragments in nuclear compartments, and significantly enhances cell proliferation. In contrast, insertion of additional mutations at the border of the membrane-binding and catalytic domains of K598R COX-2 blocks fragment formation and prevents the increase in proliferation. Transcriptomic analyses show that K598R COX-2 significantly affects the expression of genes involved in RNA metabolism, and subsequent proteomics suggest that it is associated with proteins that regulate mRNA processing. We observe a similar increase in proliferation by expressing just that catalytic domain of COX-2 (ΔNT- COX-2), which is completely devoid of catalytic activity in the absence of its other domains. Moreover, we show that the ΔNT- COX-2 protein also interacts in the nucleus with β-catenin, a central regulator of gene transcription. Together these data suggest that the cleavage products of COX-2 can affect cell proliferation by mechanisms that are independent of prostaglandin synthesis.
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20
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Oliveira PG, Ferreira C, Almeida R, Curvo-Semedo L. Colo-colonic intussusception as the first manifestation of familial adenomatous polyposis - index case. BMJ Case Rep 2020; 13:13/2/e234209. [PMID: 32047092 DOI: 10.1136/bcr-2019-234209] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Affiliation(s)
- Pedro Gil Oliveira
- Radiology, Centro Hospitalar e Universitário de Coimbra EPE, Coimbra, Portugal
| | - Cristina Ferreira
- Radiology, Centro Hospitalar e Universitário de Coimbra EPE, Coimbra, Portugal
| | - Rui Almeida
- Pathology, Centro Hospitalar e Universitário de Coimbra EPE, Coimbra, Portugal
| | - Luís Curvo-Semedo
- Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Medical Imaging, Clinical Academic Centre of Coimbra, Coimbra, Portugal
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21
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Niu T, Yang M, Liu Q, Li H, Jiang L, Li F, He X, Wang L, Li J. The Somatic Mutation Hit on Top of Genetic APC mutations Cause Skin Tumor. Transl Oncol 2019; 13:300-307. [PMID: 31877462 PMCID: PMC6931217 DOI: 10.1016/j.tranon.2019.11.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 11/18/2019] [Accepted: 11/18/2019] [Indexed: 12/15/2022] Open
Abstract
Inactivation of the adenomatous polyposis coli (APC) gene is the initiating event in familial adenomatous polyposis (FAP) patients. Up to 90% of FAP patients show intestinal tumors and other extracolonic malignancies including hepatoblastomas, desmoid tumors, and brain cancer. APC mutation mice (ApcMin/+ mice) develop benign polyps in the intestinal tract. It has been reported that small numbers of ApcMin/+ mice develop breast carcinomas. Here, we found that approximately 1.6% of ApcMin/+ mice suffered skin neoplasm. The results demonstrated that these skin tumors are not derived from intestinal adenomas. Sequencing of skin tumors of ApcMin/+ mice and ApcMin/+ mice skin. The data showed that somatic mutations and gene expression levels changed greatly in skin tumors compared to control. Similarly, APC mutation accounts for 27% in the patients of nonmelanoma skin carcinomas in cancer database, and two above genes mutation coexist was observed in all patients. Furthermore, using gene mutation reagent (DMBA)-treated ApcMin/+ mice skin, the skin epithelium and glandular begin hyperplasia in ApcMin/+ mice. These findings revealed that the somatic mutation hit on the germline mutation increase the tumor incidence, suggesting that the somatic mutation should be avoided if the germline mutation exists in one body.
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Affiliation(s)
- Ting Niu
- Vascular Biology Research Institute, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Mingming Yang
- Vascular Biology Research Institute, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Qing Liu
- Vascular Biology Research Institute, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Haobin Li
- Vascular Biology Research Institute, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Lingbi Jiang
- Vascular Biology Research Institute, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Fanggu Li
- The First Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, China
| | - Xiaodong He
- Vascular Biology Research Institute, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Lijing Wang
- Vascular Biology Research Institute, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510006, China.
| | - Jiangchao Li
- Vascular Biology Research Institute, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510006, China.
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22
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Pinna R, Cocco F, Campus G, Conti G, Milia E, Sardella A, Cagetti MG. Genetic and developmental disorders of the oral mucosa: Epidemiology; molecular mechanisms; diagnostic criteria; management. Periodontol 2000 2019; 80:12-27. [PMID: 31090139 DOI: 10.1111/prd.12261] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
A large number of disorders may affect the oral cavity, including genetic diseases, infections, cancers, blood diseases, skin diseases, endocrine and metabolic disorders, autoimmune and rheumatologic diseases, local lesions, to name a few. Oral mucosa shows a considerable variation in its normal structure and a wide range of conditions may affect it. Such conditions are often harmless or minor and could be primary or secondary to systemic disease. Several of them are quite rare and, hence, the diagnosis is not easy. Clinically, lesions may appear as ulcers, discoloration of the oral mucosa and alterations in size and configuration of oral anatomy. Genetic disorders have specific manifestations and can be caused by a derangement of one or more components of the tissue. Many of them follow the skin or systemic signs of the underlying genetic disease, but in a few cases oral signs could be the first manifestation of the disorder. Among them genodermatoses are prominent. They are inherited disorders characterized by a multisystem involvement. This review describes chondro-ectodermal dysplasia, dyskeratosis congenita, Ehlers-Danlos syndrome, hereditary benign intraepithelial dyskeratosis, keratosis follicularis, lipoid proteinosis, multiple hamartoma syndrome, pachyonychia congenita, Peutz-Jeghers syndrome, tuberous sclerosis and white sponge nevus. Other genetic disorders not included in the genodermatosis group and reported in the present review are: acanthosis nigricans, angio-osteo-hypertrophic syndrome, encephalotrigeminal angiomatosis, familial adenomatous polyposis, focal dermal hypoplasia, focal palmoplantar and oral mucosa hyperkeratosis syndrome, gingival fibromatosis, Maffucci's syndrome, neurofibromatosis (type 1) and oro-facial-digital syndrome (type 1). Disorders during embryonic development might lead to a wide range of abnormalities in the oral cavity; some of them are quite common but of negligible concern, whereas others are rare but serious, affecting not only the oral mucosa, but also other structures of the oral cavity (ie palate, tongue and gingiva). Fordyce's granules, leukoedema, cysts of the oral mucosa in newborns, retrocuspid papilla, geographic tongue, fissured tongue, median rhomboid glossitis, hairy tongue, lingual varices and lingual thyroid nodule are described. This review may help dentists, dental hygienists, but also general internists and pediatricians to diagnose different disorders of the oral mucosa, to understand the pathogenesis and to schedule a treatment plan.
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Affiliation(s)
- Roberto Pinna
- Department of Surgery, Medicine and Experimental Sciences, University of Sassari, Sassari, Italy
| | - Fabio Cocco
- Department of Surgery, Medicine and Experimental Sciences, University of Sassari, Sassari, Italy.,WHO Collaboration Centre for Epidemiology and Community Dentistry, University of Milan, Milan, Italy
| | - Guglielmo Campus
- Department of Surgery, Medicine and Experimental Sciences, University of Sassari, Sassari, Italy.,WHO Collaboration Centre for Epidemiology and Community Dentistry, University of Milan, Milan, Italy.,Klinik für Zahnerhaltung, Präventiv-und Kinderzahnmedizin Zahnmedizinische Kliniken (ZMK), University of Bern, Switzerland
| | - Giulio Conti
- IRCCS "Ca Granda-Ospedale Maggiore", University of Milan, Milan, Italy
| | - Egle Milia
- Department of Surgery, Medicine and Experimental Sciences, University of Sassari, Sassari, Italy
| | - Andrea Sardella
- IRCCS "Ca Granda-Ospedale Maggiore", University of Milan, Milan, Italy.,Department of Biomedical, Surgical and Dental Science, University of Milan, Milan, Italy
| | - Maria Grazia Cagetti
- WHO Collaboration Centre for Epidemiology and Community Dentistry, University of Milan, Milan, Italy.,Department of Biomedical, Surgical and Dental Science, University of Milan, Milan, Italy
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23
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Dinarvand P, Davaro EP, Doan JV, Ising ME, Evans NR, Phillips NJ, Lai J, Guzman MA. Familial Adenomatous Polyposis Syndrome: An Update and Review of Extraintestinal Manifestations. Arch Pathol Lab Med 2019; 143:1382-1398. [PMID: 31070935 DOI: 10.5858/arpa.2018-0570-ra] [Citation(s) in RCA: 108] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
CONTEXT.— Familial adenomatous polyposis (FAP) is a rare genetic disorder with autosomal dominant inheritance, defined by numerous adenomatous polyps, which inevitably progress to colorectal carcinoma unless detected and managed early. Greater than 70% of patients with this syndrome also develop extraintestinal manifestations, such as multiple osteomas, dental abnormalities, and a variety of other lesions located throughout the body. These manifestations have historically been subcategorized as Gardner syndrome, Turcot syndrome, or gastric adenocarcinoma and proximal polyposis of the stomach. Recent studies, however, correlate the severity of gastrointestinal disease and the prominence of extraintestinal findings to specific mutations within the adenomatous polyposis coli gene (APC), supporting a spectrum of disease as opposed to subcategorization. Advances in immunohistochemical and molecular techniques shed new light on the origin, classification, and progression risk of different entities associated with FAP. OBJECTIVE.— To provide a comprehensive clinicopathologic review of neoplastic and nonneoplastic entities associated with FAP syndrome, with emphasis on recent developments in immunohistochemical and molecular profiles of extraintestinal manifestations in the thyroid, skin, soft tissue, bone, central nervous system, liver, and pancreas, and the subsequent changes in classification schemes and risk stratification. DATA SOURCES.— This review will be based on peer-reviewed literature and the authors' experiences. CONCLUSIONS.— In this review we will provide an update on the clinicopathologic manifestations, immunohistochemical profiles, molecular features, and prognosis of entities seen in FAP, with a focus on routine recognition and appropriate workup of extraintestinal manifestations.
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Affiliation(s)
- Peyman Dinarvand
- From the Departments of Pathology (Drs Dinarvand, Davaro, Doan, Phillips, and Guzman and Ms Ising) and Internal Medicine (Dr Evans), Saint Louis University School of Medicine, Saint Louis, Missouri; and the Department of Pathology, University of Florida, College of Medicine, Gainesville (Dr Lai)
| | - Elizabeth P Davaro
- From the Departments of Pathology (Drs Dinarvand, Davaro, Doan, Phillips, and Guzman and Ms Ising) and Internal Medicine (Dr Evans), Saint Louis University School of Medicine, Saint Louis, Missouri; and the Department of Pathology, University of Florida, College of Medicine, Gainesville (Dr Lai)
| | - James V Doan
- From the Departments of Pathology (Drs Dinarvand, Davaro, Doan, Phillips, and Guzman and Ms Ising) and Internal Medicine (Dr Evans), Saint Louis University School of Medicine, Saint Louis, Missouri; and the Department of Pathology, University of Florida, College of Medicine, Gainesville (Dr Lai)
| | - Mary E Ising
- From the Departments of Pathology (Drs Dinarvand, Davaro, Doan, Phillips, and Guzman and Ms Ising) and Internal Medicine (Dr Evans), Saint Louis University School of Medicine, Saint Louis, Missouri; and the Department of Pathology, University of Florida, College of Medicine, Gainesville (Dr Lai)
| | - Neil R Evans
- From the Departments of Pathology (Drs Dinarvand, Davaro, Doan, Phillips, and Guzman and Ms Ising) and Internal Medicine (Dr Evans), Saint Louis University School of Medicine, Saint Louis, Missouri; and the Department of Pathology, University of Florida, College of Medicine, Gainesville (Dr Lai)
| | - Nancy J Phillips
- From the Departments of Pathology (Drs Dinarvand, Davaro, Doan, Phillips, and Guzman and Ms Ising) and Internal Medicine (Dr Evans), Saint Louis University School of Medicine, Saint Louis, Missouri; and the Department of Pathology, University of Florida, College of Medicine, Gainesville (Dr Lai)
| | - Jinping Lai
- From the Departments of Pathology (Drs Dinarvand, Davaro, Doan, Phillips, and Guzman and Ms Ising) and Internal Medicine (Dr Evans), Saint Louis University School of Medicine, Saint Louis, Missouri; and the Department of Pathology, University of Florida, College of Medicine, Gainesville (Dr Lai)
| | - Miguel A Guzman
- From the Departments of Pathology (Drs Dinarvand, Davaro, Doan, Phillips, and Guzman and Ms Ising) and Internal Medicine (Dr Evans), Saint Louis University School of Medicine, Saint Louis, Missouri; and the Department of Pathology, University of Florida, College of Medicine, Gainesville (Dr Lai)
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24
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Harlid S, Xu Z, Kirk E, Wilson LE, Troester MA, Taylor JA. Hormone therapy use and breast tissue DNA methylation: analysis of epigenome wide data from the normal breast study. Epigenetics 2019; 14:146-157. [PMID: 30821641 PMCID: PMC6557608 DOI: 10.1080/15592294.2019.1580111] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Hormone therapy (HT) is associated with increased risk of breast cancer, strongly dependent on type, duration, and recency of use. HT use could affect cancer risk by changing breast tissue transcriptional programs. We hypothesize that these changes are preceded by changes in DNA methylation. To explore this hypothesis we used histologically normal-appearing breast tissue from the Normal Breast Study (NBS). DNA methylation β-values were obtained using the Illumina HumanMethylation 450 BeadChips for 90 samples including all NBS-participants who used HT within 5 y before surgery. Data were analyzed using the reference-free cell mixture method. Cancer Genome Atlas (TCGA) mRNA-Seq data were used to assess correlation between DNA methylation and gene expression. We identified 527 CpG sites in 403 genes that were associated with ever using HT at genome wide significance (FDR q < 0.05), of these, 68 sites were also significantly associated with duration of use or recency of use. Twelve sites reached significance in all analyses one of which was cg01382688 in ARHGEF4 (p < 1.2x10−7). Mutations in ARHGEF4 have been reported in breast tumors, but this is the first report of possible breast cancer-related DNA methylation changes. In addition, 22 genes included more than one significant CpG site and a majority of these sites were significantly correlated with gene expression. Although based on small numbers, these findings support the hypothesis that HT is associated with epigenetic alterations in breast tissue, and identifies genes with altered DNA methylation states which could be linked to breast cancer development.
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Affiliation(s)
- Sophia Harlid
- a Epigenetics & Stem Cell Biology Laboratory , National Institute of Environmental Health Sciences, NIH , Research Triangle Park , NC , USA.,b Department of Radiation Sciences, Oncology , Umeå University , Umeå , Sweden
| | - Zongli Xu
- c Epidemiology Branch , National Institute of Environmental Health Sciences, NIH , Research Triangle Park , NC , USA
| | - Erin Kirk
- d Department of Epidemiology , University of North Carolina at Chapel Hill , Chapel Hill , NC , USA
| | - Lauren E Wilson
- c Epidemiology Branch , National Institute of Environmental Health Sciences, NIH , Research Triangle Park , NC , USA.,e Department of Population Health Sciences , Duke University School of Medicine , Durham , NC , USA
| | - Melissa A Troester
- d Department of Epidemiology , University of North Carolina at Chapel Hill , Chapel Hill , NC , USA
| | - Jack A Taylor
- a Epigenetics & Stem Cell Biology Laboratory , National Institute of Environmental Health Sciences, NIH , Research Triangle Park , NC , USA.,c Epidemiology Branch , National Institute of Environmental Health Sciences, NIH , Research Triangle Park , NC , USA
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25
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Baldino ME, Koth VS, Silva DN, Figueiredo MA, Salum FG, Cherubini K. Gardner syndrome with maxillofacial manifestation: A case report. SPECIAL CARE IN DENTISTRY 2018; 39:65-71. [PMID: 30417483 DOI: 10.1111/scd.12339] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 10/29/2018] [Accepted: 10/30/2018] [Indexed: 11/28/2022]
Abstract
Gardner syndrome is a hereditary disease in which patients develop gastrointestinal polyps, osteomas, desmoid tumors, epidermoid cysts, fibromas, lipomas, and retinal lesions. Dental abnormalities such as supernumerary or impacted teeth, odontomas and dentigerous cysts are also reported. The most serious concern in this syndrome is the extremely high risk of gastrointestinal polyps undergoing malignant transformation. Since the maxillofacial findings usually precede gastrointestinal polyps, the dentist plays a crucial role in the diagnosis of Gardner syndrome, and panoramic radiography is an important tool in the diagnosis of the disease. We report here a case of Gardner syndrome in a patient showing mandibular osteomas and impacted teeth. Also, cases of Gardner syndrome with maxillofacial manifestations reported in the literature were reviewed and compared with ours. According to the findings, osteomas are important manifestations of this syndrome, and regardless of the absence of family history of intestinal polyposis, their occurrence should prompt diagnostic evaluation for this disease.
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Affiliation(s)
- Maria Eduarda Baldino
- Postgraduate Program, Dental College, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Valesca Sander Koth
- Postgraduate Program, Dental College, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, RS, Brazil
| | | | - Maria Antonia Figueiredo
- Postgraduate Program, Dental College, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Fernanda Gonçalves Salum
- Postgraduate Program, Dental College, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Karen Cherubini
- Postgraduate Program, Dental College, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, RS, Brazil
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26
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Majumder S, Shah R, Elias J, Mistry Y, Coral K, Shah P, Maurya AK, Mittal B, D’Silva JK, Murugan S, Mahadevan L, Sathian R, Ramprasad VL, Chakraborty P, Gupta R, Chaudhuri A, Khanna-Gupta A. A neoepitope derived from a novel human germline APC gene mutation in familial adenomatous polyposis shows selective immunogenicity. PLoS One 2018; 13:e0203845. [PMID: 30256815 PMCID: PMC6157866 DOI: 10.1371/journal.pone.0203845] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Accepted: 08/28/2018] [Indexed: 01/21/2023] Open
Abstract
Familial adenomatous polyposis (FAP) is an inherited condition arising from genetic defects in the Adenomatous polyposis coli (APC) gene. Carriers with mutations in the APC gene develop polyps in the colon and rectum which if not managed, transition into colon cancer. In this study, we identified a novel germline mutation in the APC gene in members of an FAP-affected (Familial adenomatous polyposis) family. This unique heterozygous variant (c.735_736insT; p.Ser246PhefsTer6) was identified in ten out of twenty six family members, ranging in age from 6 to 60 years. Polyps were detected in six of the ten individuals (35–60 years) carrying this mutation. The remaining four members (6–23 years) remain polyp free. A significant fraction of FAP affected individuals eventually develop colon cancer and therapeutic interventions to prevent cancer progression remain elusive. To address this issue, we sought to determine if peptides derived from the novel APC mutation could induce a cytotoxic T cell response, thereby qualifying them as vaccine candidates. Peptides harboring the variant amino acids were first interrogated in silico for their immunogenicity using a proprietary neoepitope prioritization pipeline, OncoPeptVAC. A single 9-mer peptide was predicted to be immunogenic. Remarkably, CD8+ T cells isolated from either an FAP+/ APCmut individual, or from a FAP-/ APCmut individual, failed to respond to the peptide, whereas those from either an unaffected family member (FAP-/ APCwt) or from healthy unrelated donors, showed a robust response, suggesting that CD8+ T cells from individuals carrying this germline APC mutation have been tolerized to the mutation. Furthermore, experimental testing of six additional reported APC gene mutation-derived peptides revealed one of the six to be immunogenic. While not all APC mutant peptides are inmmunogenic, a few qualify as vaccine candidates offering novel treatment opportunities to patients with somatic APC gene mutations to delay/treat colorectal cancer.
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Affiliation(s)
| | | | - Jisha Elias
- MedGenome Labs Pvt. Ltd., Bangalore, India
- KCHRC, Muni Seva Ashram, Goraj, Gujarat, India
| | | | | | | | | | | | | | | | | | | | | | | | - Ravi Gupta
- MedGenome Labs Pvt. Ltd., Bangalore, India
| | - Amitabha Chaudhuri
- MedGenome Labs Pvt. Ltd., Bangalore, India
- MedGenome Inc., Foster City, CA, United States of America
- * E-mail: (AKG); (AC)
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27
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Trobaugh-Lotrario AD, López-Terrada D, Li P, Feusner JH. Hepatoblastoma in patients with molecularly proven familial adenomatous polyposis: Clinical characteristics and rationale for surveillance screening. Pediatr Blood Cancer 2018; 65:e27103. [PMID: 29719120 DOI: 10.1002/pbc.27103] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Revised: 03/01/2018] [Accepted: 03/26/2018] [Indexed: 12/19/2022]
Abstract
Familial adenomatous polyposis (FAP) due to APC mutation is associated with an increased risk of hepatoblastoma. All cases of hepatoblastoma in patients with FAP reported in the literature were reviewed. One hundred and nine patients were identified. Thirty-five patients (of 49 with data) were diagnosed with hepatoblastoma prior to a later diagnosis of FAP (often in association with advanced colorectal carcinoma), emphasizing a need to identify patients earlier with germline APC mutations for early colorectal carcinoma screening. Hepatoblastoma may present at birth, and screening for hepatoblastoma in infancy in families with FAP prior to APC mutation testing results may be warranted.
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Affiliation(s)
| | - Dolores López-Terrada
- Department of Pathology, Texas Children's Hospital and Baylor College of Medicine, Houston, TX, USA
| | - Peng Li
- Department of Pathology, Texas Children's Hospital and Baylor College of Medicine, Houston, TX, USA
| | - James H Feusner
- Division of Hematology/Oncology, Children's Hospital & Research Center Oakland, Oakland, CA, USA
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28
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APC and MUTYH Analysis in FAP Patients: A Novel Mutation in APC Gene and Genotype-Phenotype Correlation. Genes (Basel) 2018; 9:genes9070322. [PMID: 29954149 PMCID: PMC6071208 DOI: 10.3390/genes9070322] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Revised: 06/21/2018] [Accepted: 06/22/2018] [Indexed: 02/06/2023] Open
Abstract
APC and MUTYH genes are mutated in 70⁻90% and 10⁻30% of familial adenomatous polyposis cases (FAP) respectively. An association between mutation localization and FAP clinical phenotype is reported. The aims of this study were to determine APC and MUTYH mutational status in a small cohort of FAP patients and to evaluate the genotype-phenotype correlation in mutated patients. Here, we report the identification of a novel APC germline mutation, c.510_511insA. Overall, mutational analysis showed pathogenic mutations in 6/10 patients: 5/10 in APC and 1/10 in MUTYH. Additionally, we found three variants of unknown significance in MUTYH gene that showed no evidence of possible splicing defects by in silico analysis. Molecular analysis was also extended to family members of mutated patients. A genotype-phenotype correlation was observed for colonic signs whereas a variation of disease onset age was revealed for the same mutation. Moreover, we found an intrafamilial variability of FAP onset age. Regarding extracolonic manifestations, the development of desmoid tumors was related to surgery and not to mutation position, while a genotype-phenotype correspondence was observed for the onset of thyroid or gastric cancer. These findings can be useful in association to clinical data for early surveillance and suitable treatment of FAP patients.
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29
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Witold K, Anna K, Maciej T, Jakub J. Adenomas - Genetic factors in colorectal cancer prevention. Rep Pract Oncol Radiother 2018; 23:75-83. [PMID: 29463957 PMCID: PMC5814382 DOI: 10.1016/j.rpor.2017.12.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2016] [Revised: 07/17/2017] [Accepted: 12/27/2017] [Indexed: 12/21/2022] Open
Abstract
Colorectal cancer is the second most common type of cancer both in Europe and Poland. During the last 30 years more than a 3-fold increase has been observed in Poland due to environmental and genetic factors. Almost all colorectal malignancies are related to the formation and malignant transformation of colorectal dysplasia and adenoma. Efforts aiming to decrease the number of colorectal cancer deaths are focused on the disease early detection. Genetic diagnosis for hereditary syndromes predisposing to colorectal cancer has been developed and is a part of the routine treatment. Most cancers are sporadic. They often develop from polyps in the colon. In addition to the genetic events described in the 1990s, showing the adenoma transformation into carcinoma that has been a prime example of malignant transformation for a long time, there are also other possibilities of neoplastic transformation. The recognition of colorectal cancer risk factors make sense as their nature is lifestyle- and diet-related. In this review paper those risk factors are presented and the prevention of colorectal cancer is discussed taking into account genetic factors.
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Affiliation(s)
- Kycler Witold
- Department of Oncological Surgery of Gastrointestinal Diseases, Greater Poland Cancer Centre, 15 Garbary St., 61-866 Poznan, Poland
- Department of Head and Neck Surgery, Poznan University of Medical Sciences, 10 Fredry St., 61-701 Poznan, Poland
| | - Kubiak Anna
- Department of Epidemiology and Cancer Prevention, Greater Poland Cancer Registry – The Greater Poland Cancer Centre, 15 Garbary St., 61-866 Poznan, Poland
| | - Trojanowski Maciej
- Department of Epidemiology and Cancer Prevention, Greater Poland Cancer Registry – The Greater Poland Cancer Centre, 15 Garbary St., 61-866 Poznan, Poland
| | - Janowski Jakub
- Department of Oncological Surgery of Gastrointestinal Diseases, Greater Poland Cancer Centre, 15 Garbary St., 61-866 Poznan, Poland
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30
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Perez-Lanzon M, Kroemer G, Maiuri MC. Organoids for Modeling Genetic Diseases. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2018; 337:49-81. [DOI: 10.1016/bs.ircmb.2017.12.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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31
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Raskov H, Burcharth J, Pommergaard HC. Linking Gut Microbiota to Colorectal Cancer. J Cancer 2017; 8:3378-3395. [PMID: 29151921 PMCID: PMC5687151 DOI: 10.7150/jca.20497] [Citation(s) in RCA: 90] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Accepted: 08/10/2017] [Indexed: 02/06/2023] Open
Abstract
Pre-clinical and clinical data produce mounting evidence that the microbiota is strongly associated with colorectal carcinogenesis. Dysbiosis may change the course of carcinogenesis as microbial actions seem to impact genetic and epigenetic alterations leading to dysplasia, clonal expansion and malignant transformation. Initiation and promotion of colorectal cancer may result from direct bacterial actions, bacterial metabolites and inflammatory pathways. Newer aspects of microbiota and colorectal cancer include quorum sensing, biofilm formation, sidedness and effects/countereffects of microbiota and probiotics on chemotherapy. In the future, targeting the microbiota will probably be a powerful weapon in the battle against CRC as gut microbiology, genomics and metabolomics promise to uncover important linkages between microbiota and intestinal health.
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Affiliation(s)
- Hans Raskov
- Speciallægecentret ved Diakonissestiftelsen, Frederiksberg, Denmark
| | - Jakob Burcharth
- Department of Surgery, Zealand University Hospital, University of Copenhagen, Denmark
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32
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Carrera S, Sancho A, Azkona E, Azkuna J, Lopez-Vivanco G. Hereditary pancreatic cancer: related syndromes and clinical perspective. Hered Cancer Clin Pract 2017; 15:9. [PMID: 28670351 PMCID: PMC5490219 DOI: 10.1186/s13053-017-0069-6] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Accepted: 06/21/2017] [Indexed: 02/07/2023] Open
Abstract
Pancreatic cancer is a very aggressive disease with a poor prognosis. The majority of them are attributed to sporadic causes, especially to many modifiable risk factors such as tobacco or alcohol abuse. The principal histologic subtype of pancreatic cancer is ductal adenocarcinoma. Pancreatic neuroendocrine tumors, which constitute a more indolent entity, represent second type of pancreatic cancer in terms of incidence. Individuals with a family history of pancreatic cancer carry an increased risk of developing the disease, which may be related to an underlying hereditary component. Unfortunately, in the majority of these families the suspected germline genetic cause responsible of the disease will not be identified, but approximately in a 20% of the cases a hereditary cancer predisposition syndrome with increased risk of pancreatic cancer development can be recognized. This review will be focused on the leading hereditary cancer syndromes related to pancreatic ductal adenocarcinoma and pancreatic neuroendocrine tumors. Additionally, we will try to explain clinical aspects related to the identification of germline mutations in pancreatic cancer patients and their potential implications in oncologic treatment decisions.
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Affiliation(s)
- Sergio Carrera
- Hereditary Cancer Genetic Counseling Unit- Medical Oncology Department, Cruces University Hospital, Plaza de Cruces s/n. 48903, Baracaldo, Bizkaia Spain
| | - Aintzane Sancho
- Medical Oncology Department, Cruces University Hospital, Baracaldo, Spain
| | - Eider Azkona
- Medical Oncology Department, Cruces University Hospital, Baracaldo, Spain
| | - Josune Azkuna
- Medical Oncology Department, Cruces University Hospital, Baracaldo, Spain
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33
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Lam AKY, Saremi N. Cribriform-morular variant of papillary thyroid carcinoma: a distinctive type of thyroid cancer. Endocr Relat Cancer 2017; 24:R109-R121. [PMID: 28314770 DOI: 10.1530/erc-17-0014] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Accepted: 02/13/2017] [Indexed: 02/06/2023]
Abstract
The aim of this systematic review is to study the features of cribriform-morular variant of papillary thyroid carcinoma (CMV-PTC) by analysing the 129 documented cases in the English literature. The disease occurred almost exclusively in women. The median age of presentation for CMV-PTC was 24 years. Slightly over half of the patients with CMV-PTC had familial adenomatous polyposis (FAP). CMV-PTC presented before the colonic manifestations in approximately half of the patients with FAP. Patients with FAP often have multifocal tumours in the thyroid. Microscopic examination of CMV-PTC revealed predominately cribriform and morular pattern of cancer cells with characteristic nuclear features of papillary thyroid carcinoma. Psammoma body is rare. On immunohistochemical studies, β-catenin is diffusely positive in CMV-PTC. The morular cells in CMV-PTC are strongly positive for CD10, bcl-2 and E-cadherin. Pre-operative diagnosis of CMV-PTC by fine-needle aspiration biopsy could be aided by cribriform architecture, epithelial morules and β-catenin immunostaining. Mutations of APC gene are found in the patients with CMV-PTC associated with FAP. In addition, mutations in CTNNB1, RET/PTC rearrangement and PI3K3CA mutations have been reported. BRAF mutation is negative in all CMV-PTC tested. Compared to conventional papillary thyroid carcinoma, CMV-PTC had a lower frequency of lymph node metastases at presentation (12%) and distant metastases (3%) as well as lower recurrence rates (8.5%) and patients' mortality rates (2%). To conclude, patients with CMV-PTC have distinctive clinical, pathological and molecular profiles when compared to conventional papillary thyroid carcinoma.
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Affiliation(s)
- Alfred King-Yin Lam
- Cancer Molecular PathologySchool of Medicine and Menzies Health Institute Queensland, Griffith University, Gold Coast, Australia
| | - Nassim Saremi
- Cancer Molecular PathologySchool of Medicine and Menzies Health Institute Queensland, Griffith University, Gold Coast, Australia
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34
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Eshghifar N, Farrokhi N, Naji T, Zali M. Tumor suppressor genes in familial adenomatous polyposis. GASTROENTEROLOGY AND HEPATOLOGY FROM BED TO BENCH 2017; 10:3-13. [PMID: 28331559 PMCID: PMC5346818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Colorectal cancer (CRC) is mostly due to a series of genetic alterations that are being greatly under the influence of the environmental factors. These changes, mutational or epigenetic modifications at transcriptional forefront and/or post-transcriptional effects via miRNAs, include inactivation and the conversion of proto-oncogene to oncogenes, and/or inactivation of tumor suppressor genes (TSG). Here, a thorough review was carried out on the role of TSGs with the focus on the APC as the master regulator, mutated genes and mal-/dysfunctional pathways that lead to one type of hereditary form of the CRC; namely familial adenomatous polyposis (FAP). This review provides a venue towards defining candidate genes that can be used as new PCR-based markers for early diagnosis of FAP. In addition to diagnosis, defining the modes of genetic alterations will open door towards genome editing to either suppress the disease or reduce its progression during the course of action.
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Affiliation(s)
- Nahal Eshghifar
- Department of Molecular and Cellular Sciences, Faculty of Advanced Sciences & Technology, Pharmaceutical Science Branch, Islamic Azad University, Tehran, Iran
| | - Naser Farrokhi
- Department of Plant Biology & Biotechnology, Faculty of Biosciences & Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Tahereh Naji
- Department of Molecular and Cellular Sciences, Faculty of Advanced Sciences & Technology, Pharmaceutical Science Branch, Islamic Azad University, Tehran, Iran
| | - Mohammadreza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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