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Liu JH, Dhamija G, Jiang Y, He D, Zhou XC. Gastric cancer metastatic to the breast: A case report. World J Gastrointest Oncol 2024; 16:3331-3340. [PMID: 39072150 PMCID: PMC11271788 DOI: 10.4251/wjgo.v16.i7.3331] [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: 03/02/2024] [Revised: 05/01/2024] [Accepted: 05/22/2024] [Indexed: 07/12/2024] Open
Abstract
BACKGROUND Metastatic breast cancer originating in the gastrointestinal tract is a rare occurrence. The limited number of cases has resulted in incomplete understanding of the disease, making it challenging to differentiate from primary breast cancer. While clinical history and immunohistochemical studies can aid in distinguishing between the two, the management principles and pathogenesis of gastrointestinal metastatic breast cancer remain controversial. The scarcity of data has hampered comprehensive knowledge. Our objective is to shed light on this rare disease through our case study. CASE SUMMARY Here, we report a case of breast metastasis from gastric cancer in a 43-year-old woman. This patient was admitted to our hospital with complaints of discomfort in the upper and middle abdomen persisting for two months, as well as black stools for over ten days. She underwent radical distal gastrectomy for gastric cancer, followed by postoperative chemotherapy. Three years later, the patient developed bilateral breast nodules. Imaging studies indicated a high probability of malignancy. She subsequently underwent a right modified radical mastectomy and excision of a left breast mass. Postoperative pathology revealed the right breast tumor was consistent with primary gastric cancer. CONCLUSION We present a case of breast metastasis from gastric cancer to contribute to the limited foundation of research into this rare disease.
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Affiliation(s)
- Jia-Hui Liu
- Department of Urology, The Dingli Clinical College of Wenzhou Medical University (Wenzhou Central Hospital), Wenzhou 325000, Zhejiang Province, China
| | - Gaurav Dhamija
- School of International Studies, Wenzhou Medical University, Wenzhou Central Hospital, Wenzhou 325000, Zhejiang Province, China
| | - Yi Jiang
- Department of Pathology, The Dingli Clinical College of Wenzhou Medical University (Wenzhou Central Hospital), Wenzhou 325000, Zhejiang Province, China
| | - Dan He
- Department of Gastroenterology, The Dingli Clinical College of Wenzhou Medical University (Wenzhou Central Hospital), Wenzhou 325000, Zhejiang Province, China
| | - Xiao-Cong Zhou
- Department of Colorectal Surgery, The Dingli Clinical College of Wenzhou Medical University (Wenzhou Central Hospital), Wenzhou 325000, Zhejiang Province, China
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Madar L, Majoros V, Szűcs Z, Nagy O, Babicz T, Butz H, Patócs A, Balogh I, Koczok K. Double Heterozygosity for Rare Deleterious Variants in the BRCA1 and BRCA2 Genes in a Hungarian Patient with Breast Cancer. Int J Mol Sci 2023; 24:15334. [PMID: 37895014 PMCID: PMC10607119 DOI: 10.3390/ijms242015334] [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: 09/06/2023] [Revised: 10/13/2023] [Accepted: 10/17/2023] [Indexed: 10/29/2023] Open
Abstract
Hereditary breast cancer is most commonly attributed to germline BRCA1 and BRCA2 gene variants. The vast majority of BRCA1 and BRCA2 mutation carriers are single heterozygotes, and double heterozygosity (DH) is a very rare finding. Here, we describe the case of a BRCA1/BRCA2 double heterozygous female proband diagnosed with breast cancer. Genetic testing for hereditary breast and ovarian cancer revealed two pathogenic variants in the BRCA1 (c.5095C>T, p.(Arg1699Trp)) and in BRCA2 genes (c.658_659delGT, p.(Val220Ilefs*4)) in heterozygous form. None of the variants were founder Jewish mutations; to our knowledge, these rare deleterious variants have not been previously described in DH patients in the literature. The patient had triple-negative unilateral breast cancer at the age of 36 and 44 years. Based on family studies, the BRCA1 variant was maternally inherited.
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Affiliation(s)
- László Madar
- Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (L.M.); (V.M.); (Z.S.); (O.N.)
- Doctoral School of Molecular Cell and Immune Biology, University of Debrecen, 4032 Debrecen, Hungary
| | - Viktória Majoros
- Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (L.M.); (V.M.); (Z.S.); (O.N.)
| | - Zsuzsanna Szűcs
- Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (L.M.); (V.M.); (Z.S.); (O.N.)
- Doctoral School of Molecular Cell and Immune Biology, University of Debrecen, 4032 Debrecen, Hungary
| | - Orsolya Nagy
- Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (L.M.); (V.M.); (Z.S.); (O.N.)
| | - Tamás Babicz
- Department of Oncoradiology, Nyíregyházi Jósa András Tagkórház, Szabolcs—Szatmár—Bereg County Teaching Hospital, 4400 Nyíregyháza, Hungary;
| | - Henriett Butz
- National Tumorbiology Laboratory Budapest, Department of Molecular Genetics, National Institute of Oncology, 1122 Budapest, Hungary; (H.B.); (A.P.)
| | - Attila Patócs
- National Tumorbiology Laboratory Budapest, Department of Molecular Genetics, National Institute of Oncology, 1122 Budapest, Hungary; (H.B.); (A.P.)
| | - István Balogh
- Department of Human Genetics, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary;
- Division of Clinical Genetics, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Katalin Koczok
- Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (L.M.); (V.M.); (Z.S.); (O.N.)
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Gastric Cancer Risk and Pathogenesis in BRCA1 and BRCA2 Carriers. Cancers (Basel) 2022; 14:cancers14235953. [PMID: 36497436 PMCID: PMC9736932 DOI: 10.3390/cancers14235953] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 11/29/2022] [Accepted: 11/30/2022] [Indexed: 12/03/2022] Open
Abstract
Carriers of a pathogenic germline variant (PV) in BRCA1 or BRCA2 are at increased risk for a number of malignancies, including breast, ovarian, pancreatic, and prostate cancer. In this review, we discuss emerging evidence that BRCA2 PV carriers, and likely also BRCA1 PV carriers, are also at increased risk for gastric cancer (GC), highlighting that GC may be part of the BRCA1/2 cancer risk spectrum. While the pathogenesis of GC among BRCA1/2 PV carriers remains unclear, increasing evidence reveals that GCs are often enriched with mutations in homologous recombination-associated genes such as BRCA1/2, and that GC prognosis and response to certain therapies can depend on BRCA1/2 expression. Given the strength of data published to date, a risk management strategy for GC among BRCA1/2 PV carriers is needed, and herein we also propose a potential strategy for GC risk management in this population. Moving forward, further study is clearly warranted to define the mechanistic relationship between BRCA1/2 PVs and development of GC as well as to determine how GC risk management should be factored into the clinical care of BRCA1/2 carriers.
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Złowocka-Perłowska E, Tołoczko-Grabarek A, Narod SA, Lubiński J. Germline BRCA1 and BRCA2 mutations and the risk of bladder or kidney cancer in Poland. Hered Cancer Clin Pract 2022; 20:13. [PMID: 35395863 PMCID: PMC8994347 DOI: 10.1186/s13053-022-00220-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 03/23/2022] [Indexed: 11/10/2022] Open
Abstract
INTRODUCTION The role of the BRCA1 and BRCA2 genes in bladder and renal tumorigenesis is unclear. Our goal was to determine the prevalence of specific founder mutations genes BRCA1 (5328 insC, C61G and 4153 delA) and BRCA2 (C5972T) mutations in bladder and kidney cancer patients from Poland. MATERIALS AND METHODS We genotyped 1028 patients with bladder cancer and 688 cases with kidney cancer and two control groups. RESULTS A BRCA1 mutation (all variants combined) was detected in peripheral blood leukocytes in 5 out of 1028 (0.5%) bladder cases and in 17 of 4000 controls (0.4%) (odds ratio [OR], (OR = 1.1; 95% CI 0.42-3.11; p = 1.0). Among 688 unselected kidney cancer cases a BRCA1 mutations was reported in three patients (0.4%) (OR = 1.0; 95% CI 0.29-3.51; p = 1.0). The mutation C5972T in BRCA2 was observed in 54 bladder cancer patients (5.2%) and in 159 of 2791 healthy controls (5.7%) (OR = 0.9; 95% CI 0.66-1.26; p = 0.6). Fifty kidney cancer cases carried a BRCA2 mutation (7.3%) (OR = 1.3; 95% CI 0.93-1.80; p = 0.1). CONCLUSION In conclusion, we found no difference in the prevalence of BRCA1 and BRCA2 founder mutations between cases and healthy controls. The mutations BRCA1 and BRCA2 seem not to play a role in bladder and kidney cancer development in Polish patients.
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Affiliation(s)
- Elżbieta Złowocka-Perłowska
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
| | - Aleksandra Tołoczko-Grabarek
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland
| | - Steven A Narod
- Women's College Research Institute, Women's College Hospital, University of Toronto, Toronto, Canada.,Dalla Lana School of Public Health, University of Toronto, Toronto, Canada
| | - Jan Lubiński
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland
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Maccaroni E, Giampieri R, Lenci E, Scortichini L, Bianchi F, Belvederesi L, Brugiati C, Pagliaretta S, Ambrosini E, Berardi R. BRCA mutations and gastrointestinal cancers: When to expect the unexpected? World J Clin Oncol 2021; 12:565-580. [PMID: 34367929 PMCID: PMC8317649 DOI: 10.5306/wjco.v12.i7.565] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 05/17/2021] [Accepted: 06/18/2021] [Indexed: 02/06/2023] Open
Abstract
BRCA1/2 pathogenic variants are widely known as major risk factors mainly for breast and ovarian cancer, while their role in gastrointestinal (GI) malignancies such as colorectal cancer (CRC), gastric cancer and oesophageal cancer (OeC) is still not well established. The main objective of this review is to summarise the available evidence on this matter. The studies included in the review were selected from PubMed/GoogleScholar/ScienceDirect databases to identify published articles where BRCA1/2 pathogenic variants were assessed either as a risk factor or a prognostic/predictive factor in these malignancies. Our review suggests that BRCA1/2 might have a role as a risk factor for colorectal, gastric and OeC, albeit with differences among these diseases: In particular BRCA1 seems to be much more frequently mutated in CRC whereas BRCA2 appears to be much more closely associated with gastric and OeC. Early-onset cancer seems to be also associated with BRCA1/2 mutations and a few studies suggest a positive prognostic role of these mutations. The assessment of a potentially predictive role of these mutations is hampered by the fact that most patients with these diseases have been treated with platinum compounds, where it is expected that a higher probability of response should be seen. A few clinical trials focused on poly (ADP-ribose) polymerase inhibitors use in GI cancers are currently ongoing.
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Affiliation(s)
- Elena Maccaroni
- Department of Oncology, Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona, Ancona 60126, Italy
| | - Riccardo Giampieri
- Department of Oncology, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona, Ancona 60126, Italy
| | - Edoardo Lenci
- Department of Oncology, Università Politecnica delle Marche, Ancona 60126, Italy
| | - Laura Scortichini
- Department of Oncology, Università Politecnica delle Marche, Ancona 60126, Italy
| | - Francesca Bianchi
- Molecular and Clinical Science Department, Università Politecnica delle Marche, Ancona 60126, Italy
| | - Laura Belvederesi
- Molecular and Clinical Science Department, Università Politecnica delle Marche, Ancona 60126, Italy
| | - Cristiana Brugiati
- Molecular and Clinical Science Department, Università Politecnica delle Marche, Ancona 60126, Italy
| | - Silvia Pagliaretta
- Molecular and Clinical Science Department, Università Politecnica delle Marche, Ancona 60126, Italy
| | - Elisa Ambrosini
- Molecular and Clinical Science Department, Università Politecnica delle Marche, Ancona 60126, Italy
| | - Rossana Berardi
- Department of Oncology, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona, Ancona 60126, Italy
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Abramov IS, Korneva YS, Shisterova OA, Ikonnikova AY, Emelyanova MA, Lisitsa TS, Krasnov GS, Nasedkina TV. Germline and Somatic Mutations in Archived Breast Cancer Specimens of Different Subtypes. Mol Biol 2021; 55:354-362. [DOI: 10.1134/s0026893321020163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 09/25/2020] [Accepted: 09/29/2020] [Indexed: 08/19/2024]
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BRCA1/2 Mutation Detection in the Tumor Tissue from Selected Polish Patients with Breast Cancer Using Next Generation Sequencing. Genes (Basel) 2021; 12:genes12040519. [PMID: 33918338 PMCID: PMC8065856 DOI: 10.3390/genes12040519] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 03/30/2021] [Accepted: 03/30/2021] [Indexed: 12/24/2022] Open
Abstract
(1) Background: Although, in the mutated BRCA detected in the Polish population of patients with breast cancer, there is a large percentage of recurrent pathogenic variants, an increasing need for the assessment of rare BRCA1/2 variants using NGS can be observed. (2) Methods: We studied 75 selected patients with breast cancer (negative for the presence of 5 mutations tested in the Polish population in the prophylactic National Cancer Control Program). DNA extracted from the cancer tissue of these patients was used to prepare a library and to sequence all coding regions of the BRCA1/2 genes. (3) Results: We detected nine pathogenic variants in 8 out of 75 selected patients (10.7%). We identified one somatic and eight germline variants. We also used different bioinformatic NGS software programs to analyze NGS FASTQ files and established that tertiary analysis performed with different tools was more likely to give the same outcome if we analyzed files received from secondary analysis using the same method. (4) Conclusions: Our study emphasizes (i) the importance of an NGS validation process with a bioinformatic procedure included; (ii) the importance of screening both somatic and germline pathogenic variants; (iii) the urgent need to identify additional susceptible genes in order to explain the high percentage of non-BRCA-related hereditary cases of breast cancer.
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8
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Renaud F, Svrcek M. [Hereditary gastric cancer: Challenges for the pathologist in 2020]. Ann Pathol 2020; 40:95-104. [PMID: 32147190 DOI: 10.1016/j.annpat.2020.02.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Revised: 01/26/2020] [Accepted: 02/05/2020] [Indexed: 12/24/2022]
Abstract
Gastric cancer is the third most common cancer worldwide. The majority of gastric cancers are sporadic but familial clustering is seen in more than 10% of cases. This manuscript is divided into two parts. The first part is dedicated to the non-syndromic hereditary gastric cancer, particularly the hereditary diffuse gastric cancer (HDGC) and other gastric polyposes including the recently described GAPPS (Gastric adenocarcinoma and proximal polyposis of the stomach). The second part concerns the syndromic gastric cancer, namely the HNPCC syndrome (Hereditary Non Polyposis Colorectal Cancer) occurring as part of a genetic predisposition syndrome to cancer. Recent advances in oncogenetics and next generation sequencing technology have enabled the identification of new entities. This enhancement in knowledge regarding inherited syndromes predisposing to gastric cancer has consequently improved the management of patients and their families. In this context, pathologists play a major role in identifying particular morphologic entities prompting genetic investigation. The aim of this manuscript is to provide an update on the current knowledge about hereditary gastric cancer.
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Affiliation(s)
- Florence Renaud
- Sorbonne université, Inserm, unité Mixte de Recherche Scientifique 938, SIRIC CURAMUS, centre de recherche Saint-Antoine, équipe instabilité des microsatellites et cancer, équipe labellisée par la Ligue Nationale contre le cancer, 75012 Paris, France; Service d'anatomie et cytologie pathologiques, hôpital Saint-Antoine, AP-HP, 184, rue du Faubourg-Saint-Antoine, 75571 Paris cedex 12, France.
| | - Magali Svrcek
- Sorbonne université, Inserm, unité Mixte de Recherche Scientifique 938, SIRIC CURAMUS, centre de recherche Saint-Antoine, équipe instabilité des microsatellites et cancer, équipe labellisée par la Ligue Nationale contre le cancer, 75012 Paris, France; Service d'anatomie et cytologie pathologiques, hôpital Saint-Antoine, AP-HP, 184, rue du Faubourg-Saint-Antoine, 75571 Paris cedex 12, France
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Goehringer C, Sutter C, Kloor M, Gebert J, Slater EP, Keller M, Treiber I, Ganschow P, Kadmon M, Moog U. Double germline mutations in APC and BRCA2 in an individual with a pancreatic tumor. Fam Cancer 2017; 16:303-309. [PMID: 27838800 DOI: 10.1007/s10689-016-9952-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
We report on three brothers affected by pancreatic tumors, all due to different causes, including mutations associated with two different cancer predisposition syndromes in the same individual. In the index patient a germline mutation both in the APC and BRCA2 gene was identified while one affected brother showed the BRCA2 mutation only and another brother is supposed to have developed pancreatic cancer due to multiple non-genetic risk factors. We outline the impact of a double germline mutation in two tumor predisposition genes in one individual and proven heterogeneity of multiple cases of pancreatic tumors in one family. With the growing implementation of next generation sequence based panel testing for multiple genes involved in tumor predisposition syndromes, relevant variants in two (or more) genes will be found more frequently. This family illustrates the importance of family studies, especially when using gene panel tests.
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Affiliation(s)
- Caroline Goehringer
- Institute of Human Genetics, Heidelberg University, Im Neuenheimer Feld 440, 69120, Heidelberg, Germany.
| | - Christian Sutter
- Institute of Human Genetics, Heidelberg University, Im Neuenheimer Feld 440, 69120, Heidelberg, Germany
| | - Matthias Kloor
- Department of Applied Tumor Biology, Institute of Pathology, Heidelberg University, Im Neuenheimer Feld 220/221, 69120, Heidelberg, Germany
| | - Johannes Gebert
- Department of Applied Tumor Biology, Institute of Pathology, Heidelberg University, Im Neuenheimer Feld 220/221, 69120, Heidelberg, Germany
| | - Emily P Slater
- Department of Surgery, Philipps-University Marburg, Baldingerstraße, 35043, Marburg, Germany
| | - Monika Keller
- Department of Psychosomatic and General Clinical Medicine, Heidelberg University, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
| | - Irmgard Treiber
- Department of General Surgery, Heidelberg University, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany
| | - Petra Ganschow
- Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Hospital of the University of Munich, Marchioninistraße 15, 81377, Munich, Germany
| | - Martina Kadmon
- Faculty of Medicine and Health Sciences, University of Oldenburg, Carl-von-Ossietzky-Str. 9-11, 26129, Oldenburg, Germany
| | - Ute Moog
- Institute of Human Genetics, Heidelberg University, Im Neuenheimer Feld 440, 69120, Heidelberg, Germany
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Ławniczak M, Jakubowska A, Białek A, Lubiński J, Jaworska-Bieniek K, Kaczmarek K, Starzyńska T. BRCA1 founder mutations do not contribute to increased risk of gastric cancer in the Polish population. Hered Cancer Clin Pract 2016; 14:3. [PMID: 26779294 PMCID: PMC4714446 DOI: 10.1186/s13053-015-0043-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Accepted: 12/14/2015] [Indexed: 12/20/2022] Open
Abstract
Background Gastric cancer (GC) is part of the spectrum of diseases linked to BRCA1 and BRCA2 mutations that increase the risk of breast and ovarian cancer. Data suggesting an increased risk of developing GC among BRCA1 and BRCA2 mutation carriers are based almost exclusively on indirect studies. The objective was to assess in a direct study whether there is a relationship between GC and selected recurrent BRCA1 and BRCA2 mutations in the Polish population. Methods Three hundred seventeen GC patients (193 males and 124 females; mean age 59.5 ± 12.8 y) diagnosed at the Department of Gastroenterology at the Pomeranian Medical University were included in this retrospective study. All patients were genotyped for 3 BRCA1 Polish founder mutations (5382insC, C61G and 4153delA) as well as for 9 known recurrent mutations in BRCA1 and BRCA2 genes. Genotyping was performed using allele-specific oligonucleotide polymerase chain reaction (ASA-PCR) for 4153delA and 5382insC, restriction fragment length polymorphism (PCR-RFLP) for C61G and TaqMan real-time PCR for 185delAG, 3819del5, 3875del4, 5370C > T, 886delGT, 4075delGT, 5467insT, 6174delT and 8138del5. Results Among tested mutations one founder BRCA1 mutation 5382insC was detected in two of 317 (0.63 %) GC cases. A comparison of frequency of detected BRCA1 founder mutations in GC patients to previously described 4570 Polish controls (0.63 % vs. 0.48 %) failed to indicate an increased risk of GC in the mutation carriers (OR = 1.3; 95 % CI 0.3-5.6, p = 0.71). A comparison of frequency of GC male cases and male controls (1.0 % vs. 0.43 %,OR = 1.5; 95 % CI 0.3-6.4, p = 0.61) allowed to formulate the same conclusion that there is no increased risk for GC for males. None of the 9 recurrent BRCA1 and BRCA2 mutations has been detected in tested GC patients. Conclusion The current study indicates that founder BRCA1 mutations reported in Polish breast/ovarian cancer patients do not contribute to increased GC risk. The nine tested recurrent BRCA1 and BRCA2 mutations were not detected in GC patients which may suggests that they are rare in GC patients in the Polish population. Further analyses, including sequencing of entire sequences of BRCA1 and BRCA2 genes, are necessary to ultimately determine the role of these two genes in GC in Poland.
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Affiliation(s)
- Małgorzata Ławniczak
- Department of Gastroenterology, Pomeranian Medical University, Unii Lubelskiej 1, Szczecin, 71-252 Poland
| | - Anna Jakubowska
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Połabska 4, Szczecin, 70-115 Poland
| | - Andrzej Białek
- Department of Gastroenterology, Pomeranian Medical University, Unii Lubelskiej 1, Szczecin, 71-252 Poland
| | - Jan Lubiński
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Połabska 4, Szczecin, 70-115 Poland
| | - Katarzyna Jaworska-Bieniek
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Połabska 4, Szczecin, 70-115 Poland
| | - Katarzyna Kaczmarek
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Połabska 4, Szczecin, 70-115 Poland
| | - Teresa Starzyńska
- Department of Gastroenterology, Pomeranian Medical University, Unii Lubelskiej 1, Szczecin, 71-252 Poland
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van der Post RS, Gullo I, Oliveira C, Tang LH, Grabsch HI, O'Donovan M, Fitzgerald RC, van Krieken H, Carneiro F. Histopathological, Molecular, and Genetic Profile of Hereditary Diffuse Gastric Cancer: Current Knowledge and Challenges for the Future. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 908:371-91. [PMID: 27573781 DOI: 10.1007/978-3-319-41388-4_18] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Familial clustering is seen in 10 % of gastric cancer cases and approximately 1-3 % of gastric cancer arises in the setting of hereditary diffuse gastric cancer (HDGC). In families with HDGC, gastric cancer presents at young age. HDGC is predominantly caused by germline mutations in CDH1 and in a minority by mutations in other genes, including CTNNA1. Early stage HDGC is characterized by a few, up to dozens of intramucosal foci of signet ring cell carcinoma and its precursor lesions. These include in situ signet ring cell carcinoma and pagetoid spread of signet ring cells. Advanced HDGC presents as poorly cohesive/diffuse type carcinoma, normally with very few typical signet ring cells, and has a poor prognosis. Currently, it is unknown which factors drive the progression towards aggressive disease, but it is clear that most intramucosal lesions will not have such progression.Immunohistochemical profile of early and advanced HDGC is often characterized by abnormal E-cadherin immunoexpression, including absent or reduced membranous expression, as well as "dotted" or cytoplasmic expression. However, membranous expression of E-cadherin does not exclude HDGC. Intramucosal HDGC (pT1a) presents with an "indolent" phenotype, characterized by typical signet ring cells without immunoexpression of Ki-67 and p53, while advanced carcinomas (pT > 1) display an "aggressive" phenotype with pleomorphic cells, that are immunoreactive for Ki-67 and p53. These features show that the IHC profile is different between intramucosal and more advanced HDGC, providing evidence of phenotypic heterogeneity, and may help to define predictive biomarkers of progression from indolent to aggressive, widely invasive carcinomas.
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Affiliation(s)
- Rachel S van der Post
- Department of Pathology, Radboud University Medical Centre, 9101, Nijmegen, 6500 HB, The Netherlands
| | - Irene Gullo
- Department of Pathology, Centro Hospitalar de São João, Al. Prof. Hernâni Monteiro, Porto, 4200-319, Portugal.,Department of Pathology and Oncology, Faculdade de Medicina da Universidade do Porto (FMUP), Al. Prof. Hernâni Monteiro, Porto, 4200-319, Portugal.,Instituto de Patologia e Imunologia Molecular da Universidade do Porto (Ipatimup), Porto, Portugal and Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Dr. Roberto Frias S/N, Porto, 4200-465, Portugal
| | - Carla Oliveira
- Department of Pathology, Centro Hospitalar de São João, Al. Prof. Hernâni Monteiro, Porto, 4200-319, Portugal.,Department of Pathology and Oncology, Faculdade de Medicina da Universidade do Porto (FMUP), Al. Prof. Hernâni Monteiro, Porto, 4200-319, Portugal
| | - Laura H Tang
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY, 10065, USA
| | - Heike I Grabsch
- GROW School of Oncology and Developmental Biology and Department of Pathology, Maastricht University Medical Centre, Peter Debyelaan 25, Maastricht, 6229 HX, The Netherlands
| | - Maria O'Donovan
- Department of Histopathology, Cambridge University Hospitals NHS Trust, Cambridge, CB2 0QQ, UK
| | - Rebecca C Fitzgerald
- MRC Cancer Unit, Hutchison-MRC Research Centre, University of Cambridge, 197, Biomedical Campus, Cambridge, CB2 0XZ, UK
| | - Han van Krieken
- Department of Pathology, Radboud University Medical Centre, 9101, Nijmegen, 6500 HB, The Netherlands
| | - Fátima Carneiro
- Department of Pathology, Centro Hospitalar de São João, Al. Prof. Hernâni Monteiro, Porto, 4200-319, Portugal. .,Department of Pathology and Oncology, Faculdade de Medicina da Universidade do Porto (FMUP), Al. Prof. Hernâni Monteiro, Porto, 4200-319, Portugal. .,Instituto de Patologia e Imunologia Molecular da Universidade do Porto (Ipatimup), Porto, Portugal and Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Dr. Roberto Frias S/N, Porto, 4200-465, Portugal.
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12
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Cavanagh H, Rogers KMA. The role of BRCA1 and BRCA2 mutations in prostate, pancreatic and stomach cancers. Hered Cancer Clin Pract 2015; 13:16. [PMID: 26236408 PMCID: PMC4521499 DOI: 10.1186/s13053-015-0038-x] [Citation(s) in RCA: 85] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Accepted: 07/28/2015] [Indexed: 02/07/2023] Open
Abstract
The association of germline mutations in the breast cancer susceptibility gene 1 (BRCA1) and the breast cancer susceptibility gene 2 (BRCA2) with the development of breast and ovarian cancers have been widely researched and recognised. It is known that these genes function at multiple sites in the body. Research has subsequently evolved into the connection of BRCA1/2 with cancers at other sites within the body. This review examines the association of BRCA1/2 germline gene mutations with prostate, pancreatic and stomach cancers. An extensive literature search revealed conflicting findings regarding the association of BRCA1/2 gene mutations with these cancers. Most studies suggest that there is an association between BRCA1/2 mutations and carcinoma of the prostate, pancreas and stomach, but some reports propose that such a correlation may be due to factors other than possessing a mutated BRCA1/2 gene, and other associations may be revealed as further epidemiological information becomes available. The review concludes that as more knowledge arises about the mechanisms of BRCA1/2 gene mutations, it should pave the way for future screening programmes to be applied effectively.
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Affiliation(s)
- Helen Cavanagh
- School of Nursing and Midwifery, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL N. Ireland
| | - Katherine M A Rogers
- School of Nursing and Midwifery, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL N. Ireland
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13
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Oliveira C, Pinheiro H, Figueiredo J, Seruca R, Carneiro F. Familial gastric cancer: genetic susceptibility, pathology, and implications for management. Lancet Oncol 2015; 16:e60-70. [PMID: 25638682 DOI: 10.1016/s1470-2045(14)71016-2] [Citation(s) in RCA: 276] [Impact Index Per Article: 27.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Familial gastric cancer comprises at least three major syndromes: hereditary diffuse gastric cancer, gastric adenocarcinoma and proximal polyposis of the stomach, and familial intestinal gastric cancer. The risk of development of gastric cancer is high in families affected b-y these syndromes, but only hereditary diffuse gastric cancer is genetically explained (caused by germline alterations of CDH1, which encodes E-cadherin). Gastric cancer is also associated with a range of several cancer-associated syndromes with known genetic causes, such as Lynch, Li-Fraumeni, Peutz-Jeghers, hereditary breast-ovarian cancer syndromes, familial adenomatous polyposis, and juvenile polyposis. We present contemporary knowledge on the genetics, pathogenesis, and clinical features of familial gastric cancer, and discuss research and technological developments, which together are expected to open avenues for new genetic testing approaches and novel therapeutic strategies.
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Affiliation(s)
- Carla Oliveira
- Ipatimub-Institute of Molecular Pathology and Immunology & Instituto Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal; Department of Pathology and Oncology, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Hugo Pinheiro
- Ipatimub-Institute of Molecular Pathology and Immunology & Instituto Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal
| | - Joana Figueiredo
- Ipatimub-Institute of Molecular Pathology and Immunology & Instituto Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal
| | - Raquel Seruca
- Ipatimub-Institute of Molecular Pathology and Immunology & Instituto Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal; Department of Pathology and Oncology, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Fátima Carneiro
- Ipatimub-Institute of Molecular Pathology and Immunology & Instituto Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal; Department of Pathology and Oncology, Faculty of Medicine, University of Porto, Porto, Portugal; Centro Hospitalar S João, Porto, Portugal.
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14
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Bardram L, Hansen TVO, Gerdes AM, Timshel S, Friis-Hansen L, Federspiel B. Prophylactic total gastrectomy in hereditary diffuse gastric cancer: identification of two novel CDH1 gene mutations-a clinical observational study. Fam Cancer 2015; 13:231-42. [PMID: 24389957 DOI: 10.1007/s10689-013-9698-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Inactivating mutations in the CDH1 (E-cadherin) gene are the predisposing cause of gastric cancer in most families with hereditary diffuse gastric cancer (HDGC). The lifetime risk of cancer in mutation positive members is more than 80 % and prophylactic total gastrectomy is recommended. Not all mutations in the CDH1 gene are however pathogenic and it is important to classify mutations before this major operation is performed. Probands from two Danish families with gastric cancer and a history suggesting HDGC were screened for CDH1 gene mutations. Two novel CDH1 gene mutations were identified and found pathogenic. In silico and mini-gene assay were used to predict the functional consequence in one of them. Mutation carriers were offered endoscopy and total gastrectomy. The gastric specimens were completely sectioned and examined histologically. Seven asymptomatic mutation carriers were operated. Hospital stay was 6-8 days and there were no complications. Small foci of diffuse gastric cancer were found in all patients-intramucosal in six and advanced in one. Preoperative endoscopic biopsies had revealed a microscopic cancer focus in two of the patients. Our data confirmed the pathogenic nature of both mutations and strongly support the recommendation of total gastrectomy in asymptomatic CDH1 gene mutation carriers. The functional consequences of novel CDH1 gene mutations with uncertain effects should be tested before correct advice and treatment can be given.
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Affiliation(s)
- Linda Bardram
- Department of Surgical Gastroenterology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100, Copenhagen, Denmark,
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15
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HNF4A immunohistochemistry facilitates distinction between primary and metastatic breast and gastric carcinoma. Virchows Arch 2014; 464:673-9. [PMID: 24711169 DOI: 10.1007/s00428-014-1574-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2013] [Revised: 02/16/2014] [Accepted: 03/20/2014] [Indexed: 12/12/2022]
Abstract
The distinction between primary gastric adenocarcinoma and gastric metastatic breast carcinoma can be difficult. Expression of hepatocyte nuclear factor 4A (HNF4A) has been described as being specific to distinguish between neoplastic gastric and breast epithelial cells. The aim of this study was to validate the use of HNF4A with immunohistochemistry in discriminating gastric from breast carcinomas. Immunohistochemical expressions of HNF4A, estrogen receptor (ER), progesterone receptor (PR), and BRST-2 were determined in primary sporadic gastric adenocarcinomas (n = 107) and breast carcinomas (n = 105). The same markers and clinicopathological features were studied in 1 patient with breast metastasis of gastric cancer, 6 patients with gastric metastases of breast cancer, and 13 patients with both primary gastric and breast carcinomas. HNF4A expression was seen in 106 of 107 primary gastric adenocarcinomas and was absent in all 105 primary breast carcinomas (sensitivity 99 %, specificity 100 %). ER, PR, and BRST-2 were 100 % specific for breast carcinomas with sensitivities of 77, 58, and 38 %, respectively. The metastasis of gastric carcinoma to the breast showed strong expression of HNF4A. None of the metastases of breast carcinomas to the stomach showed expression of HNF4A. Tissues of patients with two primary carcinomas showed strong expression of HNF4A in all gastric carcinomas and no expression in breast carcinomas. Our results indicate that HNF4A is a very good marker to discriminate between primary and metastatic gastric and breast carcinomas.
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16
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Szwiec M, Jakubowska A, Górski B, Huzarski T, Tomiczek-Szwiec J, Gronwald J, Dębniak T, Byrski T, Kluźniak W, Wokołorczyk D, Birkenfeld B, Akbari MR, Narod SA, Lubiński J, Cybulski C. Recurrent mutations of BRCA1 and BRCA2 in Poland: an update. Clin Genet 2014; 87:288-92. [PMID: 24528374 DOI: 10.1111/cge.12360] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2013] [Revised: 02/10/2014] [Accepted: 02/12/2014] [Indexed: 11/27/2022]
Abstract
Three founder alleles of BRCA1 (C61G, 4153delA, 5382insC) were reported in Poland in 2000, and these three mutations have comprised the standard testing panel used throughout the country. However, since 2000, other recurrent mutations of BRCA1 and BRCA2 have been reported. To establish if the inclusion of one or more of these mutations will increase the sensitivity of the standard test panel, we studied 1164 Polish women with unselected breast cancer diagnosed at age of 50 or below. All women were genotyped for 12 recurrent mutations of BRCA1 and BRCA2. We identified a mutation in 83 of 1164 patients (7.1%) including 61 women with one of the original three mutations (C61G, 4153delA, 5382insC) and 22 women with a different mutation (1.9%). Three new mutations (3819del5, 185delAG and 5370C>T) were seen in multiple families. By including these three mutations in the extended panel, the mutant frequency increased from 5.2 to 6.7%. Polish women with breast cancer diagnosed at age of 50 or below should be screened with a panel of six founder mutations of BRCA1 (C61G, 4153delA, 5382insC, 3819del5, 185delAG and 5370C>T).
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Affiliation(s)
- M Szwiec
- Department of Clinical Oncology, Tadeusz Koszarowski Regional Oncology Center, Opole, Poland
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17
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Incidence of colorectal cancer in BRCA1 and BRCA2 mutation carriers: results from a follow-up study. Br J Cancer 2013; 110:530-4. [PMID: 24292448 PMCID: PMC3899769 DOI: 10.1038/bjc.2013.741] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2013] [Revised: 10/22/2013] [Accepted: 10/25/2013] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The BRCA1 and BRCA2 genes confer increased susceptibility to breast and ovarian cancer and to a spectrum of other cancers. There is controversy regarding the risk of colorectal cancer conferred by germline mutations in these two genes. METHODS We followed 7015 women with a BRCA mutation for new cases of colorectal cancer. Incidence rates in carriers were compared with population-specific incidence rates, and standardised incidence ratios (SIRs) were estimated. The expected numbers of cancers were computed by multiplying person-years at risk by the appropriate age-, sex- and country-specific incidence rates from the five countries. RESULTS Twenty-one incident colorectal cancer cases were observed among all mutation carriers, compared with 23.6 cases expected. The SIR for BRCA1 carriers was 0.92 (95% confidence interval (CI), 0.54-1.40, P=0.7) and for BRCA2 carriers was 0.82 (95% CI, 0.30-1.81, P=0.7). The SIR for colon cancer was 3.81 (95% CI 1.77-7.23) for women below the age of 50 years (both genes combined) and was 0.60 (95% CI 0.33-1.00) for women aged 50 years and above. CONCLUSION The risk of colorectal cancer is increased in female carriers of BRCA1 mutations below the age of 50 years but not in women with BRCA2 mutations or in older women.
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Abstract
In 1998, Guilford et al. identified the hereditary diffuse gastric cancer (HDGC) syndrome, caused by germline alterations at the CDH1 (E-cadherin) gene. To date, 141 probands harboring more than 100 different germline CDH1 alterations, mainly point mutations and large deletions, have been described. In mutation-positive individuals prophylactic total gastrectomy is recommended. The systematic histological study of prophylactic gastrectomies shows intramucosal signet-ring cell carcinoma and pre-invasive lesions including in situ signet ring carcinoma with pagetoid spread of signet ring cells. In 2011, a new hereditary gastric cancer syndrome was identified: gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). GAPPS is a unique gastric polyposis syndrome with a significant risk of gastric adenocarcinoma, characterized by the autosomal dominant transmission of fundic gland polyposis, with areas of dysplasia or intestinal-type GC, restricted to the proximal stomach, with no evidence of colorectal or duodenal polyposis or other heritable gastrointestinal cancer syndromes.
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Berzina D, Nakazawa-Miklasevica M, Zestkova J, Aksenoka K, Irmejs A, Gardovskis A, Kalniete D, Gardovskis J, Miklasevics E. BRCA1/2 mutation screening in high-risk breast/ovarian cancer families and sporadic cancer patient surveilling for hidden high-risk families. BMC MEDICAL GENETICS 2013; 14:61. [PMID: 23767878 PMCID: PMC3686592 DOI: 10.1186/1471-2350-14-61] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/06/2012] [Accepted: 06/11/2013] [Indexed: 11/10/2022]
Abstract
BACKGROUND The estimated ratio of hereditary breast/ovarian cancer (HBOC) based on family history is 1.5% in Latvia. This is significantly lower than the European average of 5-10%. Molecular markers like mutations and SNPs can help distinguish HBOC patients in the sporadic breast and ovarian cancer group. METHODS 50 patients diagnosed with HBOC in the Latvian Cancer Registry from January 2005 to December 2008 were screened for BRCA1 founder mutation-negatives and subjected to targeted resequencing of BRCA1 and BRCA2 genes. The newly found mutations were screened for in the breast and ovarian cancer group of 1075 patients by Real Time-PCR/HRM analysis and RFLP. RESULTS Four BRCA2 mutations including three novel BRCA2 frameshift mutations and one previously known BRCA2 frameshift mutation and one BRCA1 splicing mutation were identified. Two of the BRCA2 mutations were found in a group of consecutive breast cancer patients with a frequency of 0.51% and 0.38%. CONCLUSIONS Molecular screening of sequential cancer patients is an important tool to identify HBOC families.
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Affiliation(s)
- Dace Berzina
- Institute of Oncology, Riga Stradins University, Dzirciema Street 16, LV1007 Riga, Latvia
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20
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Abstract
Gastric cancer is a global public health concern, ranking as the fourth leading cause of cancer mortality, with a 5-year survival of only 20%. Approximately 10% of gastric cancers appear to have a familial predisposition, and about half of these can be attributed to hereditary germline mutations. We review the genetic syndromes and current standards for genetic counseling, testing, and medical management for screening and treatment of gastric cancer. Recently, germline mutations in the E-cadherin/CDH1 gene have been identified in families with an autosomal dominant inherited predisposition to gastric cancer of the diffuse type. The cumulative lifetime risk of developing gastric cancer in CDH1 mutation carriers is up to 80%, and women from these families also have an increased risk for developing lobular breast cancer. Prophylactic gastrectomies are recommended in unaffected CDH1 mutation carriers, because screening endoscopic examinations and blind biopsies have proven inadequate for surveillance. In addition to this syndrome, gastric cancer risk is elevated in Lynch syndrome associated with germline mutations in DNA mismatch repair genes and microsatellite instability, in hereditary breast and ovarian cancer syndrome due to germline BRCA1 and BRCA2 mutations, in familial adenomatous polyposis caused by germline APC mutations, in Li-Fraumeni syndrome due to germline p53 mutations, in Peutz-Jeghers syndrome associated with germline STK11 mutations, and in juvenile polyposis syndrome associated with germline mutations in the SMAD4 and BMPR1A genes. Guidelines for genetic testing, counseling, and management of individuals with hereditary diffuse gastric cancer are suggested. A raised awareness among the physician and genetic counseling communities regarding these syndromes may allow for increased detection and prevention of gastric cancers in these high-risk individuals.
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21
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Rodríguez AO, Llacuachaqui M, Pardo GG, Royer R, Larson G, Weitzel JN, Narod SA. BRCA1 and BRCA2 mutations among ovarian cancer patients from Colombia. Gynecol Oncol 2011; 124:236-43. [PMID: 22044689 DOI: 10.1016/j.ygyno.2011.10.027] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2011] [Revised: 10/21/2011] [Accepted: 10/25/2011] [Indexed: 12/21/2022]
Abstract
OBJECTIVE The contribution of BRCA1 and BRCA2 mutations to ovarian cancer in Colombia has not yet been explored. Five founder mutations have been identified in two previous studies of breast cancer patients in the Bogota region [1,2]. It is important that the frequency of mutations be established among unselected cases of ovarian cancer in order to estimate the genetic burden of this cancer in Colombia and to plan genetic and preventive services. METHODS We enrolled 100 unselected women with ovarian cancer from the Bogota region, and from northern and southern central regions of Colombia. A detailed family history was obtained from each patient and a blood sample was processed for DNA analysis. DNA quality was adequate for BRCA testing for 96 women. Mutations in BRCA1 and BRCA2 were sought using a Hispanic BRCA mutation testing panel. All mutations were confirmed by direct sequencing. RESULTS Fifteen mutations were identified (two in BRCA2 and thirteen in BRCA1) representing 15.6% of the total (95% CI: 7.8% to 21.3%). Among the 15 mutation-positive families there were nine breast-ovarian cancer families, one gastric cancer family, one prostate cancer family, three uterine cancer families, and one family with no history of cancer. A single founder mutation in BRCA1 (3450del4) was seen in 11 patients. CONCLUSION In summary, BRCA1 founder mutations are common in Colombian women with ovarian cancer. Approximately 11.5% of all ovarian cancer cases in the Bogota region are attributable to a single BRCA1 founder mutation.
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22
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Gutiérrez Espeleta GA, Llacuachaqui M, García-Jiménez L, Aguilar Herrera M, Loáiciga Vega K, Ortiz A, Royer R, Li S, Narod SA. BRCA1andBRCA2mutations among familial breast cancer patients from Costa Rica. Clin Genet 2011; 82:484-8. [DOI: 10.1111/j.1399-0004.2011.01774.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
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Kaufman B, Laitman Y, Gronwald J, Lubinski J, Friedman E. Haplotype of the C61G BRCA1 mutation in Polish and Jewish individuals. Genet Test Mol Biomarkers 2009; 13:465-9. [PMID: 19594371 DOI: 10.1089/gtmb.2009.0001] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Recurring mutations in the BRCA1 gene are noted in some populations and represent either founder mutations or a mutational hot spot. The C61G*BRCA1 (c.181T>G) missense mutation is a pathogenic one commonly reported in Polish individuals. A Jewish non-Ashkenazi family (of Italian ancestry) was found to carry this mutation, and the present study aimed at evaluating whether this mutation represents a founder mutation or a mutational hot spot. To that end, multilocus allelotyping using five markers intragenic to and flanking the BRCA1 gene spanning a genomic region of approximately 1.5 Mbp was carried out in that family and in 20 unrelated Polish C61G*BRCA1 mutation carriers. Phasing was done using affected and unaffected Jewish family members. The alleles that compose the pathogenic, mutation-carrying intragenic BRCA1 haplotype of the Jewish mutation carriers were detected in 18/20 Polish mutation carriers. The two flanking markers farthest away showed more diversity, between and even within Polish individuals. In conclusion, the *BRCA1 missense mutation is a founder mutation that can be detected in geographically related populations.
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Affiliation(s)
- Bella Kaufman
- Institute of Oncology, Chaim Sheba Medical Center, Tel-Hashomer, Israel
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Abstract
Gastric cancer is a heterogeneous and highly prevalent disease, being the fourth most common cancer and the second leading cause of cancer associated death worldwide. Most cases are sporadic and familial clustering is observed in about 10% of the cases. Hereditary gastric cancer accounts for a very low percentage of cases (1-3%) and a single hereditary syndrome - Hereditary Diffuse Gastric Cancer (HDGC) - has been characterised. Among families that fulfil the clinical criteria for HDGC, about 40% carry CDH1 germline mutations, the genetic cause of the others being unknown. The management options for CDH1 asymptomatic germline carriers are intensive endoscopic surveillance and prophylactic gastrectomy. In this chapter we review the pathophysiology and clinicopathological features of HDGC and discuss issues related with genetic testing and management of family members.
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Affiliation(s)
- Carla Oliveira
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal.
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25
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Gronwald J, Byrski T, Huzarski T, Oszurek O, Janicka A, Szymanska-Pasternak J, Górski B, Menkiszak J, Rzepka-Górska I, Lubinski J. Hereditary breast and ovarian cancer. Hered Cancer Clin Pract 2008; 6:88-98. [PMID: 19804604 PMCID: PMC2735784 DOI: 10.1186/1897-4287-6-2-88] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Affiliation(s)
- Jacek Gronwald
- International Hereditary Cancer Centre, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
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Abstract
Gastric cancer is relatively common worldwide, mainly in its sporadic form, but familial aggregation of the disease may be seen in approximately 10% of the cases. This suggests a genetic cause for the cancer in those families that has not been identified in most cases. Despite all efforts to determine its genetic basis, a single syndrome has been characterized-the hereditary diffuse gastric cancer (HDGC)-which is specifically associated with CDH1 (E-cadherin) germline mutations in one third of the families. The other two thirds and all the gastric cancer families not fulfilling the HDGC criteria remain without molecular diagnosis. In this article we review the state of the art of familial gastric cancer regarding the molecular aspects, the clinical criteria, the pathology features, and the management recommendations described so far to be associated with this cancer disease.
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Affiliation(s)
- Carla Oliveira
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
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27
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Abstract
This article is based upon a literature overview of cancer in Jews. It involves a comparison of variation in incidence and prevalence rates between Jews and non-Jews. However, the reader must exercise a certain amount of skepticism when considering secular changes in cancer incidence and prevalence and the public health implications of such cancer variation. Ashkenazi Jews have a lifetime CRC risk of 9--15%. This elevated CRC risk is similar to that of individuals in the "familial risk'' category, and differs strikingly from the 5-6% CRC risk for non-Ashkenazi members of general Western populations. A MedLine search tested the hypothesis that site-specific and/or all-cancer incidence and mortality rates are either higher or lower than expected in Ashkenazi Jews worldwide, when compared with reference populations. Results showed that all cancer incidence and mortality is not higher in Ashkenazi Jews when compared to North American non-Hispanic whites. Indeed, rates for some cancers, such as carcinoma of the lung in Ashkenazi males, are low; this example is likely attributable in large part to decreased tobacco use. Carcinoma of the ovary, pancreas, stomach, and non-Hodgkin's lymphoma have a higher incidence rate in Ashkenazi. Even though BRCA1 and BRCA2 founder mutations which predispose to carcinoma of the breast and ovary appear increased in Ashkenazi breast cancer affected women, there was no evidence supporting an elevated risk of breast cancer among Ashkenazi women. Our primary concern, however, is that Ashkenazi Jews may have one of the highest lifetime CRC risks of any ethnic group in the world, a risk that diverges significantly from that of the general population; therein, it logically calls for more intensive CRC screening guidelines. We have emphasized that the reader use caution in the interpretation of statistics which portray variation in incidence and prevalence figures for cancer in any racial, ethnic, or religious group, inclusive, of course, of Jews. Clearly, more research will be required in the interest of accuracy in the understanding of these cancer variations, since they portend the need for special cancer control strategies. A lesser degree of attention can then be given to carcinoma of the penis and uterine cervix, which occur very infrequently in Jews. We urge our colleagues to continue to probe further into these statistical differences in cancer's incidence and prevalence in order to garner a better understanding of cancer's etiology and pathogenesis.
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Affiliation(s)
- Henry T Lynch
- Department of Preventive Medicine and Public Health, Creighton University School of Medicine, 2500 California Plaza, Omaha, NE 68131, USA.
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Królewska K, Jakubowska A, Zajaczek S. Breast Cancers with Ocular Metastases are Early Onset, Non-Familial and Non-BRCA1/BRCA2 Tumours. Hered Cancer Clin Pract 2004; 2:45-6. [PMID: 20233483 PMCID: PMC2839993 DOI: 10.1186/1897-4287-2-1-45] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2003] [Accepted: 12/22/2003] [Indexed: 11/10/2022] Open
Affiliation(s)
- Katarzyna Królewska
- Department of Genetics and Pathology - International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
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29
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Oliveira C, Suriano G, Ferreira P, Canedo P, Kaurah P, Mateus R, Ferreira A, Ferreira AC, Oliveira MJ, Figueiredo C, Carneiro F, Keller G, Huntsman D, Machado JC, Seruca R. Genetic screening for familial gastric cancer. Hered Cancer Clin Pract 2004; 2:51-64. [PMID: 20233471 PMCID: PMC2839995 DOI: 10.1186/1897-4287-2-2-51] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2004] [Accepted: 05/16/2004] [Indexed: 12/21/2022] Open
Abstract
Approximately 10% of gastric cancer cases show familial clustering but only 1-3% of gastric carcinomas arise as a result of inherited gastric cancer predisposition syndromes. Direct proof that Hereditary Gastric Cancer a genetic disease with a germline gene defect has come from the demonstration of co-segregation of germline E-cadherin (CDH1) mutations with early onset diffuse gastric cancer in families with an autosomal dominant pattern of inheritance (HDGC). E-cadherin is a transmembrane calcium-dependent cell-adhesion molecule involved in cell-junction formation and the maintenance of epithelial integrity. In this review, we describe frequency and type of CDH1 mutations in sporadic and familial gastric cancer. Further we demonstrate the functional significance of some CDH1 germline missense mutations found in HDGC. We also discuss the CDH1 polymorphisms that have been associated to gastric cancer. We report other types of malignancies associated to HDGC, besides diffuse gastric cancer. Moreover, we review the data available on putative alternative candidate genes screened in familial gastric cancer. Finally, we briefly discuss the role of low-penetrance genes and Helicobacter pylori in gastric cancer. This knowledge is a fundamental step towards accurate genetic counselling, in which a highly specialised pre-symptomatic therapeutic intervention should be offered.
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Affiliation(s)
- Carla Oliveira
- Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, Portugal.
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