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Kozak M, Negrete D, Balzer BL, Gaddam S, Guindi M, Hutchings DA, Larson BK, Waters KM. Analysis of the Application of Professional Society Screening Guidelines for Colorectal Polyposis Syndromes at a Single Institution. Mod Pathol 2024; 37:100567. [PMID: 39025407 DOI: 10.1016/j.modpat.2024.100567] [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: 04/10/2024] [Revised: 07/03/2024] [Accepted: 07/11/2024] [Indexed: 07/20/2024]
Abstract
Several professional society guidelines suggest germline genetic testing for colorectal polyposis syndromes in patients with ≥10 lifetime adenomatous polyps. This study evaluated the factors associated with genetic testing decisions and outcomes when germline testing was recommended per guidelines. Surgical archives revealed 145 patients with a recommendation for germline genetic polyposis testing based on guidelines. Demographic data and medical history were collected to examine their association with testing decisions and results. Germline genetic testing was ordered in 90 out of 145 patients and was ordered in younger patients with more lifetime adenomas. Pathogenic alterations were detected in 12 out of 53 patients who completed testing. Younger ages and higher numbers of lifetime adenomas were not associated with the detection of germline genetic alterations. In fact, patients with a pathogenic germline alteration had higher median ages and fewer lifetime adenomas than those without an alteration. Half of the 12 patients with a pathogenic germline mutation were not White non-Hispanic, although White non-Hispanic patients comprised 75.5% of those tested. This study supports the 10 adenomatous polyp threshold for recommending germline genetic polyposis testing, as an alteration was detected in a sizable proportion (>20%) of patients tested. Although a younger age and a higher number of lifetime adenomas were associated with an increased likelihood of ordered tests, no evidence was found to support these additional factors in testing decisions.
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Affiliation(s)
- Michael Kozak
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - David Negrete
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - Bonnie L Balzer
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - Srinivas Gaddam
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California
| | - Maha Guindi
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - Danielle A Hutchings
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - Brent K Larson
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - Kevin M Waters
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California.
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Pugaev DM, Lyubchenko LN, Ryabov AB, Kaprin AD. Early-onset gasrtric cancer (review). SIBERIAN JOURNAL OF ONCOLOGY 2024; 22:153-171. [DOI: 10.21294/1814-4861-2023-22-6-153-171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Abstract
Objective. Early-onset gastric cancer (EOGC) constitutes a serious medical and social problem. Early-onset gastric cancer accounts for approximately 6% of all malignant epithelial neoplasms.Material and Methods. We reviewed retrospective and prospective randomized trials using Medline and Elibrary databases.Results. The applied significance of the molecular genetic classifications consist in the formation of groups for evaluating prognosis of the disease using multifactorial analysis. This classification indicates that EOGC diagnosed at a locally advanced stage and primary dissemination is most often caused by GS (TCGA) and MSS/EMT(ACRG) subtypes and is characterized by mutations in CDH1, RhoA, CLDN18-ARHGAP genes. These changes are accompanied by the prevalence of diffuse histological type of gastric cancer according to the Lauren classification and ulcerated or infiltrative type according to the Borrmann classification (type III and IV) with the presence of high-grade adenocarcinoma with a signet ring cell component.Conclusion. Considering the aggressiveness of gastric cancer in young patients, who more frequently present with locally advanced and metastatic disease at the time of diagnosis, there is a need for increased cancer alertness among physicians of other specialties, early endoscopic controls to detect cancer at early stages and benefit from both surgical and multimodal treatment.
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Affiliation(s)
- D. M. Pugaev
- Kommunarka Moscow Multidisciplinary Clinical Center, Moscow City Health Department
| | - L. N. Lyubchenko
- N.A. Lopatkin Research Institute of Urology and Interventional Radiology – branch National Medical Research Radiological Centre of the Ministry of Health of the Russia;
National Medical Research Radiological Centre of the Ministry of Health of the Russia
| | - A. B. Ryabov
- P.A. Hertsen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Centre of the Ministry of Health of the Russia;
National Medical Research Radiological Centre of the Ministry of Health of the Russia
| | - A. D. Kaprin
- RUDN University;
P.A. Hertsen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Centre of the Ministry of Health of the Russia;
National Medical Research Radiological Centre of the Ministry of Health of the Russia
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Corcoran NME, Mair FS, Nicholl B, Macdonald S, Jani BD. Long-term conditions, multimorbidity and colorectal cancer risk in the UK Biobank cohort. JOURNAL OF MULTIMORBIDITY AND COMORBIDITY 2022; 12:26335565221110123. [PMID: 36132374 PMCID: PMC9483970 DOI: 10.1177/26335565221110123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 06/06/2022] [Indexed: 06/15/2023]
Abstract
PURPOSE Early identification of colorectal cancer (CRC) is an international priority. Multimorbidity (presence of ≥2 long-term conditions (LTCs)) is increasing and the relationship between CRC and LTCs is little-understood. This study explores the relationship between individual LTCs, multimorbidity and CRC incidence and mortality. METHODS Longitudinal analysis of the UK Biobank cohort, participants recruited 2006-2010; N = 500,195; excluding previous CRC at baseline. Baseline data was linked with cancer/mortality registers. Demographic characteristics, lifestyle factors, 43 LTCs, CRC family history, non-CRC cancers, and multimorbidity count were recorded. Variable selection models identified candidate LTCs potentially predictive of CRC outcomes and Cox regression models tested for significance of associations between selected LTCs and outcomes. RESULTS Participants' age range: 37-73 (mean age 56.5; 54.5% female). CRC was diagnosed in 3669 (0.73%) participants, and 916 (0.18%) died from CRC during follow-up (median follow-up 7 years). CRC incidence was higher in the presence of heart failure (Hazard Ratio (HR) 1.96, 95% Confidence Interval (CI) 1.13-3.40), diabetes (HR 1.15, CI 1.01-1.32), glaucoma (HR 1.36, CI 1.06-1.74), male cancers (HR 1.44, CI 1.01-2.08). CRC mortality was higher in presence of epilepsy (HR 1.83, CI 1.03-3.26), diabetes (HR 1.32, CI 1.02-1.72), osteoporosis (HR 1.67, CI 1.12-2.58). No significant association was found between multimorbidity (≥2 LTCs) and CRC outcomes. CONCLUSIONS The associations of certain LTCs with CRC incidence and mortality has implications for clinical practice: presence of certain LTCs in patients presenting with CRC symptoms could trigger early investigation and diagnosis. Future research should explore causative mechanisms and patient perspectives.
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Affiliation(s)
- Neave ME Corcoran
- General Practice and Primary Care,
Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK
| | - Frances S Mair
- General Practice and Primary Care,
Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK
| | - Barbara Nicholl
- General Practice and Primary Care,
Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK
| | - Sara Macdonald
- General Practice and Primary Care,
Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK
| | - Bhautesh Dinesh Jani
- General Practice and Primary Care,
Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK
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Abstract
PURPOSE OF REVIEW Peutz-Jeghers syndrome is a rare, autosomal dominant, hereditary polyposis syndrome defined by gastrointestinal hamartomas and mucocutaneous pigmentations, caused by a germline mutation in the serine/ threonine kinase 11 or liver kinase B1 (STK11/LKB1) genes. Hamartomatous polyps located throughout the gastrointestinal tract can be complicated by bleeding and small bowel intussusception, potentially leading to the need for emergency surgery. Individuals suffering from Peutz-Jeghers syndrome have an increased lifetime risk of various forms of cancer (gastrointestinal, pancreatic, lung, breast, uterine, ovarian and testicular). Surveillance should lead to the prevention of complications and thus a reduction in mortality and morbidity of patients. RECENT FINDINGS A combined approach based on wireless capsule endoscopy, magnetic resonance enterography and device-assisted enteroscopy is effective in reduction of the polyp burden and thus decreasing the risk of bleeding and intussusception. Current guidelines for screening and surveillance are mostly based on expert opinion rather than evidence. SUMMARY Peutz-Jeghers syndrome is an emerging disease that significantly affects the quality of life enjoyed by patients. Despite of all the progress in improved early diagnostics, options for advanced endoscopic therapy and elaborate surveillance, acute and chronic complications decrease the life expectancy of patients suffering from Peutz-Jeghers syndrome.
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Affiliation(s)
- Ilja Tacheci
- 2nd Department of Internal Medicine - Gastroenterology, Charles University, Faculty of Medicine in Hradec Kralove and University Hospital, Hradec Kralove, Czech Republic
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Valle L, Vilar E, Tavtigian SV, Stoffel EM. Genetic predisposition to colorectal cancer: syndromes, genes, classification of genetic variants and implications for precision medicine. J Pathol 2019; 247:574-588. [PMID: 30584801 PMCID: PMC6747691 DOI: 10.1002/path.5229] [Citation(s) in RCA: 121] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 12/21/2018] [Accepted: 12/23/2018] [Indexed: 12/15/2022]
Abstract
This article reviews genes and syndromes associated with predisposition to colorectal cancer (CRC), with an overview of gene variant classification. We include updates on the application of preventive and therapeutic measures, focusing on the use of non-steroidal anti-inflammatory drugs (NSAIDs) and immunotherapy. Germline pathogenic variants in genes conferring high or moderate risk to cancer are detected in 6-10% of all CRCs and 20% of those diagnosed before age 50. CRC syndromes can be subdivided into nonpolyposis and polyposis entities, the most common of which are Lynch syndrome and familial adenomatous polyposis, respectively. In addition to known and novel genes associated with highly penetrant CRC risk, identification of pathogenic germline variants in genes associated with moderate-penetrance cancer risk and/or hereditary cancer syndromes not traditionally linked to CRC may have an impact on genetic testing, counseling, and surveillance. The use of multigene panels in genetic testing has exposed challenges in the classification of variants of uncertain significance. We provide an overview of the main classification systems and strategies for improving these. Finally, we highlight approaches for integrating chemoprevention in the care of individuals with genetic predisposition to CRC and use of targeted agents and immunotherapy for treatment of mismatch repair-deficient and hypermutant tumors. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Laura Valle
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Barcelona, Spain
- Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain
| | - Eduardo Vilar
- Departments of Clinical Cancer Prevention, GI Medical Oncology and Clinical Cancer Genetics Program, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Sean V. Tavtigian
- Department of Oncological Sciences, University of Utah School of Medicine, Salt Lake City, UT, United States
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States
| | - Elena M. Stoffel
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States
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Hiller DJ, Gilliam JH, Waters GS. Extensive Small Bowel Polyposis of Unknown Origin. Am Surg 2018. [DOI: 10.1177/000313481808400609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- David J. Hiller
- Department of General Surgery Wake Forest School of Medicine Winston-Salem, North Carolina
| | - John H. Gilliam
- Department of Gastroenterology Wake Forest School of Medicine Winston-Salem, North Carolina
| | - Gregory S. Waters
- Department of General Surgery Wake Forest School of Medicine Winston-Salem, North Carolina
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Lorans M, Dow E, Macrae FA, Winship IM, Buchanan DD. Update on Hereditary Colorectal Cancer: Improving the Clinical Utility of Multigene Panel Testing. Clin Colorectal Cancer 2018; 17:e293-e305. [PMID: 29454559 DOI: 10.1016/j.clcc.2018.01.001] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Revised: 12/17/2017] [Accepted: 01/09/2018] [Indexed: 12/30/2022]
Abstract
Colorectal cancer (CRC), one of the most common cancers, is a major public health issue globally, especially in Westernized countries. Up to 35% of CRCs are thought to be due to heritable factors, but currently only 5% to 10% of CRCs are attributable to high-risk mutations in known CRC susceptibility genes, predominantly the mismatch repair genes (Lynch syndrome) and adenomatous polyposis coli gene (APC; familial adenomatous polyposis). In this era of precision medicine, high-risk mutation carriers, when identified, can be offered various risk management options that prevent cancers and improve survival, including risk-reducing medication, screening for early detection, and surgery. The practice of clinical genetics is currently transitioning from phenotype-directed single gene testing to multigene panels, now offered by numerous providers. For CRC, the genes included across these panels vary, ranging from well established, clinically actionable susceptibility genes with quantified magnitude of risk, to genes that lack extensive validation or have less evidence of association with CRC and, therefore, have minimal clinical utility. The current lack of consensus regarding inclusion of genes in CRC panels presents challenges in patient counseling and management, particularly when a variant in a less validated gene is identified. Furthermore, there remain considerable challenges regarding variant interpretation even for the well established CRC susceptibility genes. Ironically though, only through more widespread testing and the accumulation of large international data sets will sufficient information be generated to (i) enable well powered studies to determine if a gene is associated with CRC susceptibility, (ii) to develop better models for variant interpretation and (iii) to facilitate clinical translation.
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Affiliation(s)
- Marie Lorans
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia
| | - Eryn Dow
- Genetic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Finlay A Macrae
- Genetic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Victoria, Australia; Department of Medicine, The University of Melbourne, Parkville, Victoria, Australia; Colorectal Medicine and Genetics, Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Ingrid M Winship
- Genetic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Victoria, Australia; Department of Medicine, The University of Melbourne, Parkville, Victoria, Australia
| | - Daniel D Buchanan
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia; Genetic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Victoria, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Carlton, Victoria, Australia; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria, Australia.
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Shaco-Levy R, Jasperson KW, Martin K, Samadder NJ, Burt RW, Ying J, Bronner MP. Gastrointestinal Polyposis in Cowden Syndrome. J Clin Gastroenterol 2017; 51:e60-e67. [PMID: 27661969 DOI: 10.1097/mcg.0000000000000703] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
GOALS To further characterize the gastrointestinal manifestations of Cowden syndrome in clinically well-annotated patients to improve the diagnosis of this syndrome. BACKGROUND The gastrointestinal manifestations of Cowden Syndrome, an important heritable and multiorgan cancer syndrome, are not well defined. Proper diagnosis is essential for effective cancer surveillance and prevention in these patients. STUDY Cowden patients with gastrointestinal polyps were selected for medical record and pathologic slide review. RESULTS Of 19 total patients, genetic testing revealed pathogenic PTEN mutations in 12. Pan-colonic (11-patients, 58%) and pan-gastrointestinal (8-patients, 42%) polyp distributions were common. Inflammatory (juvenile) polyps were the most common of the hamartomatous polyp (18 patients, 95%), along with expansive lymphoid follicle polyps (12 patients, 63%), ganglioneuromatous polyps (10 patients, 53%), and intramucosal lipomas (5 patients, 26%). The findings of 2 or more hamartomatous polyp types per patient emerged as a newly described and highly prevalent (79%) feature of Cowden syndrome. Ganglioneuromatous polyps, rare in the general population, and intramucosal lipomas, which may be unique to Cowden syndrome, should both prompt further evaluation. Colonic adenomas and adenocarcinomas were common; 10 patients (53%) had single and 3 (16%) had ≥3 adenomas, whereas 2 (11%) had colonic adenocarcinoma, strengthening the emerging association of colorectal cancer with Cowden syndrome. CONCLUSIONS The clinical phenotypes and gastrointestinal manifestations in Cowden syndrome are quite variable but this series adds the following new considerations for this syndromic diagnosis: multiple gastrointestinal hamartomas, especially 2 or more hamartoma types, and any intramucosal lipomas or ganglioneuromas. These features should warrant consideration of Cowden syndrome.
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Affiliation(s)
- Ruthy Shaco-Levy
- *Department of Pathology, Soroka Medical Center, Ben-Gurion University of the Negev, Beer Sheva, Israel †Department of Pathology & ARUP Laboratories ∥Department of Internal Medicine ‡Huntsman Cancer Institute §Genetic Counseling ¶Division of Gastroenterology #Division of Epidemiology, University of Utah, Salt Lake City, UT
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Shaco-Levy R, Jasperson KW, Martin K, Samadder NJ, Burt RW, Ying J, Bronner MP. Morphologic characterization of hamartomatous gastrointestinal polyps in Cowden syndrome, Peutz-Jeghers syndrome, and juvenile polyposis syndrome. Hum Pathol 2016; 49:39-48. [DOI: 10.1016/j.humpath.2015.10.002] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2015] [Revised: 10/05/2015] [Accepted: 10/08/2015] [Indexed: 01/14/2023]
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10
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Lakritz JR, Poutahidis T, Mirabal S, Varian BJ, Levkovich T, Ibrahim YM, Ward JM, Teng EC, Fisher B, Parry N, Lesage S, Alberg N, Gourishetti S, Fox JG, Ge Z, Erdman SE. Gut bacteria require neutrophils to promote mammary tumorigenesis. Oncotarget 2016; 6:9387-96. [PMID: 25831236 PMCID: PMC4496224 DOI: 10.18632/oncotarget.3328] [Citation(s) in RCA: 87] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2015] [Accepted: 02/09/2015] [Indexed: 12/26/2022] Open
Abstract
Recent studies suggest that gastrointestinal tract microbiota modulate cancer development in distant non-intestinal tissues. Here we tested mechanistic hypotheses using a targeted pathogenic gut microbial infection animal model with a predilection to breast cancer. FVB-Tg(C3-1-TAg)cJeg/JegJ female mice were infected by gastric gavage with Helicobacter hepaticus at three-months-of-age putting them at increased risk for mammary tumor development. Tumorigenesis was multifocal and characterized by extensive infiltrates of myeloperoxidase-positive neutrophils otherwise implicated in cancer progression in humans and animal models. To test whether neutrophils were important in etiopathogenesis in this bacteria-triggered model system, we next systemically depleted mice of neutrophils using thrice weekly intraperitoneal injections with anti-Ly-6G antibody. We found that antibody depletion entirely inhibited tumor development in this H. hepaticus-infected model. These data demonstrate that host neutrophil-associated immune responses to intestinal tract microbes significantly impact cancer progression in distal tissues such as mammary glands, and identify gut microbes as novel targets for extra-intestinal cancer therapy.
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Affiliation(s)
- Jessica R Lakritz
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Theofilos Poutahidis
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.,Laboratory of Pathology, Faculty of Veterinary Medicine, Aristotle University of Thessaloniki, Greece 54124
| | - Sheyla Mirabal
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Bernard J Varian
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Tatiana Levkovich
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Yassin M Ibrahim
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | | | - Ellen C Teng
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Brett Fisher
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Nicola Parry
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Stephanie Lesage
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Natalie Alberg
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Sravya Gourishetti
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - James G Fox
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Zhongming Ge
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Susan E Erdman
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
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Abstract
PURPOSE OF REVIEW Gastrointestinal polyps are commonly encountered during childhood and are one of the most common causes of rectal bleeding in this age group. Most polyps are benign and located in the colon, with the most frequent type being juvenile polyps. However, in older pediatric patients, if multiple polyps are present, in patients who have a positive family history, or if polyps are located outside of the colon, either adenomatous polyps or polyps associated with genetic abnormalities are more common. RECENT FINDINGS Imaging techniques such as ultrasound and computed tomographic colonoscopy have recently been utilized to identify simple juvenile colonic polyps in children with rectal bleeding in whom there is a high index of suspicion. Colonoscopy with polypectomy is still required for histologic evaluation and resection of the polyp. There have been significant advances in genetic testing and management of hereditary gastrointestinal cancer syndromes with onset in childhood or adolescence that may ultimately reduce long-term morbidity and mortality. In addition to enhanced gastrointestinal and extraintestinal malignancy screening for affected individuals, specific gene mutations within a given condition such as adenomatous polyposis coli may predict clinical course and timing of specific interventions such as colectomy. In other conditions such as phosphatase and tensin homolog hamartoma tumor syndrome, phenotype may not be predicted by genotype. SUMMARY Pediatricians, pediatric gastroenterologists, and adult gastroenterologists caring for children should understand how to differentiate benign polyps in the pediatric age group from those associated with a higher risk of complications including recurrence risk and risk of development of intestinal or extraintestinal malignancy. Recent advances in genetic testing, as well as development of consensus guidelines, are key in the identification, screening, and follow-up of children and adolescents with polyposis syndromes.
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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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Tomas C, Soyer P, Dohan A, Dray X, Boudiaf M, Hoeffel C. Update on imaging of Peutz-Jeghers syndrome. World J Gastroenterol 2014; 20:10864-10875. [PMID: 25152588 PMCID: PMC4138465 DOI: 10.3748/wjg.v20.i31.10864] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2013] [Accepted: 05/19/2014] [Indexed: 02/06/2023] Open
Abstract
Peutz-Jeghers syndrome (PJS) is a rare, autosomal dominant disease linked to a mutation of the STK 11 gene and is characterized by the development of benign hamartomatous polyps in the gastrointestinal tract in association with a hyperpigmentation on the lips and oral mucosa. Patients affected by PJS have an increased risk of developing gastrointestinal and extra-digestive cancer. Malignancy most commonly occurs in the small-bowel. Extra-intestinal malignancies are mostly breast cancer and gynecological tumors or, to a lesser extent, pancreatic cancer. These polyps are also at risk of acute gastrointestinal bleeding, intussusception and bowel obstruction. Recent guidelines recommend regular small-bowel surveillance to reduce these risks associated with PJS. Small-bowel surveillance allows for the detection of large polyps and the further referral of selected PJS patients for endoscopic enteroscopy or surgery. Video capsule endoscopy, double balloon pushed enteroscopy, multidetector computed tomography and magnetic resonance enteroclysis or enterography, all of which are relatively new techniques, have an important role in the management of patients suffering from PJS. This review illustrates the pathological, clinical and imaging features of small-bowel abnormalities as well as the role and performance of the most recent imaging modalities for the detection and follow-up of PJS patients.
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14
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Hereditary disorders of DNA repair and DNA damage tolerance that predispose to neoplastic transformation. Mol Oncol 2013. [DOI: 10.1017/cbo9781139046947.037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
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Chen Y, Zhai Y, Jiang X, Zhang Z. Malignant transformation of residual endometriosis following hysterectomy and bilateral salpingo-oophorectomy in a female patient from a family with hereditary non-polyposis colorectal cancer. Oncol Lett 2013; 5:1253-1257. [PMID: 23599774 PMCID: PMC3629112 DOI: 10.3892/ol.2013.1182] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2012] [Accepted: 12/18/2012] [Indexed: 12/02/2022] Open
Abstract
The aim of this study was to report a case of malignant transformation from residual endometriosis following hysterectomy and bilateral salpingo-oophorectomy in a female patient with a positive family history of ovarian and colon cancer resulting from residual endometriosis. A 42-year-old female patient from a family with hereditary non-polyposis colorectal cancer (HNPCC) diagnosed with bilateral ovarian endometriosis underwent a hysterectomy and bilateral salpingo-oophorectomy. Two years later, the patient was diagnosed with malignant ovarian cancer. Histological examination revealed an endometrioid adenocarcinoma with transitions between endometriosis and adenocarcinoma. The patient was diagnosed with ovarian endometrioid carcinoma, at FIGO stage IIC. In future, the family history of female patients with endometriosis should be collected. The association between the malignant transformation of endometriosis and HNPCC should be studied further in a research setting.
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Affiliation(s)
- Yuxuan Chen
- Beijing Chaoyang Hospital, Beijing, P.R. China
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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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Herrmann JL, Byekova Y, Elmets CA, Athar M. Liver kinase B1 (LKB1) in the pathogenesis of epithelial cancers. Cancer Lett 2011; 306:1-9. [PMID: 21450399 PMCID: PMC3085567 DOI: 10.1016/j.canlet.2011.01.014] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2010] [Revised: 01/16/2011] [Accepted: 01/19/2011] [Indexed: 12/26/2022]
Abstract
LKB1 acts as a master kinase, with its major protein targets being the family of AMPKs. Through activation of multiple signaling pathways, LKB1's main physiologic functions involve regulating cellular growth, metabolism, and polarity. Germline mutations in LKB1 result in Peutz-Jeghers Syndrome, a rare cancer susceptibility syndrome. In addition, multiple LKB1 mutations have been identified in sporadic cancers, especially those of the lung. Recent studies from a variety of murine models have helped characterize LKB1's role in the pathogenesis of epithelial cancers. In some tumor types, LKB1 might function chiefly to suppress cell growth or invasion, while in other cases, it may serve to prevent metastasis. Moreover, molecular signatures of individual tumors likely influence LKB1's operational role, as multiple studies have shown that LKB1 can synergize with other tumor suppressors and/or oncogenes to accelerate tumorigenesis. To date, LKB1 has been considered mainly a tumor suppressor; however, some studies have suggested its potential oncogenic role, mainly through the suppression of apoptosis. In short, LKB1 is a tissue and context-specific kinase. This review aims to summarize our current understanding of its role in the pathogenesis of epithelial cancers.
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Affiliation(s)
- Jennifer L. Herrmann
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Yevgeniya Byekova
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Craig A. Elmets
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama, USA
- Skin Diseases Research Center, Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Mohammad Athar
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama, USA
- Skin Diseases Research Center, Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA
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Balloon-assisted enteroscopy with prophylactic polypectomy for Peutz-Jeghers syndrome: experience in Taiwan. Dig Dis Sci 2011; 56:1472-5. [PMID: 21086168 DOI: 10.1007/s10620-010-1464-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2010] [Accepted: 10/12/2010] [Indexed: 12/22/2022]
Abstract
BACKGROUND Peutz-Jeghers syndrome (PJS) is a very rare disease that often causes severe complications such as bowel obstruction or gastrointestinal tract bleeding. In the past, it was usually treated by using surgical intervention despite the associated complications. Balloon-assisted enteroscopy (BAE) has been documented as an effective and safe method for the diagnosis and treatment of small bowel lesions. Hence, we conducted this study to verify whether BAE is useful for patients with PJS. AIM To evaluate the safety and efficacy of BAE with prophylactic polypectomy in patients with PJS. METHODS AND PATIENTS From August 2005 to February 2010, 6 consecutive patients were diagnosed with PJS after pathological and clinical examination, and underwent BAE examination and polypectomy at Chang Gung Memorial Hospital, an academic tertiary referral center. RESULTS Six consecutive patients (4 men and 2 women) diagnosed with PJS underwent BAE with polypectomy. BAE was performed 17 times for complete examination of the entire small bowel. The range of the diameter of the removed polyps was 1-6 cm. No immediate complications such as hemorrhage or hollow organ perforation were noted during the procedure, and no patient developed intussusception during the follow-up period (32 ± 17.5 months). CONCLUSION BAE with polypectomy is useful for patients with PJS in order to reduce the complications of the condition.
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van Lier MGF, Mathus-Vliegen EMH, Wagner A, van Leerdam ME, Kuipers EJ. High cumulative risk of intussusception in patients with Peutz-Jeghers syndrome: time to update surveillance guidelines? Am J Gastroenterol 2011; 106:940-5. [PMID: 21157440 DOI: 10.1038/ajg.2010.473] [Citation(s) in RCA: 114] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Peutz-Jeghers syndrome (PJS) is characterized by gastrointestinal hamartomas. The hamartomas are located predominantly in the small intestine and may cause intussusceptions. We aimed to assess the characteristics, risk, and onset of intussusception in a large cohort of PJS patients to determine whether enteroscopy with polypectomy should be incorporated into surveillance recommendations. METHODS All PJS patients from two academic hospitals were included in this cohort study (prospective follow-up between 1995 and July 2009). We obtained clinical data by interview and chart review. Deceased family members with PJS were included retrospectively. Cumulative intussusception risks were calculated by Kaplan–Meier analysis. RESULTS We included 110 PJS patients (46% males) from 50 families. In all, 76 patients (69%) experienced at least one intussusception (range 1-6), at a median age of 16 (3-50) years at first occurrence. The intussusception risk was 50% at the age of 20 years (95% confidence interval 17-23 years) and the risk was independent of sex, family history, and mutation status. The intussusceptions occurred in the small intestine in 95% of events, and 80% of all intussusceptions (n=128) presented as an acute abdomen. Therapy was surgical in 92.5% of events. Based on 37 histology reports, the intussusceptions were caused by polyps with a median size of 35 mm (range 15-60 mm). CONCLUSIONS PJS patients carry a high cumulative intussusception risk at young age. Intussusceptions are generally caused by polyps >15 mm and treatment is mostly surgical. These results support the approach of enteroscopic surveillance, with removal of small-intestinal polyps >10-15 mm to prevent intussusceptions. The effect of such an approach on the incidence of intussusception remains to be established in prospective trials.
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Affiliation(s)
- M G F van Lier
- Department of Gastroenterology and Hepatology, University Medical Center, Rotterdam, The Netherlands.
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High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations. Am J Gastroenterol 2010; 105:1258-64; author reply 1265. [PMID: 20051941 DOI: 10.1038/ajg.2009.725] [Citation(s) in RCA: 328] [Impact Index Per Article: 21.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Peutz-Jeghers syndrome (PJS) is an autosomal dominant inherited disorder associated with increased cancer risk. Surveillance and patient management are, however, hampered by a wide range in cancer risk estimates. We therefore performed a systematic review to assess cancer risks in PJS patients and used these data to develop a surveillance recommendation. METHODS A systematic PubMed search was performed up to February 2009, and all original articles dealing with PJS patients with confirmed cancer diagnoses were included. Data involving cancer frequencies, mean ages at cancer diagnosis, relative risks (RRs), and cumulative risks were collected. RESULTS Twenty-one original articles, 20 cohort studies, and one meta-analysis fulfilled the inclusion criteria. The cohort studies showed some overlap in the patient population and included a total of 1,644 patients; 349 of them developed 384 malignancies at an average age of 42 years. The most common malignancy was colorectal cancer, followed by breast, small bowel, gastric, and pancreatic cancers. The reported lifetime risk for any cancer varied between 37 and 93%, with RRs ranging from 9.9 to 18 in comparison with the general population. Age-related cumulative risks were given for any cancer and gastrointestinal, gynecological, colorectal, pancreatic, and lung cancers. CONCLUSIONS PJS patients are markedly at risk for several malignancies, in particular gastrointestinal cancers and breast cancer. On the basis of these elevated risks, a surveillance recommendation is developed to detect malignancies in an early phase and to remove polyps that may be premalignant and may cause complications, so as to improve the outcome.
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McCann S, MacAuley D, Barnett Y, Bunting B, Bradley A, Jeffers L, Morrison PJ. Family communication, genetic testing and colonoscopy screening in hereditary non-polyposis colon cancer: a qualitative study. Psychooncology 2010; 18:1208-15. [PMID: 19177338 DOI: 10.1002/pon.1487] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
OBJECTIVE Genetic testing and colonoscopy is recommended for people with a strong history of colorectal cancer (CRC). However, families must communicate so that all members are aware of the risk. The study aimed to explore the factors influencing family communication about genetic risk and colonoscopy among people with a strong family history of CRC who attended a genetic clinic with a view to having a genetic test for hereditary non-polyposis colon cancer (HNPCC). METHODS Interviews were held with 30 people with a high familial risk of colon cancer. The transcripts were transcribed verbatim and analysed using Interpretative Phenomenological Analysis. RESULTS The family context, family history and perceptions about family duties and responsibilities were important motivators for communication about risk, genetic testing and colonoscopy and influenced participation in genetic testing and screening programmes. Participants reported usually communicating openly with their relatives about genetic risk and colonoscopy. Individuals felt a duty towards affected relatives and to their own children. The influence of the spouse and other relatives, particularly those affected by CRC, was also important. Colonoscopy was perceived to be embarrassing, unpleasant and sometimes painful. While there was sometimes anxiety about the result of the colonoscopy the results were usually reassuring. CONCLUSIONS The family context and the experience of the family history can have an impact on communication, genetic testing and screening in HNPCC and this should be explored during counselling. Some individuals might benefit from support in communicating with relatives about genetic risk. Ways of improving the individual's experience of colonoscopy should also be examined.
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Affiliation(s)
- Siobhan McCann
- Psychology Research Institute, University of Ulster, Londonderry, Northern Ireland.
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Katsinelos P, Kountouras J, Chatzimavroudis G, Zavos C, Pilpilidis I, Fasoulas K, Paroutoglou G. Wireless capsule endoscopy in detecting small-intestinal polyps in familial adenomatous polyposis. World J Gastroenterol 2009; 15:6075-9. [PMID: 20027680 PMCID: PMC2797664 DOI: 10.3748/wjg.15.6075] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To detect the prevalence of small bowel polyps by wireless capsule endoscopy (WCE) in patients with familial adenomatous polyposis (FAP).
METHODS: We examined prospectively 14 patients with FAP to assess the location, size and number of small-intestinal polyps. Patients’ age, sex, years of observation after surgery, type of surgery, duodenal polyps and colorectal cancer at surgery were analyzed.
RESULTS: During WCE, polyps were detected in 9/14 (64.3%) patients. Duodenal adenomatous polyps were found in nine (64.3%) patients, and jejunal and ileal polyps in seven (50%) and eight (57.1%), respectively. The Spigelman stage of duodenal polyposis was associated with the presence of jejunal and ileal polyps. Identification of the ampulla of Vater was not achieved with WCE. Importantly, the findings of WCE had no immediate impact on the further clinical management of FAP patients. No procedure-related complications were observed in the patients.
CONCLUSION: WCE is a promising noninvasive new method for the detection of small-intestinal polyps. Further investigation is required to determine which phenotype of FAP is needed for surveillance with WCE.
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Ekstrand AI, Jönsson M, Lindblom A, Borg Å, Nilbert M. Frequent alterations of the PI3K/AKT/mTOR pathways in hereditary nonpolyposis colorectal cancer. Fam Cancer 2009; 9:125-9. [DOI: 10.1007/s10689-009-9293-1] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Functional characterization of rare missense mutations in MLH1 and MSH2 identified in Danish colorectal cancer patients. Fam Cancer 2009; 8:489-500. [PMID: 19697156 DOI: 10.1007/s10689-009-9274-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2009] [Accepted: 07/20/2009] [Indexed: 12/21/2022]
Abstract
Recently, we have performed a population based study to analyse the frequency of colorectal cancer related MLH1 and MSH2 missense mutations in the Danish population. Half of the analyzed mutations were rare and most likely only present in the families where they were identified originally. Some of the missense mutations were located in conserved regions in the MLH1 and MSH2 proteins indicating a relation to disease development. In the present study, we functionally characterized 10 rare missense mutations in MLH1 and MSH2 identified in 13 Danish CRC families. To elucidate the pathogenicity of the missense mutations, we carried out in vitro functional analyses. The missense mutations were analyzed for their effect on protein expression and repair efficiency. The results of the functional analysis were correlated with clinical data on the families carrying these mutations. Eight missense mutations resulted in proteins with expression and repair efficiency similar to the wild type. One missense mutation (MSH2 p.Met688Val) caused reduced protein expression and one (MSH2 p.Leu187Arg) caused both reduced protein expression and repair deficiency. The MSH2 p.Leu187Arg mutation was found in an Amsterdam II family presenting with high microsatellite instability and loss of MSH2 and MSH6 proteins in tumours. In conclusion, only 1/10 missense mutations displayed repair deficiency and could be classified as pathogenic. No final conclusion can be drawn on the MSH2 p.Met688Val mutation, which caused reduced protein expression. Although, no deficiencies have been identified in the proteins harbouring the other missense mutations, pathogenicity of these variants cannot be unambiguously excluded.
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Foo W, Young JM, Solomon MJ, Wright CM. Family history? The forgotten question in high-risk colorectal cancer patients. Colorectal Dis 2009; 11:450-5. [PMID: 19508517 DOI: 10.1111/j.1463-1318.2009.01898.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM The aim of the study was to investigate the frequency and detail of family history recorded for patients diagnosed with potentially high-risk colorectal cancer, and to determine the proportion of these patients referred to a high-risk assessment clinic. METHOD Medical records of patients diagnosed with colorectal cancer under the age of 50 admitted to a major Sydney teaching hospital were reviewed. The proportion of records containing information about family history was calculated. Associations between recording of family history and demographic and clinical characteristics of patients were investigated. Logistic regression modelling was performed to identify significant, independent predictors of study outcomes. RESULTS Of 113 patients with colorectal cancer diagnosed under the age of 50 years, 61 (54%, 95% CI: 44-63%) had an entry in their hospital medical record about family history. Family history was significantly less likely to be recorded for females, for those admitted via the Emergency Department, and for those with shorter lengths of stay. A significant family history was found in 51% of the 61 patients who had a family history recorded. Records of patients attending specialist colorectal surgeons were significantly more likely to contain information about family history than those who attended other specialists (P = 0.04). Only 14 patients (12%, 95% CI: 7-20%) were formally referred for further genetic assessment. CONCLUSION These results suggest that family history is still being neglected in routine clinical practice, and high-risk assessment services are underutilized, implying the need for further dissemination of guidelines with regard to the recognition and management of hereditary colorectal cancer.
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Affiliation(s)
- W Foo
- Surgical Outcomes Research Centre, The University of Sydney, Sydney, New South Wales, Australia
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de Ferro SM, Suspiro A, Fidalgo P, Lage P, Rodrigues P, Fragoso S, Vitoriano I, Baltazar C, Albuquerque C, Bettencourt A, Leitão CN. Aggressive phenotype of MYH-associated polyposis with jejunal cancer and intra-abdominal desmoid tumor: report of a case. Dis Colon Rectum 2009; 52:742-5. [PMID: 19404084 DOI: 10.1007/dcr.0b013e318199db93] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
MYH-associated polyposis is an inherited autosomal recessive disease, linked to biallelic germline MYH mutations, which predisposes to the development of multiple colorectal adenomas and cancer. The colonic and extracolonic phenotype of this syndrome is very heterogeneous. We report the case of a young male patient with an aggressive MYH-associated polyposis phenotype. He presented at aged 30 years with more than 100 colonic polyps and 4 colonic adenocarcinomas. At aged 35 years, Spigelman Stage IV duodenal adenomatosis was detected. When he was 39 years old, he developed three synchronous jejunal adenocarcinomas and a mesenteric desmoid tumor. Based on this report, we believe that screening of the entire small bowel should be recommended in MYH-associated polyposis patients, especially in those with duodenal adenomas. Similar to patients with familial adenomatous polyposis, desmoid tumors also may be part of the clinical spectrum of MYH-associated polyposis and may prove to be a significant clinical problem in patients submitted to prophylactic colectomy.
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Affiliation(s)
- Susana Mão de Ferro
- Instituto Português de Oncologia de Lisboa Francisco Gentil, EPE, Gastrenterologia, Lisbon, Portugal.
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Sanz Gallego I, López Rodríguez M, Romera Rabasa A, Zamora Vargas FJ, Pérez Valero I, Vázquez Rodríguez JJ. [Mixed hereditary polyposis with atypical extracolonic manifestations]. Rev Clin Esp 2007; 207:77-8. [PMID: 17397567 DOI: 10.1016/s0014-2565(07)73314-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
We present the case of a 31 year-old-man with mixed hereditary polyposis and atypical extracolonic manifestations, as patent ductus arteriosus and mental retardation, with cranial hyperostosis. This is an extremely uncommon polyposis syndrome and has a moderate risk to progress to colon cancer.
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Affiliation(s)
- I Sanz Gallego
- Servicio de Neurología, Hospital Universitario La Paz, Madrid, Spain.
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Chan OTM, Haghighi P. Hamartomatous polyps of the colon: ganglioneuromatous, stromal, and lipomatous. Arch Pathol Lab Med 2006; 130:1561-6. [PMID: 17090203 DOI: 10.5858/2006-130-1561-hpotcg] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/06/2006] [Indexed: 11/06/2022]
Abstract
Intestinal ganglioneuromas comprise benign, hamartomatous polyps characterized by an overgrowth of nerve ganglion cells, nerve fibers, and supporting cells in the gastrointestinal tract. This polyposis has been divided into 3 subgroups, each with a different degree of ganglioneuroma formation: polypoid ganglioneuroma, ganglioneuromatous polyposis, and diffuse ganglioneuromatosis. The ganglioneuromatous polyposis subgroup is not known to coexist with systemic disorders that often have an associated intestinal polyposis, such as multiple endocrine neoplasia type IIb, neurofibromatosis type I, and Cowden syndrome. We report a case of ganglioneuromatous polyposis plus cutaneous lipomatosis in a 41-year-old man with no established systemic disease. However, he possessed unique anatomic findings in addition to his ganglioneuromatosis, suggesting that the ganglioneuromatosis-lipomatosis in our patient may represent an unrecognized syndrome. This case report and brief review of the literature provide an overview of intestinal ganglioneuromatosis in relation to the hereditary polyposis syndromes and describe the individual ganglioneuromatosis subgroups.
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Affiliation(s)
- Owen T M Chan
- Department of Pathology, University of California-San Diego and VA Medical Center, San Diego, Calif, USA.
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Katajisto P, Vallenius T, Vaahtomeri K, Ekman N, Udd L, Tiainen M, Mäkelä TP. The LKB1 tumor suppressor kinase in human disease. Biochim Biophys Acta Rev Cancer 2006; 1775:63-75. [PMID: 17010524 DOI: 10.1016/j.bbcan.2006.08.003] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2006] [Revised: 07/25/2006] [Accepted: 08/12/2006] [Indexed: 12/31/2022]
Abstract
Inactivating germline mutations in the LKB1 gene underlie Peutz-Jeghers syndrome characterized by hamartomatous polyps and an elevated risk for cancer. Recent studies suggest the involvement of LKB1 also in more common human disorders including diabetes and in a significant fraction of lung adenocarcinomas. These observations have increased the interest towards signaling pathways of this tumor suppressor kinase. The recent breakthroughs in understanding the molecular functions of the LKB1 indicate its contribution as a regulator of cell polarity, energy metabolism and cell proliferation. Here we review how the substrates and cellular functions of LKB1 may be linked to Peutz-Jeghers syndrome and other diseases, and discuss how some of the molecular changes associated with altered LKB1 signaling might be used in therapeutic approaches.
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Affiliation(s)
- Pekka Katajisto
- Molecular Cancer Biology Program, Translational Genome-Scale Biology and Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Finland
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Campos FG, Habr-Gama A, Kiss DR, Atuí FC, Rawet V, Goldstein PJ, Gama-Rodrigues J. Cowden syndrome: report of two cases and review of clinical presentation and management of a rare colorectal polyposis. ACTA ACUST UNITED AC 2006; 63:15-9. [PMID: 16373153 DOI: 10.1016/j.cursur.2005.04.015] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2004] [Revised: 04/09/2005] [Accepted: 04/09/2005] [Indexed: 11/25/2022]
Abstract
BACKGROUND/AIMS Cowden syndrome (CS) is a rare and complex disease inherited through an autosomal dominant trait associated with germline mutations of the PTEN gene. OBJECTIVE This article reports 2 female patients with classic features of the syndrome and reviews the current guidelines regarding diagnosis and surveillance. REVIEW Although it exhibits variable clinical expressivity, the diagnosis is based on characteristic mucocutaneous alterations such as multiple facial trichilemmomas, oral mucosal papillomatosis, and acral and palmoplantar keratoses. These manifestations often precede systemic involvement. Extracutaneous lesions include fibrocystic disease of the breast, thyroid goiters or adenomas, multiple polyposis of the gastrointestinal tract, and ovarian cysts. Gastrointestinal polyps are usually asymptomatic, and the risk of gastrointestinal cancer is not greatly increased. Otherwise, an important feature of Cowden's disease is the greater risk of breast and thyroid cancer. CONCLUSIONS Because of the potentially serious associations with internal malignancy, early and accurate diagnosis of CS is essential. For this reason, all patients must be screened for occult malignancies and undergo close surveillance throughout lifetime.
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Affiliation(s)
- Fábio Guilherme Campos
- Department of Gastroenterology, Colorectal Surgery Unit, Hospital das Clínicas, University of São Paulo Medical School, São Paulo, Brazil.
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van Kouwen MCA, Drenth JPH, van Krieken JHJM, van Goor H, Friederich P, Oyen WJG, Nagengast FM. Ability of FDG-PET to detect all cancers in patients with familial adenomatous polyposis, and impact on clinical management. Eur J Nucl Med Mol Imaging 2005; 33:270-4. [PMID: 16292630 DOI: 10.1007/s00259-005-1955-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2005] [Accepted: 08/12/2005] [Indexed: 01/27/2023]
Abstract
PURPOSE Familial adenomatous polyposis (FAP) is characterised by colonic and duodenal adenomatous polyps that carry a risk of malignant transformation. Malignant degeneration of duodenal adenomas is difficult to detect. We speculated that 2-((18)F)-fluoro-2-deoxy-D: -glucose positron emission tomography (FDG-PET) might be able to detect early duodenal cancer in FAP. Accordingly, we investigated the role of FDG-PET in the management of FAP patients. METHODS FDG-PET was performed in 24 FAP patients. Eight had advanced duodenal adenomas (Spigelman IV), including two patients with duodenal cancer. Scans were defined as positive on the basis of focal FDG accumulation. RESULTS Pathological FDG accumulation was absent in 19 of 24 patients. All six patients with Spigelman IV duodenal adenomas (without cancer) were negative; two of these underwent a duodenectomy and pathological examination did not reveal duodenal cancer. In five patients, FDG-PET revealed significant uptake, in the duodenum (2), lower abdomen (1), lung (1) and multiple sites in the abdomen (1). These hot spots correlated with duodenal cancer (2), abdominal metastasis (1) and sclerosing haemangioma of the lung (1). We failed to make a histopathological diagnosis in the single patient with multiple intra-abdominal sites of FDG uptake. None of the patients from the FDG-PET-negative group developed cancer during follow-up (mean 2.8 years). CONCLUSION FDG-PET detected all the cancers present, and none of the patients with negative FDG-PET developed cancer. This suggests that positive FDG-PET in FAP patients should lead to further examinations to rule out cancer. In patients with negative FDG-PET a more conservative approach seems justified.
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Affiliation(s)
- Mariëtte C A van Kouwen
- Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Centre 9101, 6500 Nijmegen, The Netherlands
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Baudhuin LM, Ferber MJ, Winters JL, Steenblock KJ, Swanson RL, French AJ, Butz ML, Thibodeau SN. Characterization of hMLH1 and hMSH2 gene dosage alterations in Lynch syndrome patients. Gastroenterology 2005; 129:846-54. [PMID: 16143124 DOI: 10.1053/j.gastro.2005.06.026] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2005] [Accepted: 06/02/2005] [Indexed: 12/02/2022]
Abstract
BACKGROUND & AIMS A significant proportion of Lynch syndrome cases are believed to be due to large genomic alterations in the mismatch repair genes hMLH1 and hMSH2. However, previous studies have not adequately identified the frequency and scope of such mutations, and routine clinical Lynch syndrome testing often does not include analysis for these mutations. Our aim was to characterize hMLH1 and hMSH2 genomic rearrangements in a large population of suspected Lynch syndrome patients. METHODS A total of 365 samples from probands referred for genetic testing for Lynch syndrome were analyzed for the presence of large genomic alterations in hMLH1 or hMSH2 by using a combination of techniques. Samples with a deletion in exons 1-6 in hMSH2 were further characterized by polymerase chain reaction to establish the presence of the hMSH2 American founder deletion. RESULTS An hMLH1 or hMSH2 mutation was identified in 153 cases, and, of these, 12 of 67 (17.9%) and 39 of 86 (45.3%) had a large genomic alteration in hMLH1 and hMSH2, respectively. Overall, 6 different hMLH1 and 12 different hMSH2 deletions/duplications, including 10 novel mutations, were identified. Analysis of the hMSH2 exon 1-6 deletion samples showed that 13 of 18 (72.2%) had the American founder deletion. CONCLUSIONS These data show a high frequency and diverse spectrum of large genomic alterations in hMLH1 and hMSH2 in suspected Lynch syndrome patients. Thus, a comprehensive mutation identification strategy that includes the ability to detect large genomic rearrangements is imperative for the clinical genetic identification of Lynch syndrome patients and families.
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Affiliation(s)
- Linnea M Baudhuin
- Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
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Baudhuin LM, Mai M, French AJ, Kruckeberg KE, Swanson RL, Winters JL, Courteau LK, Thibodeau SN. Analysis of hMLH1 and hMSH2 gene dosage alterations in hereditary nonpolyposis colorectal cancer patients by novel methods. J Mol Diagn 2005; 7:226-35. [PMID: 15858146 PMCID: PMC1867519 DOI: 10.1016/s1525-1578(10)60549-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
A significant fraction of hereditary nonpolyposis colorectal cancer cases with defective mismatch repair (ie, Lynch syndrome) have large genomic deletions or duplications in the mismatch repair genes, hMLH1 and hMSH2, which can be challenging to detect by traditional methods. For this study, we developed and validated a novel Southern blot analysis method that allows for ascertainment of the extent of the dosage alterations on an exon-by-exon basis and compared this method to a second novel technique, multiplex ligation-dependent probe amplification (MLPA). From a total of 254 patients referred for Lynch syndrome testing, 20 of the 118 MLH1 cases and 42 of the 136 MSH2 cases had large genomic alterations, as detected by Southern blot. MLPA and Southern blot results were concordant with the exception of three major discrepancies: one because of a lack of MLPA probes for the region altered, another because of a point mutation near the MLPA probe ligation site, and another that was unexplained. Compared to Southern blot, MLPA has a shorter turn-around time, the analysis is less costly, less time-consuming, and less labor-intensive, and results are generally clear and unambiguous. However, concerns with MLPA include the presence of false-negatives and -positives because of positioning of probes and DNA variants near the probe ligation site. Overall, both Southern blot and MLPA provide important tools for the complete evaluation of patients with Lynch syndrome.
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Affiliation(s)
- Linnea M Baudhuin
- Department of Laboratory Medicine and Pathology, Division of Laboratory Genetics, Mayo Clinic, 200 First St. SW, 920 Hilton Bldg., Rochester, MN 55905, USA
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Mata A, Llach J, Castells A, Rovira JM, Pellisé M, Ginès A, Fernández-Esparrach G, Andreu M, Bordas JM, Piqué JM. A prospective trial comparing wireless capsule endoscopy and barium contrast series for small-bowel surveillance in hereditary GI polyposis syndromes. Gastrointest Endosc 2005; 61:721-5. [PMID: 15855978 DOI: 10.1016/s0016-5107(05)00289-0] [Citation(s) in RCA: 98] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Capsule endoscopy has demonstrated its clinical utility in the evaluation of the small bowel, and, accordingly, it has been suggested that it could be useful for the identification of small-intestinal polyps in patients with polyposis syndromes. The objective was to establish the effectiveness of wireless capsule endoscopy for detecting small-bowel polyps in patients with hereditary GI polyposis syndromes in comparison with barium contrast series. METHODS Consecutive patients with GI polyposis syndromes were included. Small-bowel follow-through series and capsule endoscopy were performed within 1 week, in a blind fashion. The number and the location of polyps were analyzed. RESULTS Twenty-four patients with familial adenomatous polyposis (n = 20) or Peutz-Jeghers syndrome (n = 4) were included. Capsule endoscopy detected small-bowel polyps in 7 of 24 patients (29%), whereas a barium contrast study identified small-intestinal polyps in only 3 of these 7 patients. In the 4 remaining patients, all of them with familial adenomatous polyposis, polyps detected by the capsule but missed in radiographic series were located at either ileum (2 patients), jejunum (1), or duodenum (1). No procedure-related complication was observed in any patient. CONCLUSIONS Wireless capsule endoscopy is a highly accurate technique for the detection of small-bowel polyps in patients with hereditary GI polyposis syndromes, and it represents a valuable alternative to barium contrast series in the surveillance of patients with Peutz-Jeghers syndrome.
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Affiliation(s)
- Alfredo Mata
- Digestive Endoscopy Unit, Gastroenterology Department, Institut de Malaties Digestives, Barcelona, Catalonia, Spain
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Abstract
Hereditary nonpolyposis colorectal cancer (HNPCC), or Lynch syndrome, is an autosomal dominant syndrome characterized by onset of colorectal cancer (CRC) at an early age, right-sided predominance, excess synchronous and metachronous colorectal neoplasms, and extracolonic neoplasms. It is the most common of the hereditary CRCs, so the practicing surgeon should expect to encounter patients with this disease. The diagnosis of HNPCC, which begins with a complete family history and a high index of suspicion by the clinician, has important implications in the management and surveillance of not only the affected individual but also for the individual's family. In this article, the diagnosis and management of Lynch syndrome will be reviewed, with emphasis on the implications for the surgeon.
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Affiliation(s)
- Courtney L Scaife
- Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
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