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Katona BW, Shukla A, Hu W, Nyul T, Dudzik C, Arvanitis A, Clay D, Dungan M, Weber M, Tu V, Hao F, Gan S, Chau L, Buchner AM, Falk GW, Jaffe DL, Ginsberg G, Palmer SN, Zhan X, Patterson AD, Bittinger K, Ni J. Microbiota and metabolite-based prediction tool for colonic polyposis with and without a known genetic driver. Gut Microbes 2025; 17:2474141. [PMID: 40069167 PMCID: PMC11913376 DOI: 10.1080/19490976.2025.2474141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 01/22/2025] [Accepted: 02/25/2025] [Indexed: 03/19/2025] Open
Abstract
Despite extensive investigations into the microbiome and metabolome changes associated with colon polyps and colorectal cancer (CRC), the microbiome and metabolome profiles of individuals with colonic polyposis, including those with (Gene-pos) and without (Gene-neg) a known genetic driver, remain comparatively unexplored. Using colon biopsies, polyps, and stool from patients with Gene-pos adenomatous polyposis (N = 9), Gene-neg adenomatous polyposis (N = 18), and serrated polyposis syndrome (SPS, N = 11), we demonstrated through 16S rRNA sequencing that the mucosa-associated microbiota in individuals with colonic polyposis is representative of the microbiota associated with small polyps, and that both Gene-pos and SPS cohorts exhibit differential microbiota populations relative to Gene-neg polyposis cohorts. Furthermore, we used these differential microbiota taxa to perform linear discriminant analysis to differentiate Gene-neg subjects from Gene-pos and from SPS subjects with an accuracy of 89% and 93% respectively. Stool metabolites were quantified via 1H NMR, revealing an increase in alanine in SPS subjects relative to non-polyposis subjects, and Partial Least Squares Discriminant Analysis (PLS-DA) analysis indicated that the proportion of leucine to tyrosine in fecal samples may be predictive of SPS. Use of these microbial and metabolomic signatures may allow for better diagnostric and risk-stratification tools for colonic polyposis patients and their families as well as promote development of microbiome-targeted approaches for polyp prevention.
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Affiliation(s)
- Bryson W. Katona
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Ashutosh Shukla
- Division of Digestive & Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Weiming Hu
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
| | - Thomas Nyul
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Christina Dudzik
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Alex Arvanitis
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Daniel Clay
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Michaela Dungan
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Marina Weber
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Vincent Tu
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
| | - Fuhua Hao
- Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, Penn State University, University Park, PA, USA
| | - Shuheng Gan
- Peter O’Donnell Jr. School of Public Health, Quantitative Biomedical Research Center, Center for the Genetics and Host Defense, The University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Lillian Chau
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Anna M. Buchner
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Gary W. Falk
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - David L. Jaffe
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Gregory Ginsberg
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Suzette N. Palmer
- Peter O’Donnell Jr. School of Public Health, Quantitative Biomedical Research Center, Center for the Genetics and Host Defense, The University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Xiaowei Zhan
- Peter O’Donnell Jr. School of Public Health, Quantitative Biomedical Research Center, Center for the Genetics and Host Defense, The University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Andrew D. Patterson
- Department of Veterinary and Biomedical Sciences, Center for Molecular Toxicology and Carcinogenesis, Penn State University, University Park, PA, USA
| | - Kyle Bittinger
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
| | - Josephine Ni
- Division of Digestive & Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
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Li H, Zhao Y, Li W, Wang W, Zhi S, Wu Y, Zhong Q, Wang R, Sun J. A WeChat-Based Decision Aid Intervention to Promote Informed Decision-Making for Family Members Regarding the Genetic Testing of Patients With Colorectal Cancer: Randomized Controlled Trial. J Med Internet Res 2025; 27:e60681. [PMID: 40258273 PMCID: PMC12053134 DOI: 10.2196/60681] [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: 05/18/2024] [Revised: 10/22/2024] [Accepted: 03/19/2025] [Indexed: 04/23/2025] Open
Abstract
BACKGROUND Identifying patients with inherited colorectal cancer (CRC) syndromes offers many potential benefits. However, individuals often experience decisional conflict regarding genetic testing for CRC, and the uptake rate remains low. Given the growing popularity of genetic testing and the increasing demands on genetic service providers, strategies are needed to promote informed decision-making, increase genetic testing uptake among at-risk individuals, and ensure the rational use of genetic service resources. OBJECTIVE This study aims to determine whether a decision aid (DA) tool could promote informed decision-making among family members regarding the genetic testing of a patient with CRC. METHODS A single-center, parallel-group, randomized controlled trial was conducted. We randomized 82 family members of patients with CRC, who were involved in major medical decision-making for the patient, to either a DA intervention or usual care. The primary outcome was informed decision-making, assessed through measures of knowledge, decisional conflict, decision self-efficacy, and preparation for decision-making. Secondary outcomes included patients' uptake of genetic counseling and testing, participants' CRC screening behavior, healthy lifestyle scores, anxiety and depression levels, quality of life, and satisfaction with the intervention. Data were collected at baseline (T0), after the intervention (T1), and 3 months after the baseline survey (T2). The DA intervention and outcome assessments at T1 and T2 were delivered via WeChat. The effects of the intervention were analyzed using generalized estimating equation models. RESULTS Statistically significant improvements were observed in knowledge (T1: β=2.049, P<.001; T2: β=3.317, P<.001), decisional conflict (T1: β=-11.660, P<.001; T2: β=-17.587, P<.001), and decision self-efficacy (T1: β=15.353, P<.001; T2: β=22.337, P<.001) in the DA group compared with the usual care group at both T1 and T2. Additionally, the DA group showed significantly greater improvement in processed and red meat intake (β=-1.494, P<.001) at T1 and in healthy lifestyle scores (β=1.073, P=.03) at T2. No differences were found between the groups for other outcomes. CONCLUSIONS A DA tool may be a safe, effective, and resource-efficient approach to facilitate informed decision-making about genetic testing. However, the current DA tool requires optimization and further evaluation-for example, by leveraging more advanced technology than WeChat to develop a simpler and more intelligent DA system. TRIAL REGISTRATION Chinese Clinical Trial Registry ChiCTR2100048051; https://www.chictr.org.cn/showproj.html?proj=129054.
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Affiliation(s)
- Huanhuan Li
- School of Nursing, Jilin University, Changchun, Jilin, China
- School of Nursing, Anhui Medical University, Hefei, Anhui, China
| | - Yanjie Zhao
- School of Nursing, Jilin University, Changchun, Jilin, China
- School of Nursing, Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Wei Li
- Hebei General Hospital, Shijiazhuang, Hebei, China
| | - Wenxia Wang
- School of Nursing, Jilin University, Changchun, Jilin, China
- School of Nursing, Peking University, Beijing, China
| | - Shengze Zhi
- School of Nursing, Jilin University, Changchun, Jilin, China
| | - Yifan Wu
- School of Nursing, Jilin University, Changchun, Jilin, China
| | - Qiqing Zhong
- School of Nursing, Jilin University, Changchun, Jilin, China
| | - Rui Wang
- School of Nursing, Jilin University, Changchun, Jilin, China
| | - Jiao Sun
- School of Nursing, Jilin University, Changchun, Jilin, China
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Henrikson NB, Scrol A, Zepp JM, Anderson ML, Blasi PR, Ewing JJ, Grafton J, Ralston JD, Fullerton SM, Leppig KA. Health System-Led Early Consent and Direct Contact of At-Risk Relatives: Pilot Study Results. Public Health Genomics 2025; 28:150-162. [PMID: 40179849 DOI: 10.1159/000545404] [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: 04/19/2024] [Accepted: 03/18/2025] [Indexed: 04/05/2025] Open
Abstract
INTRODUCTION At-risk relatives of probands with genetic variants associated with hereditary cancer risk should receive cascade genetic testing. In the USA, probands are expected to notify their own at-risk relatives, but many relatives never learn of their risk, representing missed opportunity to reduce morbidity and mortality associated with hereditary cancers. Direct contact of relatives could reach relatives not contacted by the proband. We conducted a single-arm, prospective pilot evaluation of a direct contact intervention based on patient and family preferences. Here, we report the study's quantitative results, measured by proband and relative participation in the intervention follow-up survey. METHODS We recruited adults receiving genetic counseling for inherited cancer risk at one US integrated health system. A genetic counselor offered to contact at-risk relatives. We surveyed probands and relatives at study enrollment and 6-8 weeks and evaluated administrative data to assess the program's outreach to probands and relatives, its acceptability, and its limited efficacy. RESULTS We approached 148 probands before their genetic counseling appointment. Fifty-five (37%) consented to study participation. Of these, 31 completed genetic testing, 29 of whom provided consent to contact 101 relatives. Forty-four percent (n = 45) of relatives consented to be contacted by the study genetic counselor. Acceptability was high for both groups and no harms were reported. All relatives reached (n = 43) received their proband's test results, including 6 pathogenic/likely pathogenic findings. CONCLUSION A direct contact program was acceptable, reached at-risk relatives, and communicated proband test results. Direct contact with early consent of relatives holds promise for future research.
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Affiliation(s)
- Nora B Henrikson
- Kaiser Permanente Washington Health Research Institute, Seattle, Washington, USA
| | - Aaron Scrol
- Kaiser Permanente Washington Health Research Institute, Seattle, Washington, USA
| | - Jamilyn M Zepp
- Department of Translational and Applied Genomics, Kaiser Permanente Northwest Center for Health Research, Portland, Oregon, USA
| | - Melissa L Anderson
- Kaiser Permanente Washington Health Research Institute, Seattle, Washington, USA
| | - Paula R Blasi
- Kaiser Permanente Washington Health Research Institute, Seattle, Washington, USA
| | - John J Ewing
- Kaiser Permanente Washington Health Research Institute, Seattle, Washington, USA
| | - Jane Grafton
- Kaiser Permanente Washington Health Research Institute, Seattle, Washington, USA
| | - James D Ralston
- Kaiser Permanente Washington Health Research Institute, Seattle, Washington, USA
| | - Stephanie M Fullerton
- Department of Bioethics and Humanities, University of Washington School of Medicine, Seattle, Washington, USA
| | - Kathleen A Leppig
- Division of Medical Genetics, University of Washington School of Medicine, Seattle, Washington, USA
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Xie Y, Jin Y, Liu Z, Li J, Tao Q, Wu Y, Chen Y, Zeng C. Identification of Diagnostic Biomarkers for Colorectal Polyps Based on Noninvasive Urinary Metabolite Screening and Construction of a Nomogram. Cancer Med 2025; 14:e70762. [PMID: 40200572 PMCID: PMC11978731 DOI: 10.1002/cam4.70762] [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: 10/15/2024] [Revised: 02/24/2025] [Accepted: 03/03/2025] [Indexed: 04/10/2025] Open
Abstract
PURPOSE/BACKGROUNDS Colorectal polyps (CRPs) are precursors to colorectal cancer (CRC), and early detection is crucial for prevention. Traditional diagnostic methods are invasive, prompting a need for noninvasive biomarkers. This study aimed to identify urinary metabolite biomarkers for diagnosing CRPs and construct a diagnostic nomogram based on noninvasive urinary metabolite screening. PATIENTS AND METHODS A total of 192 participants, including 64 CRP patients and 128 healthy controls, were recruited. Urine samples were analyzed using untargeted gas chromatography-mass spectrometry (GC-MS) and ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). Metabolite screening was performed using weighted gene coexpression network analysis (WGCNA), least absolute shrinkage and selection operator (LASSO), and support vector machine-recursive feature elimination (SVM-RFE). A diagnostic nomogram was developed based on identified metabolites, and its performance was evaluated using receiver operating characteristic (ROC) curves, calibration plots, and decision curve analysis (DCA). RESULTS A total of 350 metabolites were identified, with 7 key metabolites significantly associated with CRP. Multivariate logistic regression analysis identified Saccharin (OR = 48.3, 95% CI: 4.44-525.32) and N-omega-acetylhistamine (OR = 27.91, 95% CI: 2.31-337.06) as significant risk factors for CRP, while N-methyl-L-proline, trimethylsilyl ester (OR = 0.08, 95% CI: 0.01-0.8) was a protective factor. A nomogram incorporating these metabolites demonstrated strong discriminatory power, with AUC values of 0.974 and 0.960 in the training and validation sets, respectively. Calibration plots and DCA confirmed the model's accuracy and clinical utility. CONCLUSIONS This study successfully identified seven urinary metabolites as potential noninvasive biomarkers for CRP. The constructed diagnostic nomogram, based on these metabolites, offers high predictive accuracy and clinical applicability, providing a promising tool for the early detection of CRP.
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Affiliation(s)
- Yang Xie
- Department of GastroenterologyJiangxi Province Hospital of Integrated Chinese and Western MedicineNanchangJiangxiChina
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, the First Affiliated Hospital, Jiangxi Medical CollegeNanchang UniversityNanchangJiangxiChina
| | - Yiyi Jin
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, the First Affiliated Hospital, Jiangxi Medical CollegeNanchang UniversityNanchangJiangxiChina
| | - Zide Liu
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, the First Affiliated Hospital, Jiangxi Medical CollegeNanchang UniversityNanchangJiangxiChina
| | - Jun Li
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, the First Affiliated Hospital, Jiangxi Medical CollegeNanchang UniversityNanchangJiangxiChina
| | - Qing Tao
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, the First Affiliated Hospital, Jiangxi Medical CollegeNanchang UniversityNanchangJiangxiChina
| | - Yonghui Wu
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, the First Affiliated Hospital, Jiangxi Medical CollegeNanchang UniversityNanchangJiangxiChina
| | - Youxiang Chen
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, the First Affiliated Hospital, Jiangxi Medical CollegeNanchang UniversityNanchangJiangxiChina
| | - Chunyan Zeng
- Department of GastroenterologyJiangxi Province Hospital of Integrated Chinese and Western MedicineNanchangJiangxiChina
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Austin S, Hanson EN, Delacroix E, Bacon E, Rice J, Gerido LH, Rizzo E, Pleasant V, Stoffel EM, Griggs JJ, Resnicow K. Impact of barriers and motivators on intention and confidence to undergo hereditary cancer genetic testing. J Genet Couns 2025; 34:e1926. [PMID: 38803214 PMCID: PMC11599461 DOI: 10.1002/jgc4.1926] [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: 06/30/2023] [Revised: 05/13/2024] [Accepted: 05/15/2024] [Indexed: 05/29/2024]
Abstract
Genetic testing for hereditary cancer syndromes can provide lifesaving information allowing for individualized cancer screening, prevention, and treatment. However, the determinants, both barriers and motivators, of genetic testing intention are not well described. A survey of barriers and motivators to genetic testing was emailed to adult patients eligible for genetic testing based on cancer diagnosis who previously have not had genetic testing (n = 201). Associations between barriers/motivators with testing intention and confidence were examined first by correlation followed by multivariable linear regression model holding constant potential covariates. Seven barrier items from two domains (logistics and genetic testing knowledge) were found to significantly negatively correlate with genetic testing intention. Unexpectedly, three barrier items had significant positive correlation with genetic testing intention; these were related to family worry (passing a condition on to future generations) and testing knowledge (needing more information on the genetic testing process and what it has to offer). Ten barrier items had significant negative correlation with confidence to get a genetic test and encompassed four domains: stigma, insurance/genetic discrimination, knowledge, and cost. All motivator items were associated with intention to get a genetic test, while none were associated with confidence. Multivariable analysis yielded six total barriers (five from the knowledge domain, one from cost domain) and two motivators (relieved to know and treatment impact) that were significantly associated with genetic testing intention or confidence when controlling for demographic characteristics. These findings indicate the need for tailored interventions to amplify motivating factors and counter-message barriers to enhance patient motivation and confidence to undergo testing.
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Affiliation(s)
- Sarah Austin
- Rogel Cancer CenterUniversity of MichiganAnn ArborMichiganUSA
| | - Erika N. Hanson
- Department of Internal MedicineUniversity of Michigan School of MedicineAnn ArborMichiganUSA
| | - Emerson Delacroix
- Rogel Cancer CenterUniversity of MichiganAnn ArborMichiganUSA
- Department of Internal MedicineUniversity of Michigan School of MedicineAnn ArborMichiganUSA
- University of Michigan School of Public HealthAnn ArborMichiganUSA
| | - Elizabeth Bacon
- Department of Internal MedicineUniversity of Michigan School of MedicineAnn ArborMichiganUSA
| | - John Rice
- University of Michigan School of Public HealthAnn ArborMichiganUSA
| | | | - Elizabeth Rizzo
- Department of Internal MedicineUniversity of Michigan School of MedicineAnn ArborMichiganUSA
| | - Versha Pleasant
- Rogel Cancer CenterUniversity of MichiganAnn ArborMichiganUSA
| | - Elena M. Stoffel
- Rogel Cancer CenterUniversity of MichiganAnn ArborMichiganUSA
- Department of Internal MedicineUniversity of Michigan School of MedicineAnn ArborMichiganUSA
| | - Jennifer J. Griggs
- Rogel Cancer CenterUniversity of MichiganAnn ArborMichiganUSA
- Department of Internal MedicineUniversity of Michigan School of MedicineAnn ArborMichiganUSA
- University of Michigan School of Public HealthAnn ArborMichiganUSA
| | - Ken Resnicow
- Rogel Cancer CenterUniversity of MichiganAnn ArborMichiganUSA
- University of Michigan School of Public HealthAnn ArborMichiganUSA
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Barauskaite E, Raciunas A, Vaicekauskas R. Endoscopic Screening and Surveillance of Gastrointestinal Cancer. Cureus 2025; 17:e79274. [PMID: 40125194 PMCID: PMC11926922 DOI: 10.7759/cureus.79274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/19/2025] [Indexed: 03/25/2025] Open
Abstract
Gastrointestinal (GI) cancer is a major health concern, contributing significantly to mortality rates in many regions, including Europe. It affects millions of people worldwide and leads to hundreds of thousands of deaths each year. Early detection and treatment through endoscopic methods play a vital role, providing less invasive and more affordable options compared to traditional surgical procedures. Targeted screening is vital for conditions such as Barrett's esophagus (BE), esophageal adenocarcinoma (EAC), gastric cancer (GC), ampullary carcinoma (AC), and colorectal cancer (CRC), particularly in high-risk populations. Endoscopic surveillance significantly reduces cancer incidence and improves survival rates, highlighting the importance of continuous advancements and updated guidelines to enhance screening efficacy and patient outcomes.
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Affiliation(s)
- Emilija Barauskaite
- Department of Family Medicine Center, Vilnius University Hospital Santaros Clinics, Vilnius, LTU
| | - Andrius Raciunas
- Department of Family Medicine Center, Vilnius University Hospital Santaros Clinics, Vilnius, LTU
| | - Rolandas Vaicekauskas
- Department of Gastroenterology, Nephrourology, and Surgery, Vilnius University Hospital Santaros Clinics, Vilnius, LTU
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Baker AM, Goehringer J, Woltz M, Romagnoli KM, Campbell-Salome G, Sturm AC, Buchanan AH, Williams MS, Kulchak Rahm A. Development and Pilot Testing of Evidence-Based Interventions to Improve Adherence after Receiving a Genetic Result. Public Health Genomics 2024; 27:197-209. [PMID: 39501610 DOI: 10.1159/000541745] [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: 04/30/2024] [Accepted: 09/30/2024] [Indexed: 11/16/2024] Open
Abstract
INTRODUCTION Previous research indicates that population genomic screening can benefit individuals who act on the genetic results. However, there remains a significant gap between individuals receiving genetic information and acting on current risk management recommendations, prompting exploration of interventions to close this gap. This study aimed to determine the feasibility and acceptability and conduct a pilot implementation of existing evidence-based interventions (EBIs) for adherence to disease management for select genetic conditions among individuals ascertained through a population genomic screening program. METHODS Surveys of and interviews with individuals who received a genomic screening result were conducted to assess barriers to guideline-recommended care and assess the acceptability of problem-solving (PS) and motivational interviewing (MI) EBIs to facilitate adherence to recommendations. A design thinking workshop was conducted with clinicians to co-develop an MI- and PS-based intervention that would fit with current workflows to be piloted. Post-pilot engagement sessions with implementers determined acceptability and feasibility of the MI/PS pilot program for clinical implementation and elicited proposed adaptations for improvement. RESULTS PS and MI EBIs were reported to be acceptable and feasible to individuals with a result, and barriers to performing recommended management were identified. The pilot program included outreach by genetic counselors to individuals with a result, review of a checklist of barriers, and delivery of PS or MI as appropriate to facilitate care. The protocol as piloted was deemed acceptable and feasible for clinicians to deliver, with adaptations suggested. CONCLUSION These results will inform an effectiveness trial to address gaps in adherence in patients who have received actionable genomic results.
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Affiliation(s)
- Anna May Baker
- Department of Psychology, Bucknell University, Lewisburg, Pennsylvania, USA
- Department of Psychology, Clemson University, Clemson, South Carolina, USA
| | | | - Makenzie Woltz
- Department of Genomic Health, Geisinger, Danville, Pennsylvania, USA
| | | | - Gemme Campbell-Salome
- Department of Genomic Health, Geisinger, Danville, Pennsylvania, USA
- Department of Population Health Sciences, Geisinger, Danville, Pennsylvania, USA
| | - Amy C Sturm
- Department of Genomic Health, Geisinger, Danville, Pennsylvania, USA
- 23andME, Sunnyvale, California, USA
| | - Adam H Buchanan
- Department of Genomic Health, Geisinger, Danville, Pennsylvania, USA
| | - Marc S Williams
- Department of Genomic Health, Geisinger, Danville, Pennsylvania, USA
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Kögl J, Pan TL, Marth C, Zeimet AG. The game-changing impact of POLE mutations in oncology-a review from a gynecologic oncology perspective. Front Oncol 2024; 14:1369189. [PMID: 39239272 PMCID: PMC11374733 DOI: 10.3389/fonc.2024.1369189] [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: 01/11/2024] [Accepted: 07/31/2024] [Indexed: 09/07/2024] Open
Abstract
Somatic mutations within the exonuclease proofreading domain (EDM) of the DNA polymerase Pol ϵ (POLE) gene are increasingly being discovered in ovarian, colorectal, urological, and, especially, endometrial carcinoma (EC), where these are found in up to 10% of the cases. In EC, there are five confirmed pathogenic somatic POLE-EDM mutations that are located at codons 286, 411, 297, 456, and 459, and these are called "hotspot" mutations. POLE mutant tumors are ultramutated entities with a frequency of base substitution mutations that is among the highest in human tumors. Interestingly, these mutations are associated with excellent clinical outcome in EC. An additional six "non-hotspot" POLE-EDM EC mutations are also considered pathogenic, and they also confer a favorable prognosis. Currently, de-escalation of adjuvant treatment is recommended for patients with EC with stage I-II tumors involving any of these 11 EDM mutations, even in patients with other clinicopathological risk factors. The high tumor mutational burden and the consequent increased infiltration of immune cells due to the overexpression of different neoantigens are probably responsible for the improved prognosis. Ongoing studies are examining POLE hotspot mutations among many non-gynecologic tumors, although the impact of such mutations on clinical outcomes is still a topic of debate. Therapeutic modalities for these hypermutated tumors are also an important consideration, including the need for or de-escalation of adjuvant treatments and the response to immune therapy. This review addresses the critical role of POLE mutations in gynecologic oncology and oncology in general, focusing on definitions, variants, underlying pathogenic mechanisms, upcoming developments in the field, and the clinic behavior associated with such mutations.
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Affiliation(s)
- Johanna Kögl
- Department of Obstetrics and Gynecology, Medical University of Innsbruck, Innsbruck, Austria
| | - Teresa L Pan
- Department of Obstetrics and Gynecology, Medical University of Innsbruck, Innsbruck, Austria
| | - Christian Marth
- Department of Obstetrics and Gynecology, Medical University of Innsbruck, Innsbruck, Austria
| | - Alain G Zeimet
- Department of Obstetrics and Gynecology, Medical University of Innsbruck, Innsbruck, Austria
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Hong YR, Wang R, Chen G, Khan M, Vadaparampil S, Bian J, George TJ, Braithwaite D. Sociodemographic and Clinical Characteristics Associated with Genetic Testing among Cancer Survivors: Evidence from Three Cancer Registries. Public Health Genomics 2024; 27:124-135. [PMID: 39102787 DOI: 10.1159/000540341] [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: 02/16/2024] [Accepted: 07/09/2024] [Indexed: 08/07/2024] Open
Abstract
INTRODUCTION Genetic tests, including germline and tumor (somatic) testing, can optimize the clinical care and outcomes for cancer patients and their family members. However, evidence on cancer patients' use of genetic testing and discussions about it with healthcare providers is limited. METHODS Study participants included cancer survivors aged 18 or older, drawn from the 2021 Health Information and National Trends Survey (HINTS)-Surveillance, Epidemiology, and End Results (SEER) linked database, which comprises three US cancer registries: Iowa, New Mexico, and the Greater Bay Area. Sociodemographic factors (e.g., age, sex, income, education) at the time of the survey and clinical characteristics (e.g., cancer site, stage) at the time of diagnosis were compared based on self-reported genetic testing status and provider discussions, using survey design-adjusted analysis. RESULTS The weighted study sample comprised 415,978 cancer survivors with a mean age of 70.5 years at the time of the survey. Overall, 17.0% reported having germline testing, 8.5% having tumor testing, and 8.6% discussing tumor testing with their healthcare providers. Higher proportions of germline genetic testing were observed among survivors under age 65 at the time of the survey, females, holding college degrees, and with private insurance coverage compared to their respective counterparts - males, aged 65 or above when surveyed, with lower educational attainment, and with public insurance or uninsured. The proportion of those who reported tumor testing was greater for those diagnosed in recent years (2015-2017 vs. before 2002). Regarding clinical characteristics, survivors with ovarian and breast cancers had a 7.0-36.4% higher prevalence of both testing compared to those with other cancer types lacking germline indication. More cancer survivors diagnosed at distant stages (vs. regional) or between 2015 and 2017 (vs. 2003-2010) reported having provider discussions about tumor testing. CONCLUSION Findings showed that the highest reports of germline testing were among young female cancer survivors and those with higher education and private insurance. Survivors diagnosed in recent years or with advanced-stage disease were more likely to report discussing tumor testing with providers. Further research is warranted to better understand the barriers and educational needs of cancer patients, caregivers, and providers to optimize genetic testing strategies.
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Affiliation(s)
- Young-Rock Hong
- Department of Health Services Research, Management and Policy, College of Public Health and Health Professions, University of Florida, Gainesville, Florida, USA
| | - Ruixuan Wang
- Department of Health Services Research, Management and Policy, College of Public Health and Health Professions, University of Florida, Gainesville, Florida, USA
| | - Guanming Chen
- Department of Health Outcomes and Bioinformatics, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Mishal Khan
- Department of Health Services Research, Management and Policy, College of Public Health and Health Professions, University of Florida, Gainesville, Florida, USA
| | - Susan Vadaparampil
- Department of Health Outcomes and Behavior, Moffit Cancer Center, Tampa, Florida, USA
| | - Jiang Bian
- Department of Health Outcomes and Bioinformatics, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Thomas J George
- Division of Hematology and Oncology, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Dejana Braithwaite
- Department of Epidemiology, College of Public Health and Health Professions, University of Florida, Gainesville, Florida, USA
- Department of Surgery, College of Medicine, University of Florida, Gainesville, Florida, USA
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10
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Yu M, Ouyang Y, Yuan Z, Wang S, Pang W, Yan S, Liu X, Wang W, Yi B, Han Q, Yao Y, Liu Y, Song J, Chu T, Feng Z, Zhang Q, Zhang X, Zhang C. Derivation and validation of a nomogram incorporating modifiable lifestyle factors to predict development of colorectal adenomas after negative index colonoscopy. Sci Rep 2024; 14:11633. [PMID: 38773186 PMCID: PMC11109095 DOI: 10.1038/s41598-024-62348-w] [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: 06/11/2023] [Accepted: 05/15/2024] [Indexed: 05/23/2024] Open
Abstract
This retrospective cohort study aimed to identify baseline patient characteristics involving modifiable lifestyle factors that are associated with the development of colorectal adenomas, and establish and validate a nomogram for risk predictions among high-risk populations with negative index colonoscopy. A total of 83,076 participants who underwent an index colonoscopy at the Tianjin Union Medical Center between 2004 and 2019 were collected. According to meticulous inclusion and exclusion criteria, 249 subjects were enrolled and categorized into the primary and validation cohorts. Based on the primary cohort, we utilized the LASSO-Cox regression and the univariate/multivariate Cox proportional hazards (Cox-PH) regression parallelly to select variables, and incorporated selected variables into two nomogram models established using the multivariate Cox-PH regression. Comparison of the Akaike information criterion and the area under the receiver operating characteristic curve of the two models demonstrated that the nomogram model constituted by four covariates retained by the LASSO-Cox regression, including baseline age, body mass index, physical activity and family history of colorectal cancer (CRC) in first-degree relatives, performed better at predicting adenoma-free survival probabilities. Further validation including the concordance index, calibration plots, decision curve analysis and Kaplan-Meier survival curves also revealed good predictive accuracy, discriminating ability, clinical utility and risk stratification capacity of the nomogram model. Our nomogram will assist high-risk individuals with negative index colonoscopy to prevent colorectal adenoma occurrence and CRC morbidity with improved cost-effectiveness.
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Affiliation(s)
- Mingqian Yu
- School of Medicine, Nankai University, Tianjin, 300071, China
| | - Yiben Ouyang
- School of Medicine, Nankai University, Tianjin, 300071, China
| | - Zhen Yuan
- School of Medicine, Nankai University, Tianjin, 300071, China
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, 300121, China
| | - Shuyuan Wang
- School of Medicine, Nankai University, Tianjin, 300071, China
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, 300121, China
| | - Wenwen Pang
- Department of Clinical Laboratory, Tianjin Union Medical Center, Tianjin, 300121, China
| | - Suying Yan
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, 300121, China
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Xinyu Liu
- Tianjin Medical University, Tianjin, 300041, China
| | - Wanting Wang
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, 300121, China
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Ben Yi
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, 300121, China
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Qiurong Han
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, 300121, China
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Yao Yao
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, 300121, China
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Yanfei Liu
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, 300121, China
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Jiachun Song
- School of Medicine, Nankai University, Tianjin, 300071, China
| | - Tianhao Chu
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, 300121, China
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Zhiqiang Feng
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, 300121, China
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Qinghuai Zhang
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, 300121, China
- The Institute of Translational Medicine, Tianjin Union Medical Center, Tianjin, 300121, China
- Tianjin Institute of Coloproctology, Tianjin, China
| | - Xipeng Zhang
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, 300121, China.
- The Institute of Translational Medicine, Tianjin Union Medical Center, Tianjin, 300121, China.
- Tianjin Institute of Coloproctology, Tianjin, China.
| | - Chunze Zhang
- School of Medicine, Nankai University, Tianjin, 300071, China.
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, 300121, China.
- The Institute of Translational Medicine, Tianjin Union Medical Center, Tianjin, 300121, China.
- Tianjin Institute of Coloproctology, Tianjin, China.
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11
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Tjandra D, Boussioutas A. Li Fraumeni Syndrome predisposes to gastro-esophageal junction tumours. Fam Cancer 2024; 23:29-33. [PMID: 38206485 PMCID: PMC10869364 DOI: 10.1007/s10689-023-00353-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Accepted: 12/04/2023] [Indexed: 01/12/2024]
Abstract
Li-Fraumeni Syndrome (LFS), caused by germline pathogenic variants in TP53, predisposes to a wide range of young-onset malignancies, particularly sarcoma, breast and brain cancer. More recently, an increased risk of gastric adenocarcinoma has been recognised, although uptake of surveillance upper endoscopy is unclear. Our retrospective review of 65 patients with LFS, of whom 53.8% had undergone endoscopy, identified four patients (6.2%) with gastro-esophageal junction (GEJ) adenocarcinomas. Two cases were found on asymptomatic screening and were early stage. No cases had family history of gastrointestinal malignancy. Reviewing genomic data from The Cancer Genome Atlas Program, 76.4% of sporadic esophageal adenocarcinomas harboured somatic TP53 pathogenic variants, compared with 39.9% of non-cardia gastric cancers. This similar pattern observed in germline and sporadic cases warrants further investigation. We propose that upper endoscopy be recommended to all patients with LFS, with a focus on appropriate surveillance of the GEJ.
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Affiliation(s)
- Douglas Tjandra
- Familial Cancer Centre, The Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Department of Gastroenterology, Alfred Hospital, 99 Commercial Rd, Melbourne, VIC, 3004, Australia
- Department of Gastroenterology, Central Clinical School, Monash University, Melbourne, VIC, Australia
| | - Alex Boussioutas
- Familial Cancer Centre, The Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
- Department of Gastroenterology, Alfred Hospital, 99 Commercial Rd, Melbourne, VIC, 3004, Australia.
- Department of Gastroenterology, Central Clinical School, Monash University, Melbourne, VIC, Australia.
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12
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Riedinger CJ, Esnakula A, Haight PJ, Suarez AA, Chen W, Gillespie J, Villacres A, Chassen A, Cohn DE, Goodfellow PJ, Cosgrove CM. Characterization of mismatch-repair/microsatellite instability-discordant endometrial cancers. Cancer 2024; 130:385-399. [PMID: 37751191 PMCID: PMC10843110 DOI: 10.1002/cncr.35030] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 08/09/2023] [Accepted: 08/14/2023] [Indexed: 09/27/2023]
Abstract
BACKGROUND Mismatch-repair (MMR)/microsatellite instability (MSI) status has therapeutic implications in endometrial cancer (EC). The authors evaluated the concordance of testing and factors contributing to MMR expression heterogeneity. METHODS Six hundred sixty-six ECs were characterized using immunohistochemistry (IHC), MSI testing, and mut-L homolog 1 (MLH1) methylation. Select samples underwent whole-transcriptome analysis and next-generation sequencing. MMR expression of metastatic/recurrent sites was evaluated. RESULTS MSI testing identified 27.3% of cases as MSI-high (n = 182), MMR IHC identified 25.1% cases as MMR-deficient (n = 167), and 3.8% of cases (n = 25) demonstrated discordant results. A review of IHC staining explained discordant results in 18 cases, revealing subclonal loss of MLH1/Pms 1 homolog 2 (PMS2) (n = 10) and heterogeneous MMR IHC (mut-S homolog 6 [MSH6], n = 7; MLH1/PMS2, n = 1). MSH6-associated Lynch syndrome was diagnosed in three of six cases with heterogeneous expression. Subclonal or heterogeneous cases had a 38.9% recurrence rate (compared with 16.7% in complete MMR-deficient cases and 9% in MMR-proficient cases) and had abnormal MMR IHC results in all metastatic recurrent sites (n = 7). Tumors with subclonal MLH1/PMS2 demonstrated 74 differentially expressed genes (determined using digital spatial transcriptomics) when stratified by MLH1 expression, including many associated with epithelial-mesenchymal transition. CONCLUSIONS Subclonal/heterogeneous MMR IHC cases showed epigenetic loss in 66.7%, germline mutations in 16.7%, and somatic mutations in 16.7%. MMR IHC reported as intact/deficient missed 21% of cases of Lynch syndrome. EC with subclonal/heterogeneous MMR expression demonstrated a high recurrence rate, and metastatic/recurrent sites were MMR-deficient. Transcriptional analysis indicated an increased risk for migration/metastasis, suggesting that clonal MMR deficiency may be a driver for tumor aggressiveness. Reporting MMR IHC only as intact/deficient, without reporting subclonal and heterogeneous staining, misses opportunities for biomarker-directed therapy. PLAIN LANGUAGE SUMMARY Endometrial cancer is the most common gynecologic cancer, and 20%-40% of tumors have a defect in DNA proofreading known as mismatch-repair (MMR) deficiency. These results can be used to guide therapy. Tests for this defect can yield differing results, revealing heterogeneous (mixed) proofreading capabilities. Tumors with discordant testing results and mixed MMR findings can have germline or somatic defects in MMR genes. Cells with deficient DNA proofreading in tumors with mixed MMR findings have DNA expression profiles linked to more aggressive characteristics and cancer spread. These MMR-deficient cells may drive tumor behavior and the risk of spreading cancer.
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Affiliation(s)
- Courtney J. Riedinger
- Department of Obstetrics and Gynecologic, Division of Gynecologic Oncology, The Ohio State University Comprehensive Cancer Center/James Cancer Hospital, Columbus, OH
| | - Ashwini Esnakula
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Paulina J. Haight
- Department of Obstetrics and Gynecologic, Division of Gynecologic Oncology, The Ohio State University Comprehensive Cancer Center/James Cancer Hospital, Columbus, OH
| | - Adrian A. Suarez
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Wei Chen
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Jessica Gillespie
- Department of Obstetrics and Gynecologic, Division of Gynecologic Oncology, The Ohio State University Comprehensive Cancer Center/James Cancer Hospital, Columbus, OH
| | - Alyssa Villacres
- Department of Obstetrics and Gynecologic, Division of Gynecologic Oncology, The Ohio State University Comprehensive Cancer Center/James Cancer Hospital, Columbus, OH
| | - Alexis Chassen
- Department of Obstetrics and Gynecologic, Division of Gynecologic Oncology, The Ohio State University Comprehensive Cancer Center/James Cancer Hospital, Columbus, OH
| | - David E. Cohn
- Department of Obstetrics and Gynecologic, Division of Gynecologic Oncology, The Ohio State University Comprehensive Cancer Center/James Cancer Hospital, Columbus, OH
| | - Paul J. Goodfellow
- Department of Obstetrics and Gynecologic, Division of Gynecologic Oncology, The Ohio State University Comprehensive Cancer Center/James Cancer Hospital, Columbus, OH
| | - Casey M. Cosgrove
- Department of Obstetrics and Gynecologic, Division of Gynecologic Oncology, The Ohio State University Comprehensive Cancer Center/James Cancer Hospital, Columbus, OH
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Vangala D, Nilius-Eliliwi V. [Novel Treatment Concepts in Patients with Colorectal Carcinomas and High Microsatellite Instability]. Zentralbl Chir 2023; 148:475-482. [PMID: 36848937 DOI: 10.1055/a-2012-4047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/01/2023]
Abstract
Approximately 15% of patients with colorectal cancer show high microsatellite instability (MSI-high) in their tumour tissue. For one third of these patients, there is a hereditary cause for this finding - that leads to the diagnosis of Lynch Syndrome. In combination with clinical findings such as the Amsterdam or the revised Bethesda criteria, MSI-high status has been used as a tool in identifying patients at risk. Today, MSI-status has gained much more importance, due to its impact on treatment decisions. Patients with UICC II cancers should not receive adjuvant treatment. For patients with distant metastases and MSI-high status, immune checkpoint inhibitors can be given as first line therapy - with tremendous success. Novel data show a deep response for immune checkpoint antibodies in patients with locally advanced colon as well as rectal cancer in a neoadjuvant setting. Especially for patients with MSI-high rectal cancer, there might be a novel therapeutic regimen utilising immune checkpoint inhibitors without neoadjuvant radio-chemotherapy and even without surgery. This could lead to a relevant reduction in morbidity in this patient cohort. In conclusion, universal MSI-testing is essential for identifying patients at risk for Lynch syndrome and for optimal decision making in treatment planning.
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Affiliation(s)
- Deepak Vangala
- Center for hemato-oncological diseases, Knappschaftskrankenhaus Bochum, Ruhr-Universität Bochum, Bochum, Deutschland
| | - Verena Nilius-Eliliwi
- Center for hemato-oncological diseases, Knappschaftskrankenhaus Bochum, Ruhr-Universität Bochum, Bochum, Deutschland
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14
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Sanchez-Mete L, Mosciatti L, Casadio M, Vittori L, Martayan A, Stigliano V. MUTYH-associated polyposis: Is it time to change upper gastrointestinal surveillance? A single-center case series and a literature overview. World J Gastrointest Oncol 2023; 15:1891-1899. [DOI: 10.4251/wjgo.v15.i11.1891] [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: 02/13/2023] [Revised: 05/28/2023] [Accepted: 06/13/2023] [Indexed: 11/15/2023] Open
Abstract
BACKGROUND The presence of Spigelman stage (SS) IV duodenal polyposis is considered the most significant risk factor for duodenal cancer in patients with MUTYH-associated polyposis (MAP). However, advanced SS disease is rarely reported in MAP patients, and no clear recommendations on small bowel (SB) surveillance have been proposed in this patient setting.
AIM To research more because that case reports of duodenal cancers in MAP suggest that they may develop in the absence of advanced benign SS disease and often involve the distal portion of the duodenum.
METHODS We describe a series of MAP patients followed up at the Regina Elena National Cancer Institute of Rome (Italy). A literature overview on previously reported SB cancers in MAP is also provided.
RESULTS We identified two (6%) SB adenocarcinomas with no previous history of duodenal polyposis. Our observations, supported by literature evidence, suggest that the formula for staging duodenal polyposis and predicting risk factors for distal duodenum and jejunal cancer may need to be adjusted to take this into account rather than focusing solely on the presence or absence of SS IV disease.
CONCLUSION Our study emphasizes the need for further studies to define appropriate upper gastrointestinal surveillance programs in MAP patients.
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Affiliation(s)
- Lupe Sanchez-Mete
- Gastroenterology and Digestive Endoscopy, Regina Elena National Cancer Institute, IRCCS, Rome 00144, Italy
| | - Lorenzo Mosciatti
- Gastroenterology and Digestive Endoscopy, Regina Elena National Cancer Institute, IRCCS, Rome 00144, Italy
| | - Marco Casadio
- Gastroenterology and Digestive Endoscopy, Regina Elena National Cancer Institute, IRCCS, Rome 00144, Italy
| | - Luigi Vittori
- Department of Radiological, Oncological and Pathological Sciences, Regina Elena National Cancer Institute, IRCCS, Rome 00144, Italy
| | - Aline Martayan
- Gastroenterology and Digestive Endoscopy, Regina Elena National Cancer Institute, IRCCS, Rome 00144, Italy
| | - Vittoria Stigliano
- Gastroenterology and Digestive Endoscopy, Regina Elena National Cancer Institute, IRCCS, Rome 00144, Italy
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McGowan KP, Delgado E, Keeley TM, Hibdon ES, Turgeon DK, Stoffel EM, Samuelson LC. Region-specific Wnt signaling responses promote gastric polyp formation in patients with familial adenomatous polyposis. JCI Insight 2023; 8:e174546. [PMID: 37943618 PMCID: PMC10896006 DOI: 10.1172/jci.insight.174546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 11/08/2023] [Indexed: 11/12/2023] Open
Abstract
Germline adenomatous polyposis coli (APC) mutation in patients with familial adenomatous polyposis (FAP) promotes gastrointestinal polyposis, including the formation of frequent gastric fundic gland polyps (FGPs). In this study, we investigated how dysregulated Wnt signaling promotes FGPs and why they localize to the corpus region of the stomach. We developed a biobank of FGP and surrounding nonpolyp corpus biopsies and organoids from patients with FAP for comparative studies. Polyp biopsies and polyp-derived organoids exhibited enhanced Wnt target gene expression. Polyp-derived organoids with intrinsically upregulated Wnt signaling showed poor tolerance to further induction, suggesting that high Wnt restricts growth. Targeted genomic sequencing revealed that most gastric polyps did not arise via APC loss of heterozygosity. Studies in genetic mouse models demonstrated that heterozygous Apc loss increased epithelial cell proliferation in the corpus but not the antrum, while homozygous Apc loss was not maintained in the corpus yet induced hyperproliferation in the antrum. Our findings suggest that heterozygous APC mutation in patients with FAP may be sufficient to drive polyp formation in the corpus region while subsequent loss of heterozygosity to further enhance Wnt signaling is not tolerated. This finding contextualizes the abundant yet benign nature of gastric polyps in FAP patient corpus compared with the rare, yet adenomatous polyps in the antrum.
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Affiliation(s)
| | | | | | | | - D. Kim Turgeon
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Elena M. Stoffel
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Linda C. Samuelson
- Department of Molecular & Integrative Physiology and
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
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Grillo F, Ali M, Paudice M, Pigozzi S, Anselmi G, Scabini S, Sciallero S, Piol N, Mastracci L. Impact of formalin fixation on mismatch repair protein evaluation by immunohistochemistry. Virchows Arch 2023; 483:677-685. [PMID: 37773452 PMCID: PMC10673985 DOI: 10.1007/s00428-023-03661-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 08/29/2023] [Accepted: 09/15/2023] [Indexed: 10/01/2023]
Abstract
Mismatch repair/microsatellite instability (MMR/MSI) status in colorectal cancer (CRC) has become fundamental as a diagnostic, prognostic, and predictive factor. MMR immunohistochemistry (IHC) is considered a simple and reliable approach; however, its effectiveness depends on pre-analytic factors. Aim of this study was to investigate the impact of different fixation times/protocols on MMR protein IHC quality. Left over tissue from surgically resected CRC samples (cold ischemia time < 30 min) where fixed as follows: standard formalin fixation (24-48 h); hypo-fixation (<20 h); hyper-fixation (>90 h); cold (4°C) fixation (24-48 h); standard fixation for small sample size (0.5×0.5 cm). Samples for each group were collected from 30 resected CRC and the following parameters were evaluated on 600 immunohistochemical stains: intensity of expression; patchiness of staining; presence of central artefact. Forty-six immunoreactions were inadequate (score 0 intensity), the majority regarding MLH1 or PMS2 in the hypo-fixation group (47.8%), followed by the hyper-fixation group (28.1%); cold formalin fixation showed the least inadequate cases. Patchiness and central artefact were more frequent in hypo-fixation and standard fixation group compared to the others. MLH1 (closely followed by PMS2) performed worse with regard to immunostaining intensity (p=0.0002) in the standard and in the hypo-fixation group (p< 0.00001). Using a small sample size improved patchiness/central artefacts. This is the first study specifically created to evaluate the impact of fixation on MMR protein IHC, showing that both formalin hypo- and hyper-fixation can cause problems; 24-h formalin fixation as well as cold (4°C) formalin fixation are recommended for successful IHC MMR evaluation.
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Affiliation(s)
- Federica Grillo
- Pathology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
- Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genoa and IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
| | - Murad Ali
- Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genoa and IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Michele Paudice
- Pathology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
- Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genoa and IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Simona Pigozzi
- Pathology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
- Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genoa and IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Giorgia Anselmi
- Molecular Diagnostic Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Stefano Scabini
- Oncological Surgical Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Stefania Sciallero
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132, Genoa, Italy
| | - Nataniele Piol
- Pathology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Luca Mastracci
- Pathology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
- Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genoa and IRCCS Ospedale Policlinico San Martino, Genoa, Italy
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Yildiz S, Musarurwa TN, Algar U, Chambuso R, Rebello G, Goldberg PA, Ramesar R. Genetic insights: High germline variant rate in an indigenous African cohort with early-onset colorectal cancer. Front Oncol 2023; 13:1253867. [PMID: 37965459 PMCID: PMC10642181 DOI: 10.3389/fonc.2023.1253867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 09/25/2023] [Indexed: 11/16/2023] Open
Abstract
Introduction The increase in incidence of colorectal cancer in young patients of African ancestry coupled with increased aggressiveness has warranted investigation of the heritable nature of these cancers. Only a limited number of published reports of hereditary colorectal cancer in indigenous African populations have been reported and no systematic screening of these groups has been performed previously. We aimed to investigate causative germline variants and to establish the incidence of pathogenic/likely pathogenic germline variants in the known colorectal cancer genes in indigenous African colorectal cancer patients using a next-generation sequencing (NGS) multigene panel. Materials and methods Patients were selected from two hospitals in Cape Town and Johannesburg, South Africa. Patients with unresolved molecular diagnosis with an age of onset below or at 60 years were selected. Germline DNA samples were analyzed using a 14-gene NGS panel on the Ion Torrent platform. Variant calling and annotation were performed, and variants were classified according to the American College of Medical Genetics and Genomics guidelines. Observed variants were verified by Sanger sequencing and/or long-range PCR. Results Out of 107 patients, 25 (23.4%) presented with a pathogenic/likely pathogenic germline variant (PGV). Fourteen PGVs in at least one mismatch repair (MMR) gene were identified and verified in 12 patients (11.2%). Of these MMR gene variants, five were novel. The remaining 10 PGVs were in the APC, BMPR1A, MUTYH, POLD1, and TP53 genes. Conclusion The high incidence of PGVs associated with early-onset colorectal cancer in indigenous African patients has important implications for hereditary colorectal cancer risk management. These findings pave the way for personalized genetic screening programs and cascade testing in South Africa. The next step would involve further screening of the unresolved cases using tools to detect copy number variation, methylation, and whole exome sequencing.
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Affiliation(s)
- Safiye Yildiz
- UCT/MRC Genomic and Precision Medicine Research Unit, Division of Human Genetics, Department of Pathology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town and Affiliated Hospitals, Cape Town, South Africa
| | - Takudzwa N. Musarurwa
- UCT/MRC Genomic and Precision Medicine Research Unit, Division of Human Genetics, Department of Pathology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town and Affiliated Hospitals, Cape Town, South Africa
| | - Ursula Algar
- The Colorectal Unit of the Department of Surgery, Groote Schuur Hospital and the University of Cape Town, Cape Town, South Africa
| | - Ramadhani Chambuso
- UCT/MRC Genomic and Precision Medicine Research Unit, Division of Human Genetics, Department of Pathology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town and Affiliated Hospitals, Cape Town, South Africa
| | - George Rebello
- UCT/MRC Genomic and Precision Medicine Research Unit, Division of Human Genetics, Department of Pathology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town and Affiliated Hospitals, Cape Town, South Africa
| | - Paul A. Goldberg
- The Colorectal Unit of the Department of Surgery, Groote Schuur Hospital and the University of Cape Town, Cape Town, South Africa
| | - Raj Ramesar
- UCT/MRC Genomic and Precision Medicine Research Unit, Division of Human Genetics, Department of Pathology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town and Affiliated Hospitals, Cape Town, South Africa
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Stone JK, Mehta NA, Singh H, El-Matary W, Bernstein CN. Endoscopic and chemopreventive management of familial adenomatous polyposis syndrome. Fam Cancer 2023; 22:413-422. [PMID: 37119510 DOI: 10.1007/s10689-023-00334-3] [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: 01/23/2023] [Accepted: 04/18/2023] [Indexed: 05/01/2023]
Abstract
Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome predisposing affected individuals to gastrointestinal (GI) cancers through a high burden of polyposis. Colorectal cancer rates reach 100% by the age of 45, making early colectomy a mainstay of treatment. While most patients undergo colectomy at an early age, ongoing screening and surveillance of the upper gastrointestinal tract and rectal pouch must continue throughout adulthood. Endoscopic therapy of gastric, duodenal, ampullary and rectal pouch polyps is critical to reduce morbidity and cancer related mortality. Management of these lesions is not uniform, and is dependent on their location, size, histology, and risk of malignant potential. Medical therapies targeting pathways that reduce the malignant progression of pre-cancerous lesions have been studied for many years. While studies on the use of aspirin and non-steroidal anti-inflammatories (NSAIDs) in chemoprevention have shown encouraging results in Lynch syndrome and primary colorectal cancer, the potential benefits of these medications have not been duplicated in FAP cohorts. While data remains limited on chemoprevention in FAP, a number of randomized trials are currently underway examining targeted therapies with the potential to slow the progression of the disease. This review aims to provide an in-depth review of the literature on current endoscopic options and chemopreventive therapies targeting FAP. While the endoscopic management has robust data for its use, chemoprevention in FAP is still in its infancy. The complementary use of chemopreventive agents and endoscopic therapy for FAP patients is quickly becoming a growing and exciting area of research.
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Affiliation(s)
- J K Stone
- Section of Gastroenterology, Department of Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada.
| | - N A Mehta
- Center for Interventional and Therapeutic Endoscopy, Digestive Diseases and Nutrition, Rush University Medical Center, Chicago, IL, USA
| | - H Singh
- Section of Gastroenterology, Department of Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada
- Research Institute, CancerCare Manitoba, Winnipeg, MB, Canada
| | - W El-Matary
- Section of Pediatric Gastroenterology, Department of Pediatrics, Max Rady College of Medicine, Winnipeg, MB, Canada
| | - C N Bernstein
- Section of Gastroenterology, Department of Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada
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Brand RM, Dudley B, Karloski E, Zyhowski A, Raphael R, Pitlor D, Metter EJ, Pai R, Lee K, Brand RE, Uttam S. Immune microenvironment profiling of normal appearing colorectal mucosa biopsied over repeat patient visits reproducibly separates lynch syndrome patients based on their history of colon cancer. Front Oncol 2023; 13:1174831. [PMID: 37637062 PMCID: PMC10457127 DOI: 10.3389/fonc.2023.1174831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 07/14/2023] [Indexed: 08/29/2023] Open
Abstract
Introduction Lynch syndrome (LS) is the most common hereditary cause of colorectal cancer (CRC), increasing lifetime risk of CRC by up to 70%. Despite this higher lifetime risk, disease penetrance in LS patients is highly variable and most LS patients undergoing CRC surveillance will not develop CRC. Therefore, biomarkers that can correctly and consistently predict CRC risk in LS patients are needed to both optimize LS patient surveillance and help identify better prevention strategies that reduce risk of CRC development in the subset of high-risk LS patients. Methods Normal-appearing colorectal tissue biopsies were obtained during repeat surveillance colonoscopies of LS patients with and without a history of CRC, healthy controls (HC), and patients with a history of sporadic CRC. Biopsies were cultured in an ex-vivo explant system and their supernatants were assayed via multiplexed ELISA to profile the local immune signaling microenvironment. High quality cytokines were identified using the rxCOV fidelity metric. These cytokines were used to perform elastic-net penalized logistic regression-based biomarker selection by computing a new measure - overall selection probability - that quantifies the ability of each marker to discriminate between patient cohorts being compared. Results Our study demonstrated that cytokine based local immune microenvironment profiling was reproducible over repeat visits and sensitive to patient LS-status and CRC history. Furthermore, we identified sets of cytokines whose differential expression was predictive of LS-status in patients when compared to sporadic CRC patients and in identifying those LS patients with or without a history of CRC. Enrichment analysis based on these biomarkers revealed an LS and CRC status dependent constitutive inflammatory state of the normal appearing colonic mucosa. Discussion This prospective pilot study demonstrated that immune profiling of normal appearing colonic mucosa discriminates LS patients with a prior history of CRC from those without it, as well as patients with a history of sporadic CRC from HC. Importantly, it suggests the existence of immune signatures specific to LS-status and CRC history. We anticipate that our findings have the potential to assess CRC risk in individuals with LS and help in preemptively mitigating it by optimizing surveillance and identifying candidate prevention targets. Further studies are required to validate our findings in an independent cohort of LS patients over multiple visits.
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Affiliation(s)
- Rhonda M. Brand
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
- Magee Womens Research Institute, Pittsburgh, PA, United States
| | - Beth Dudley
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - Eve Karloski
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - Ashley Zyhowski
- Magee Womens Research Institute, Pittsburgh, PA, United States
| | - Rebecca Raphael
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, United States
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, United States
| | - Danielle Pitlor
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, United States
| | - E. Jeffrey Metter
- Department of Neurology, University of Tennessee Health Science Center, Memphis, TN, United States
| | - Reet Pai
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA, United States
| | - Kenneth Lee
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States
| | - Randall E. Brand
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, United States
| | - Shikhar Uttam
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, United States
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, United States
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20
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Zhang M, Zhu S, Chen L, Wu Y, Ye Y, Wang G, Gui Z, Zhang C, Zhang M. Knowledge mapping of early-onset colorectal cancer from 2000 to 2022: A bibliometric analysis. Heliyon 2023; 9:e18499. [PMID: 37560685 PMCID: PMC10407048 DOI: 10.1016/j.heliyon.2023.e18499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 07/11/2023] [Accepted: 07/19/2023] [Indexed: 08/11/2023] Open
Abstract
The incidence of early-onset colorectal cancer (EO-CRC), diagnosed in patients younger than 50 years, has increased in incidence alarmingly over the past few decades, while overall incidence and mortality of colorectal cancer are stabilizing or declining in many high-income countries. These unfavorable changes have raised significant concerns and led to extensive research, resulting in a surge in studies on EO-CRC. Our aim was to obtain a more comprehensive understanding of the current state of this field and to identify prospective research directions by performing a bibliometric analysis of EO-CRC. A total of 1952 papers on EO-CRC published from 2000 to 2022 were identified after a thorough search of the Web of Science Core Collection. The United States dominated this field, with Harvard University contributing the greatest number of papers, while the journal Familial Cancer (n = 52) published the most articles. Cooperation network analysis revealed close internal cooperation among countries, institutions and authors. Based on reference and keyword analysis, high-frequency keywords showed several popular research directions, including epidemiology (incidence, young patients, age of onset, etc.), risk factors (obesity, family history, lynch syndrome, etc.) and molecular characterization (germline mutation, genome wide association, MLH1, etc.). Overall, our research provides an overview of the current status in this field, which we hope will give researchers a comprehensive perspective on the present trends within this domain.
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Affiliation(s)
- Mengmeng Zhang
- Department of Integrated Chinese and Western Medicine Oncology, The First Affiliated Hospital of Anhui Medical University, 230031, Hefei, Anhui, China
- The Traditional and Western Medicine (TCM)-Integrated Cancer Center of Anhui Medical University, 230031, Hefei, Anhui, China
| | - Shentao Zhu
- Department of Integrated Chinese and Western Medicine Oncology, The First Affiliated Hospital of Anhui Medical University, 230031, Hefei, Anhui, China
- Graduate School of Anhui University of Traditional Chinese Medicine, 230031, Hefei, Anhui, China
| | - Lili Chen
- Department of Integrated Chinese and Western Medicine Oncology, The First Affiliated Hospital of Anhui Medical University, 230031, Hefei, Anhui, China
- Graduate School of Anhui University of Traditional Chinese Medicine, 230031, Hefei, Anhui, China
| | - Yue Wu
- Department of Integrated Chinese and Western Medicine Oncology, The First Affiliated Hospital of Anhui Medical University, 230031, Hefei, Anhui, China
- The Traditional and Western Medicine (TCM)-Integrated Cancer Center of Anhui Medical University, 230031, Hefei, Anhui, China
| | - Yingquan Ye
- Department of Integrated Chinese and Western Medicine Oncology, The First Affiliated Hospital of Anhui Medical University, 230031, Hefei, Anhui, China
- The Traditional and Western Medicine (TCM)-Integrated Cancer Center of Anhui Medical University, 230031, Hefei, Anhui, China
| | - Gaoxiang Wang
- Department of Integrated Chinese and Western Medicine Oncology, The First Affiliated Hospital of Anhui Medical University, 230031, Hefei, Anhui, China
- The Traditional and Western Medicine (TCM)-Integrated Cancer Center of Anhui Medical University, 230031, Hefei, Anhui, China
| | - Zhongxuan Gui
- Department of Integrated Chinese and Western Medicine Oncology, The First Affiliated Hospital of Anhui Medical University, 230031, Hefei, Anhui, China
- The Traditional and Western Medicine (TCM)-Integrated Cancer Center of Anhui Medical University, 230031, Hefei, Anhui, China
| | - Congjun Zhang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, 230031, Hefei, Anhui, China
| | - Mei Zhang
- Department of Integrated Chinese and Western Medicine Oncology, The First Affiliated Hospital of Anhui Medical University, 230031, Hefei, Anhui, China
- The Traditional and Western Medicine (TCM)-Integrated Cancer Center of Anhui Medical University, 230031, Hefei, Anhui, China
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21
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Grillo F, Paudice M, Gambella A, Bozzano S, Sciallero S, Puccini A, Lastraioli S, Dono M, Parente P, Vanoli A, Angerilli V, Fassan M, Mastracci L. Evaluating mismatch repair deficiency in colorectal cancer biopsy specimens. Histochem Cell Biol 2023; 160:113-125. [PMID: 37284845 PMCID: PMC10386921 DOI: 10.1007/s00418-023-02202-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/25/2023] [Indexed: 06/08/2023]
Abstract
Mismatch repair (MMR) testing on all new cases of colorectal cancer (CRC) has customarily been preferably performed on surgical specimens, as more tissue is available; however, new clinical trials for the use of immune checkpoint inhibitors in the neoadjuvant setting require MMR testing on biopsy samples. This study aims at identifying advantages, disadvantages and any potential pitfalls in MMR evaluation on biopsy tissue and how to cope with them. The study is prospective-retrospective, recruiting 141 biopsies (86 proficient (p)MMR and 55 deficient (d)MMR) and 97 paired surgical specimens (48 pMMR; 49 dMMR). In biopsy specimens, a high number of indeterminate stains was observed, in particular for MLH1 (31 cases, 56.4%). The main reasons were a punctate nuclear expression of MLH1, relatively weak MLH1 nuclear expression compared to internal controls, or both (making MLH1 loss difficult to interpret), which was solved by reducing primary incubation times for MLH1. A mean of ≥ 5 biopsies had adequate immunostains, compared to ≤ 3 biopsies in inadequate cases. Conversely, surgical specimens rarely suffered from indeterminate reactions, while weaker staining intensity (p < 0.007) for MLH1 and PMS2 and increased patchiness grade (p < 0.0001) were seen. Central artefacts were almost exclusive to surgical specimens. MMR status classification was possible in 92/97 matched biopsy/resection specimen cases, and all of these were concordant (47 pMMR and 45 dMMR). Evaluation of MMR status on CRC biopsy samples is feasible, if pitfalls in interpretation are known, making laboratory-specific appropriate staining protocols fundamental for high-quality diagnoses.
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Affiliation(s)
- F Grillo
- IRCCS Ospedale Policlinico San Martino, Largo Benzi 10, 16132, Genoa, Italy.
- Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genoa, Genoa, Italy.
| | - M Paudice
- IRCCS Ospedale Policlinico San Martino, Largo Benzi 10, 16132, Genoa, Italy
- Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genoa, Genoa, Italy
| | - A Gambella
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - S Bozzano
- Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genoa, Genoa, Italy
| | - S Sciallero
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132, Genoa, Italy
| | - A Puccini
- Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Humanitas Cancer Center, Rozzano, Milan, Italy
| | - S Lastraioli
- Molecular Diagnostic Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - M Dono
- Molecular Diagnostic Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - P Parente
- Pathology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy
| | - A Vanoli
- Department of Molecular Medicine, Unit of Anatomic Pathology, University of Pavia, Pavia, Italy
- Anatomic Pathology Unit, Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - V Angerilli
- Department of Medicine (DIMED), Surgical Pathology Unit, University Hospital of Padua, Padua, Italy
| | - M Fassan
- Department of Medicine (DIMED), Surgical Pathology Unit, University Hospital of Padua, Padua, Italy
- Veneto Institute of Oncology IOV - IRCCS, Padua, Italy
| | - L Mastracci
- IRCCS Ospedale Policlinico San Martino, Largo Benzi 10, 16132, Genoa, Italy
- Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genoa, Genoa, Italy
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22
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Barnoy S, Dagan E, Kim S, Caiata-Zufferey M, Katapodi MC. Privacy and utility of genetic testing in families with hereditary cancer syndromes living in three countries: the international cascade genetic screening experience. Front Genet 2023; 14:1109431. [PMID: 37229185 PMCID: PMC10203600 DOI: 10.3389/fgene.2023.1109431] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Accepted: 04/17/2023] [Indexed: 05/27/2023] Open
Abstract
Background: Hereditary breast and ovarian cancer and Lynch syndrome are associated with increased lifetime risk for common cancers. Offering cascade genetic testing to cancer-free relatives of individuals with HBOC or LS is a public health intervention for cancer prevention. Yet, little is known about the utility and value of information gained from cascade testing. This paper discusses ELSI encountered during the implementation of cascade testing in three countries with national healthcare systems: Switzerland, Korea, and Israel. Methods: A workshop presented at the 5th International ELSI Congress discussed implementation of cascade testing in the three countries based on exchange of data and experiences from the international CASCADE cohort. Results: Analyses focused on models of accessing genetic services (clinic-based versus population-based screening), and models of initiating cascade testing (patient-mediated dissemination versus provider-mediated dissemination of testing results to relatives). The legal framework of each country, organization of the healthcare system, and socio-cultural norms determined the utility and value of genetic information gained from cascade testing. Conclusion: The juxtaposition of individual versus public health interests generates significant ELSI controversies associated with cascade testing, which compromise access to genetic services and the utility and value of genetic information, despite national healthcare/universal coverage.
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Affiliation(s)
- Sivia Barnoy
- Department of Nursing, Tel-Aviv University, Tel-Aviv, Israel
| | - Efrat Dagan
- The Cheryl Spencer Department of Nursing, University of Haifa, Haifa, Israel
| | - Sue Kim
- College of Nursing, Yonsei University, Seoul, South Korea
| | - Maria Caiata-Zufferey
- Department of Business Economics, Health and Social Care, University of Applied Sciences and Arts of Southern Switzerland, Manno, Switzerland
| | - Maria C. Katapodi
- Department of Clinical Research, University of Basel, Basel, Switzerland
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23
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Guzauskas GF, Garbett S, Zhou Z, Schildcrout JS, Graves JA, Williams MS, Hao J, Jones LK, Spencer SJ, Jiang S, Veenstra DL, Peterson JF. Population Genomic Screening for Three Common Hereditary Conditions : A Cost-Effectiveness Analysis. Ann Intern Med 2023; 176:585-595. [PMID: 37155986 PMCID: PMC11791829 DOI: 10.7326/m22-0846] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/10/2023] Open
Abstract
BACKGROUND The cost-effectiveness of screening the U.S. population for Centers for Disease Control and Prevention (CDC) Tier 1 genomic conditions is unknown. OBJECTIVE To estimate the cost-effectiveness of simultaneous genomic screening for Lynch syndrome (LS), hereditary breast and ovarian cancer syndrome (HBOC), and familial hypercholesterolemia (FH). DESIGN Decision analytic Markov model. DATA SOURCES Published literature. TARGET POPULATION Separate age-based cohorts (ages 20 to 60 years at time of screening) of racially and ethnically representative U.S. adults. TIME HORIZON Lifetime. PERSPECTIVE U.S. health care payer. INTERVENTION Population genomic screening using clinical sequencing with a restricted panel of high-evidence genes, cascade testing of first-degree relatives, and recommended preventive interventions for identified probands. OUTCOME MEASURES Incident breast, ovarian, and colorectal cancer cases; incident cardiovascular events; quality-adjusted survival; and costs. RESULTS OF BASE-CASE ANALYSIS Screening 100 000 unselected 30-year-olds resulted in 101 (95% uncertainty interval [UI], 77 to 127) fewer overall cancer cases and 15 (95% UI, 4 to 28) fewer cardiovascular events and an increase of 495 quality-adjusted life-years (QALYs) (95% UI, 401 to 757) at an incremental cost of $33.9 million (95% UI, $27.0 million to $41.1 million). The incremental cost-effectiveness ratio was $68 600 per QALY gained (95% UI, $41 800 to $88 900). RESULTS OF SENSITIVITY ANALYSIS Screening 30-, 40-, and 50-year-old cohorts was cost-effective in 99%, 88%, and 19% of probabilistic simulations, respectively, at a $100 000-per-QALY threshold. The test costs at which screening 30-, 40-, and 50-year-olds reached the $100 000-per-QALY threshold were $413, $290, and $166, respectively. Variant prevalence and adherence to preventive interventions were also highly influential parameters. LIMITATIONS Population averages for model inputs, which were derived predominantly from European populations, vary across ancestries and health care environments. CONCLUSION Population genomic screening with a restricted panel of high-evidence genes associated with 3 CDC Tier 1 conditions is likely to be cost-effective in U.S. adults younger than 40 years if the testing cost is relatively low and probands have access to preventive interventions. PRIMARY FUNDING SOURCE National Human Genome Research Institute.
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Affiliation(s)
- Gregory F. Guzauskas
- The CHOICE Institute, Department of Pharmacy, University of Washington, Seattle, Washington
| | - Shawn Garbett
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Zilu Zhou
- Department of Health Policy, Vanderbilt University Medical Center, Nashville, Tennessee
| | | | - John A. Graves
- Department of Health Policy, Vanderbilt University Medical Center, Nashville, Tennessee
| | | | - Jing Hao
- Department of Genomic Health and Department of Population Health Sciences, Geisinger, Danville, Pennsylvania
| | - Laney K. Jones
- Department of Population Health Sciences and Heart Institute, Geisinger, Danville, Pennsylvania
| | - Scott J. Spencer
- Institute for Public Health Genetics, University of Washington, Seattle, Washington
| | - Shangqing Jiang
- The CHOICE Institute, Department of Pharmacy, University of Washington, Seattle, Washington
| | - David L. Veenstra
- The CHOICE Institute, Department of Pharmacy, and Institute for Public Health Genetics, University of Washington, Seattle, Washington
| | - Josh F. Peterson
- Department of Biomedical Informatics and Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
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Xiong K, Bao T, Cao Y, Hu W, Deng J, Chen J, Xiao T. Efficacy and safety of total neoadjuvant therapy in locally advanced rectal cancer: a meta-analysis. Int J Colorectal Dis 2023; 38:89. [PMID: 37004572 DOI: 10.1007/s00384-023-04376-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/17/2023] [Indexed: 04/04/2023]
Abstract
PURPOSE The standard of care for locally advanced rectal cancer (LARC) has changed from a single radical surgical treatment to the current multimodality treatment (standard chemoradiotherapy (CRT) and total neoadjuvant therapy (TNT)). The efficacy and safety of both TNT and standard CRT are evaluated in randomized controlled trials (RCTs). METHODS RCTs were comprehensively searched in Chinese and English electronic databases. The experimental and control groups were TNT and the standard CRT, respectively, included in this meta-analysis. The outcomes were assessed through a fixed-effect or random-effect model of pooled odds (OR) or hazard ratios (HR). RESULTS Eleven RCTs, involving 3,101 patients were included in the final analysis. TNT showed increase in the pathological complete response (pCR) (OR = 1.95, 95% confidence interval (CI): 1.57-2.41; P < 0.05) and the R0 resection (OR = 1.19, 95% CI: 0.99-1.43; P = 0.062). There was no significant difference in local recurrence-free survival (LRFS) (HR = 0.97, P = 0.803), but TNT had better 3-year disease-free survival (DFS) (HR = 0.82, 95% CI: 0.72-0.93, P < 0.05), overall survival (OS) (HR = 0.87, 95% CI: 0.74-1.02, P = 0.08) and distant metastasis-free survival (DMFS) (HR = 0.79, 95% CI: 0.67-0.93, P < 0.05) than standard CRT. CONCLUSIONS TNT was safe and feasible as it improved pCR and survival outcomes, and reduced the risk of distant metastasis compared with standard CRT. TNT may be a superior strategy for LARC, but more RCTs are needed to prove it. REGISTRATION AND PROTOCOL PROSPERO CRD42022327697. We added the Chinese database after registration because of the inclusion of fewer RCTs www.crd.york.ac.uk/PROSPERO/ .
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Affiliation(s)
- Kai Xiong
- College of Clinical Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Tiantian Bao
- Colorectal and Anal Surgery, the First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, No 71 Baoshan North Road, 550001, Guiyang, China
| | - Yibo Cao
- Colorectal and Anal Surgery, the First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, No 71 Baoshan North Road, 550001, Guiyang, China
| | - Wenting Hu
- College of Clinical Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Jia Deng
- College of Clinical Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Jiang Chen
- Colorectal and Anal Surgery, the First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, No 71 Baoshan North Road, 550001, Guiyang, China.
| | - Tianbao Xiao
- Colorectal and Anal Surgery, the First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, No 71 Baoshan North Road, 550001, Guiyang, China.
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25
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Underkofler KA, Ring KL. Updates in gynecologic care for individuals with lynch syndrome. Front Oncol 2023; 13:1127683. [PMID: 36937421 PMCID: PMC10014618 DOI: 10.3389/fonc.2023.1127683] [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: 12/19/2022] [Accepted: 02/16/2023] [Indexed: 03/05/2023] Open
Abstract
Lynch syndrome is an autosomal dominant hereditary cancer syndrome caused by germline pathogenic variants (PVs) in DNA mismatch repair genes (MLH1, MSH2, PMS2, MSH6) or the EPCAM gene. It is estimated to affect 1 in 300 individuals and confers a lifetime risk of cancer of 10-90%, depending on the specific variant and type of cancer. Lynch syndrome is the most common cause of inherited colorectal cancer, but for women, endometrial cancer is more likely to be the sentinel cancer. There is also evidence that certain PVs causing Lynch syndrome confer an increased risk of ovarian cancer, while the risk of ovarian cancer in others is not well defined. Given this, it is essential for the practicing gynecologist and gynecologic oncologist to remain up to date on the latest techniques in identification and diagnosis of individuals with Lynch syndrome as well as evidence-based screening and risk reduction recommendations for those impacted. Furthermore, as the landscape of gynecologic cancer treatment shifts towards treatment based on molecular classification of tumors, knowledge of targeted therapies well-suited for mismatch repair deficient Lynch tumors will be crucial. The objective of this review is to highlight recent updates in the literature regarding identification and management of individuals with Lynch syndrome as it pertains to endometrial and ovarian cancers to allow gynecologic providers the opportunity to both prevent and identify Lynch-associated cancers earlier, thereby reducing the morbidity and mortality of the syndrome.
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Affiliation(s)
| | - Kari L. Ring
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Virginia, Charlottesville, VA, United States
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26
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Saraiva MR, Rosa I, Claro I. Early-onset colorectal cancer: A review of current knowledge. World J Gastroenterol 2023; 29:1289-1303. [PMID: 36925459 PMCID: PMC10011966 DOI: 10.3748/wjg.v29.i8.1289] [Citation(s) in RCA: 66] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 12/18/2022] [Accepted: 02/15/2023] [Indexed: 02/28/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide. Although most prevalent among older people, its incidence above 50 years old has been decreasing globally in the last decades, probably as a result of better screening. Paradoxically, its incidence in patients below 50 years old [early-onset CRC (EO-CRC)] has been increasing, for reasons not yet fully understood. EO-CRC's increasing incidence is genre independent but shows racial disparities and has been described to occur worldwide. It follows a birth-cohort effect which probably reflects a change in exposure to CRC risk factors. Its incidence is predicted to double until 2030, which makes EO-CRC a serious public health issue. Both modifiable and non-modifiable risk factors have been identified - some are potential targets for preventive measures. EO-CRC is often diagnosed at advanced stages and histological features associated with poor prognosis have been described. EO-CRC presents some distinctive features: Microsatellite in-stability is common, but another subtype of tumours, both microsatellite and chromosome stable also seems relevant. There are no age-specific treatment protocols and studies on EO-CRC survival rates have shown conflicting data. Due to the higher germline pathological mutations found in EO-CRC patients, an accurate genetic risk evaluation should be performed. In this review, we summarize the current evidence on epidemiological, clinical, histopathological and molecular features of EO-CRC and discuss the contribution of genetics and lifestyle risk factors. We further comment on screening strategies and specific dimensions to consider when dealing with a younger cancer patient.
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Affiliation(s)
- Margarida R Saraiva
- Department of Gastroenterology, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa 1099-023, Portugal
| | - Isadora Rosa
- Department of Gastroenterology, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa 1099-023, Portugal
| | - Isabel Claro
- Department of Gastroenterology, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa 1099-023, Portugal
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del Carmen G, Reyes-Uribe L, Goyco D, Evans K, Bowen CM, Kinnison JL, Sepeda VO, Weber DM, Moskowitz J, Mork ME, Thirumurthi S, Lynch PM, Rodriguez-Bigas MA, Taggart MW, You YN, Vilar E. Colorectal surveillance outcomes from an institutional longitudinal cohort of lynch syndrome carriers. Front Oncol 2023; 13:1146825. [PMID: 37168379 PMCID: PMC10164917 DOI: 10.3389/fonc.2023.1146825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 04/11/2023] [Indexed: 05/13/2023] Open
Abstract
Objective Lynch Syndrome (LS) carriers have a significantly increased risk of developing colorectal cancer (CRC) during their lifetimes. Further stratification of this patient population may help in identifying additional risk factors that predispose to colorectal carcinogenesis. In most LS patients CRC may arise from adenomas, although an alternative non-polypoid carcinogenesis pathway has been proposed for PMS2 carriers. Using data from our institutional LS cohort, our aim was to describe our current colorectal screening outcomes with a focus on the incidence of adenomas in the context of different MMR genotypes and patient demographics such as gender, race, and ethnicity. Design We collected demographics, genetic, colonoscopy, and pathology results from a total of 163 LS carriers who obtained regular screening care at MD Anderson Cancer Center. Data were extracted from the electronic health records into a REDCap database for analysis. Logistic regressions were performed to measure the association between MMR variants and the likelihood of adenomas, advanced adenomas, and CRC. Then, we analyzed the cumulative incidences of these outcomes for the first 36 months following enrollment using Kaplan-Meier incidence curves, and Cox proportional hazard regressions. Results On multivariate analysis, age (≥45 years old) was associated with an increased risk of developing adenomas (P=0.034). Patients with a prior or active cancer status were less likely to develop adenomas (P=0.015), despite of the lack of association between surgical history with this outcome (P=0.868). We found no statistically significant difference in likelihood of adenoma development between MLH1 and MSH2/EPCAM, MSH6, and PMS2 carriers. Moreover, we observed no statistically significant difference in the likelihood of advanced adenomas or CRC for any measured covariates. On Cox proportional hazard, compared to MLH1 carriers, the incidence of adenomas was highest among MSH2/EPCAM carriers during for the first 36-months of follow-up (P<0.001). We observed a non-statistically significant trend for Hispanics having a higher and earlier cumulative incidence of adenomas compared to non-Hispanics (P=0.073). No MMR carrier was more likely to develop advanced adenomas. No difference in the incidence of CRC by MMR gene (P=0.198). Conclusion Screening recommendations for CRC in LS patients should be based on specific MMR variants and should also be tailored to consider patient demographics.
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Affiliation(s)
- Gabriel del Carmen
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- McGovern Medical School, University of Texas Health Science Center, Houston, TX, United States
| | - Laura Reyes-Uribe
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Daniel Goyco
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Department of Medicine, Baylor College of Medicine, Houston, TX, United States
| | - Kyera Evans
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Charles M. Bowen
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Jennifer L. Kinnison
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Valerie O. Sepeda
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Diane M. Weber
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Julie Moskowitz
- Clinical Cancer Genetics Program, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Maureen E. Mork
- Clinical Cancer Genetics Program, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Selvi Thirumurthi
- Clinical Cancer Genetics Program, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Patrick M. Lynch
- Clinical Cancer Genetics Program, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Miguel A. Rodriguez-Bigas
- Clinical Cancer Genetics Program, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Department of Colorectal Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Melissa W. Taggart
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Y. Nancy You
- Clinical Cancer Genetics Program, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Department of Colorectal Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Eduardo Vilar
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Clinical Cancer Genetics Program, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- *Correspondence: Eduardo Vilar,
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Feldman D, Rodgers-Fouche L, Hicks S, Chung DC. Clinical features and long-term outcomes of patients with colonic oligopolyposis of unknown etiology. World J Gastroenterol 2022; 28:6950-6961. [PMID: 36632322 PMCID: PMC9827588 DOI: 10.3748/wjg.v28.i48.6950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 11/14/2022] [Accepted: 12/13/2022] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Colonic adenomatous polyposis of unknown etiology (CPUE) is an adenomatous polyposis phenotype that resembles Familial Adenomatous Polyposis (FAP) even though no germline pathogenic variant is identified.
AIM We sought to better characterize the clinical features and outcomes in a cohort of CPUE patients.
METHODS This is a retrospective case series of patients 18 years old or older with aden-omatous oligopolyposis (between 10-100 adenomas) and negative genetic testing, identified through the Hereditary Gastrointestinal Cancer Database at Massachusetts General Hospital, a tertiary academic referral center. A retrospective chart review was performed with a focus on demographics, alcohol and tobacco use, medication use, familial malignancy and polyp burden, genetic testing information, endoscopic surveillance data including the corresponding histopathology, colonic and extracolonic malignancies, mortality events, and their etiology. Spearman correlation and Pearson Chi-square test (or Fisher's exact test) were used for continuous and categorical variables respectively.
RESULTS CPUE patients were primarily male (69%) and presented for genetic counseling at 63.7 years. Only 2 patients (2.9%) reported a first-degree relative with polyposis. During an average surveillance period of 12.3 years, 0.5 colonoscopies per year were performed. Patients developed 2.3 new adenomas per year. 4 (5.7%) were diagnosed with colorectal cancer (CRC) at a mean age of 66 years, and 3 were diagnosed prior to the onset of oligopolyposis. 7 (10%) required colectomy due to advanced dysplasia or polyp burden. With respect to upper gastrointestinal manifestations, 1 patient had a gastric adenoma, but there were no cases of gastric or small bowel polyposis. During surveillance, 10 (14%) patients died at a mean age of 72, and none were due to CRC.
CONCLUSION CPUE is distinct from familial adenomatous polyposis (FAP) syndrome and the use of FAP surveillance guidelines may result in unnecessarily frequent upper and lower endoscopies.
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Affiliation(s)
- Dan Feldman
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts 02114, United States
| | - Linda Rodgers-Fouche
- Center for Cancer Risk Assessment, Massachusetts General Hospital, Boston, Massachusetts 02114, United States
| | - Stephanie Hicks
- Center for Cancer Risk Assessment, Massachusetts General Hospital, Boston, Massachusetts 02114, United States
| | - Daniel C Chung
- Division of Gastroenterology and Center for Cancer Risk Assessment, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, United States
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Jain A, Alimirah M, Hampel H, Pearlman R, Ma J, Peng J, Kalady MF, Stanich PP. Multiple colorectal adenomas in Lynch syndrome. Front Oncol 2022; 12:1038678. [PMID: 37078003 PMCID: PMC10107368 DOI: 10.3389/fonc.2022.1038678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 11/30/2022] [Indexed: 12/24/2022] Open
Abstract
BackgroundLynch syndrome has not traditionally been considered to have a high colorectal adenoma burden. However, with increasing adenoma detection rates in the general population, the incidence of adenoma detection in Lynch syndrome may also be increasing and leading to higher cumulative adenoma counts.AimTo clarify the prevalence and clinical impact of multiple colorectal adenomas (MCRA) in Lynch syndrome.MethodsA retrospective review of patients with Lynch syndrome at our institution was performed to assess for MCRA (defined as ≥10 cumulative adenomas).ResultsThere were 222 patients with Lynch syndrome among whom 14 (6.3%) met MCRA criteria. These patients had increased incidence of advanced neoplasia (OR 10, 95% CI: 2.7-66.7).ConclusionsMCRA is not unusual in Lynch syndrome and is associated with a significantly increased likelihood of advanced colon neoplasia. Consideration should be given to differentiating colonoscopy intervals based on the presence of polyposis in Lynch syndrome.
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Affiliation(s)
- Ayushi Jain
- Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Maryam Alimirah
- Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Heather Hampel
- Division of Clinical Cancer Genomics, City of Hope National Medical Center, Duarte, CA, United States
| | - Rachel Pearlman
- Division of Human Genetics, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Jianing Ma
- Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Jing Peng
- Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Matthew F. Kalady
- Division of Human Genetics, The Ohio State University Wexner Medical Center, Columbus, OH, United States
- Division of Colorectal Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Peter P. Stanich
- Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, United States
- *Correspondence: Peter P. Stanich,
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Ashkenazi Jewish and Other White APC I1307K Carriers Are at Higher Risk for Multiple Cancers. Cancers (Basel) 2022; 14:cancers14235875. [PMID: 36497357 PMCID: PMC9740723 DOI: 10.3390/cancers14235875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 11/25/2022] [Accepted: 11/25/2022] [Indexed: 12/02/2022] Open
Abstract
Purpose: APC I1307K has a higher prevalence among Ashkenazi Jews (AJ), and a two-fold increased risk for colorectal cancer (CRC) compared to non-Jewish populations. We assessed CRC and extracolonic malignancies among I1307K carriers from AJ and non-AJ whites (NAW). Methods: We compared the rate of I1307K in cancer patients who underwent germline genetic testing via a multi-gene panel with healthy subjects retrieved from the gnomAD database. Cases undergoing testing were not selected and testing was undertaken through a commercial laboratory. Results: Overall, 586/7624 (7.6%) AJ with cancer carried I1307K compared to 342/4918 (6.9%) in the AJ control group (p = NS). In the NAW, 318/141,673 (0.2%) cancer patients and 73/58,918 (0.1%) controls carried the variant [OR = 1.8, (95% CI 1.41−2.35), p < 0.001]. I1307K in NAW was associated with an increased risk of CRC [OR = 1.95, (95% CI 1.39−2.73), p < 0.01], melanoma [OR = 2.54, (95% CI 1.57−3.98)], breast [females, OR = 1.73, (95% CI 1.18−2.65), p < 0.01], and prostate cancer [males, OR = 2.42, (95% CI 1.45−3.94), p < 0.01]. Among AJ, the variant increased the risk for CRC [OR = 1.67, (95% CI 1.36−2.05), p < 0.001] and renal cancer [OR = 1.64, (95% CI 1.04−2.47)]. AJ men had a higher risk for any cancer [OR = 1.32, (95% CI 1.05−1.66), p < 0.05] and melanoma [OR = 2.04, (95% CI 1.24−3.22); p < 0.05]. Conclusions: This is the most extensive study to date conducted on I1307K carriers, although it is amenable to selection bias. NAW carrying I1307K had a higher risk of any cancer and several specific cancer types, whereas AJ carrying the variant had a risk for only a few select cancers. Our data add to the research base on I1307 carriers concerning future risk management.
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Chaves JJ, Chaves-Cabezas V, Parra-Medina R, Chaves-Chamorro JO. Familial Adenomatous Polyposis: Case Report and Literature Review. Cureus 2022; 14:e31609. [DOI: 10.7759/cureus.31609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/17/2022] [Indexed: 11/18/2022] Open
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Dusic EJ, Theoryn T, Wang C, Swisher EM, Bowen DJ. Barriers, interventions, and recommendations: Improving the genetic testing landscape. Front Digit Health 2022; 4:961128. [PMID: 36386046 PMCID: PMC9665160 DOI: 10.3389/fdgth.2022.961128] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Accepted: 09/27/2022] [Indexed: 11/06/2022] Open
Abstract
Individual, provider, clinic, and societal level barriers have been shown to undermine the potential impact of genetic testing. The current approach in the primary care setting places an exorbitant burden on both providers and patients. Current literature provides insight into how to address barriers across multiple levels (patient, provider, clinic, system) and at multiple stages in the testing process (identification, referral, counseling, and testing) but interventions have had limited success. After outlining the current approach to genetic testing in the primary care setting, including the barriers that prevent genetic testing uptake and the methods proposed to address these issues, we recommend integrating genetic testing into routine medical care through population-based testing. Success in efforts to increase the uptake of genetic testing will not occur without significant changes to the way genetic services are delivered. These changes will not be instantaneous but are critical in moving this field forward to realize the potential for cancer risk genetic assessment to reduce cancer burden.
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Affiliation(s)
- E. J. Dusic
- Institute of Public Health Genetics, Department of Biostatistics, University of Washington, Seattle, WA, United States
- Correspondence: E. J. Dusic
| | - Tesla Theoryn
- Institute of Public Health Genetics, Department of Biostatistics, University of Washington, Seattle, WA, United States
| | - Catharine Wang
- Department of Community Health Sciences, Boston University School of Public Health, Boston, MA, United States
| | - Elizabeth M. Swisher
- Department of Obstetrics and Gynecology, Fred Hutchinson Cancer Center, University of Washington, Seattle, WA, United States
| | - Deborah J. Bowen
- Institute of Public Health Genetics, Department of Biostatistics, University of Washington, Seattle, WA, United States
- Department of Bioethics, University of Washington, Seattle, WA, United States
| | - EDGE Study Team
- Beth Devine, Department of Pharmacy, University of Washington, Seattle, WA, United States
- Barbara Norquist, Department of Obstetrics & Gynecology, University of Washington Medical Center, University of Washington, Seattle, WA, United States
- Brian Shirts, Department of Laboratory Medicine & Pathology, University of Washington Medical Center, University of Washington, Seattle, WA, United States
- Mariebeth Velasquez, Department of Family Medicine, University of Washington Medical Center, University of Washington, Seattle, WA, United States
- Michael Raff, Genomics Institute, MultiCare Health System, Tacoma, WA, United States
- Jeannine M. Brant, Clinical Science & Innovation, Billings Clinic, Billings, MT, United States
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Schwartz A, Manning DK, Koeller DR, Chittenden A, Isidro RA, Hayes CP, Abraamyan F, Manam MD, Dwan M, Barletta JA, Sholl LM, Yurgelun MB, Rana HQ, Garber JE, Ghazani AA. An integrated somatic and germline approach to aid interpretation of germline variants of uncertain significance in cancer susceptibility genes. Front Oncol 2022; 12:942741. [PMID: 36091175 PMCID: PMC9453486 DOI: 10.3389/fonc.2022.942741] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 07/12/2022] [Indexed: 11/13/2022] Open
Abstract
Genomic profiles of tumors are often unique and represent characteristic mutational signatures defined by DNA damage or DNA repair response processes. The tumor-derived somatic information has been widely used in therapeutic applications, but it is grossly underutilized in the assessment of germline genetic variants. Here, we present a comprehensive approach for evaluating the pathogenicity of germline variants in cancer using an integrated interpretation of somatic and germline genomic data. We have previously demonstrated the utility of this integrated approach in the reassessment of pathogenic germline variants in selected cancer patients with unexpected or non-syndromic phenotypes. The application of this approach is presented in the assessment of rare variants of uncertain significance (VUS) in Lynch-related colon cancer, hereditary paraganglioma-pheochromocytoma syndrome, and Li-Fraumeni syndrome. Using this integrated method, germline VUS in PMS2, MSH6, SDHC, SHDA, and TP53 were assessed in 16 cancer patients after genetic evaluation. Comprehensive clinical criteria, somatic signature profiles, and tumor immunohistochemistry were used to re-classify VUS by upgrading or downgrading the variants to likely or unlikely actionable categories, respectively. Going forward, collation of such germline variants and creation of cross-institutional knowledgebase datasets that include integrated somatic and germline data will be crucial for the assessment of these variants in a larger cancer cohort.
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Affiliation(s)
- Alison Schwartz
- Division of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA, United States
| | - Danielle K. Manning
- Department of Pathology, Brigham and Women’s Hospital, Boston, MA, United States
| | - Diane R. Koeller
- Division of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA, United States
| | - Anu Chittenden
- Division of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA, United States
| | - Raymond A. Isidro
- Department of Pathology, Brigham and Women’s Hospital, Boston, MA, United States
- Harvard Medical School, Boston, MA, United States
| | - Connor P. Hayes
- Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States
| | - Feruza Abraamyan
- Harvard Medical School, Boston, MA, United States
- Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States
| | - Monica Devi Manam
- Department of Pathology, Brigham and Women’s Hospital, Boston, MA, United States
| | - Meaghan Dwan
- Division of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA, United States
| | - Justine A. Barletta
- Department of Pathology, Brigham and Women’s Hospital, Boston, MA, United States
- Harvard Medical School, Boston, MA, United States
| | - Lynette M. Sholl
- Department of Pathology, Brigham and Women’s Hospital, Boston, MA, United States
- Harvard Medical School, Boston, MA, United States
| | - Matthew B. Yurgelun
- Division of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA, United States
- Harvard Medical School, Boston, MA, United States
- Division of Population Sciences, Dana-Farber Cancer Institute, Boston, MA, United States
| | - Huma Q. Rana
- Division of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA, United States
- Harvard Medical School, Boston, MA, United States
- Division of Population Sciences, Dana-Farber Cancer Institute, Boston, MA, United States
| | - Judy E. Garber
- Division of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA, United States
- Harvard Medical School, Boston, MA, United States
- Division of Population Sciences, Dana-Farber Cancer Institute, Boston, MA, United States
| | - Arezou A. Ghazani
- Department of Pathology, Brigham and Women’s Hospital, Boston, MA, United States
- Harvard Medical School, Boston, MA, United States
- Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States
- *Correspondence: Arezou A. Ghazani,
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Knerr S, Guo B, Mittendorf KF, Feigelson HS, Gilmore MJ, Jarvik GP, Kauffman TL, Keast E, Lynch FL, Muessig KR, Okuyama S, Veenstra DL, Zepp JM, Goddard KA, Devine B. Risk-reducing surgery in unaffected individuals receiving cancer genetic testing in an integrated health care system. Cancer 2022; 128:3090-3098. [PMID: 35679147 PMCID: PMC9308746 DOI: 10.1002/cncr.34349] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 05/03/2022] [Accepted: 05/19/2022] [Indexed: 12/17/2022]
Abstract
BACKGROUND Germline genetic testing enables primary cancer prevention, including through prophylactic surgery. We examined risk-reducing surgeries in unaffected individuals tested for hereditary cancer susceptibly between 2010 and 2018 in the Kaiser Permanente Northwest health system. METHODS We used an internal genetic testing database to create a cohort of individuals who received tests including one or more high-penetrance hereditary cancer susceptibility gene. We then identified, after testing, bilateral mastectomy, bilateral salpingo-oophorectomy (BSO), and total hysterectomy procedures in electronic health record and claims data through 2019. We describe surgery utilization by genetic test results and National Comprehensive Cancer Network (NCCN) guidelines. RESULTS The cohort included 1020 individuals, 16% with pathogenic/likely pathogenic (P/LP) variants in one or more of the following genes: BRCA1, BRCA2, CHEK2, APC, MUTYH, ATM, MSH2, PALB2, BRIP1, MLH1, MSH6, EPCAM, FLCN, RAD51C, RAD51D, or TP53. Among individuals with P/LP variants making them candidates for mastectomy, BSO, or hysterectomy per NCCN guidelines, 34% (33/97), 24% (23/94), and 8% (1/12), respectively, underwent surgery during follow-up. Fifty-three percent (18/37) of hysterectomies were among APC, BRCA1, and BRCA2 P/LP variant heterozygotes, typically concurrent with BSO. Three individuals with variants of uncertain significance (only) and 22 with negative results had prophylactic surgery after genetic testing. CONCLUSIONS Uptake of risk-reducing surgery following usual care genetic testing appears to be lower than in studies that actively recruit high-risk patients and provide testing and follow-up care in specialized settings. Factors in addition to genetic test results and NCCN guidelines motivate prophylactic surgery use and deserve further study.
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Affiliation(s)
- Sarah Knerr
- School of Public Health, University of Washington, Seattle, WA
| | - Boya Guo
- School of Public Health, University of Washington, Seattle, WA
| | - Kathleen F. Mittendorf
- Department of Translational and Applied Genomics, Center for Health Research, Kaiser Permanente Northwest, Portland, OR
| | | | - Marian J. Gilmore
- Department of Translational and Applied Genomics, Center for Health Research, Kaiser Permanente Northwest, Portland, OR
| | - Gail P. Jarvik
- School of Medicine, University of Washington, Seattle, WA
| | - Tia L. Kauffman
- Center for Health Research, Kaiser Permanente Northwest, Portland OR
| | - Erin Keast
- Center for Health Research, Kaiser Permanente Northwest, Portland OR
| | - Frances L. Lynch
- Center for Health Research, Kaiser Permanente Northwest, Portland OR
| | - Kristin R. Muessig
- Department of Translational and Applied Genomics, Center for Health Research, Kaiser Permanente Northwest, Portland, OR
| | - Sonia Okuyama
- Division of Oncology, Denver Health and Hospital Authority, Denver, CO
| | - David L. Veenstra
- The Comparative Health Outcomes, Policy and Economics (CHOICE) Institute, School of Pharmacy, University of Washington, Seattle, WA
| | - Jamilyn M. Zepp
- Department of Translational and Applied Genomics, Center for Health Research, Kaiser Permanente Northwest, Portland, OR
| | - Katrina A.B. Goddard
- Department of Translational and Applied Genomics, Center for Health Research, Kaiser Permanente Northwest, Portland, OR
| | - Beth Devine
- The Comparative Health Outcomes, Policy and Economics (CHOICE) Institute, School of Pharmacy, University of Washington, Seattle, WA
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Chambuso R, Robertson B, Ramesar R. A Scoring Model and Protocol to Adapt Universal Screening for Lynch Syndrome to Identify Germline Pathogenic Variants by Next Generation Sequencing from Colorectal Cancer Patients and Cascade Screening. Cancers (Basel) 2022; 14:cancers14122901. [PMID: 35740566 PMCID: PMC9220991 DOI: 10.3390/cancers14122901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 04/14/2022] [Accepted: 04/22/2022] [Indexed: 12/03/2022] Open
Abstract
Simple Summary Lynch syndrome (LS) is an autosomal-dominantly inherited form of cancer predisposition dominated by colorectal cancer (CRC). LS is caused by germline pathogenic variants (PV) occurring in known mismatch repair genes. For effective cascade screening, it is critical to identify PV for LS predisposition. When limited resources are available, next generation sequencing (NGS) of an entire cohort of colorectal cancer (CRC) patients, even those under 50 or 60 years of age, places a huge burden on the system. Here, we present an innovative LS ascertainment and follow-up program that includes LS molecular analysis, PV screening with NGS technology, and cascade screening. The goal is to improve LS ascertainment in light of the growing burden of early-onset CRC, particularly in low- and middle-income countries. Abstract Identification of germline pathogenic variants (PV) predisposing to Lynch syndrome (LS) is an important step for effective use of cascade screening of extended at-risk lineages, leading to reduced morbidity and mortality due to colorectal cancer (CRC). As a general rule, however, next generation sequencing (NGS, either of gene panels or whole exomes) is relatively expensive and unaffordable for general clinical use. In resource-poor settings, performing NGS testing on an entire cohort of CRC patients, even if limited to those under 50 or 60 years of age, still places an enormous burden on limited resources. Although family history can be a good indicator for LS testing, identifying at-risk family members and offering cascade screening may not benefit many patients/probands without an obvious family history. This article presents a novel program called Modified Ascertainment and follow-up Program (MAP) with a scoring model for LS ascertainment and molecular screening by NGS with diagnosis confirmation of PV and cascade screening. The goal is to improve LS ascertainment in light of the growing burden of early-onset CRC, particularly in low- and middle-income countries. Through MAP, judiciously applied molecular genetics will improve identification of PV predisposing to LS and cascade screening.
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Affiliation(s)
- Ramadhani Chambuso
- Colorectal Cancer Research Group, Division of Human Genetics, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town 7701, South Africa;
- MRC Unit for Genomic and Precision Medicine, Division of Human Genetics, Department of Pathology, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town 7701, South Africa
- Correspondence:
| | - Barbara Robertson
- Division of Radiation Oncology, Department of Radiation Medicine, Groote Schuur Hospital, University of Cape Town, Cape Town 7945, South Africa;
| | - Raj Ramesar
- Colorectal Cancer Research Group, Division of Human Genetics, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town 7701, South Africa;
- MRC Unit for Genomic and Precision Medicine, Division of Human Genetics, Department of Pathology, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town 7701, South Africa
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Murray MF, Khoury MJ, Abul-Husn NS. Addressing the routine failure to clinically identify monogenic cases of common disease. Genome Med 2022; 14:60. [PMID: 35672798 PMCID: PMC9175445 DOI: 10.1186/s13073-022-01062-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 05/16/2022] [Indexed: 12/14/2022] Open
Abstract
Changes in medical practice are needed to improve the diagnosis of monogenic forms of selected common diseases. This article seeks to focus attention on the need for universal genetic testing in common diseases for which the recommended clinical management of patients with specific monogenic forms of disease diverges from standard management and has evidence for improved outcomes.We review evidence from genomic screening of large patient cohorts, which has confirmed that important monogenic case identification failures are commonplace in routine clinical care. These case identification failures constitute diagnostic misattributions, where the care of individuals with monogenic disease defaults to the treatment plan offered to those with polygenic or non-genetic forms of the disease.The number of identifiable and actionable monogenic forms of common diseases is increasing with time. Here, we provide six examples of common diseases for which universal genetic test implementation would drive improved care. We examine the evidence to support genetic testing for common diseases, and discuss barriers to widespread implementation. Finally, we propose recommendations for changes to genetic testing and care delivery aimed at reducing diagnostic misattributions, to serve as a starting point for further evaluation and development of evidence-based guidelines for implementation.
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Affiliation(s)
- Michael F. Murray
- grid.47100.320000000419368710Yale Center for Genomic Health, Department of Genetics, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06520 USA
| | - Muin J. Khoury
- grid.416738.f0000 0001 2163 0069Office of Genomics and Precision Public Health, Office of Science, Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30329 USA
| | - Noura S. Abul-Husn
- grid.59734.3c0000 0001 0670 2351Institute for Genomic Health, Division of Genomic Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1041, New York, NY 10029 USA
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Comment on Colletti et al. Prevalence and Management of Cancer of the Rectal Stump after Total Colectomy and Rectal Sparing in Patients with Familial Polyposis: Results from a Registry-Based Study. Cancers 2022, 14, 298. Cancers (Basel) 2022; 14:cancers14112650. [PMID: 35681630 PMCID: PMC9179353 DOI: 10.3390/cancers14112650] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 05/25/2022] [Indexed: 12/30/2022] Open
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Vagher J, Gammon A, Kohlmann W, Jeter J. Non-Melanoma Skin Cancers and Other Cutaneous Manifestations in Bone Marrow Failure Syndromes and Rare DNA Repair Disorders. Front Oncol 2022; 12:837059. [PMID: 35359366 PMCID: PMC8960432 DOI: 10.3389/fonc.2022.837059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 02/17/2022] [Indexed: 11/17/2022] Open
Abstract
Although most non-melanoma skin cancers are felt to be sporadic in origin, these tumors do play a role in several cancer predisposition syndromes. The manifestations of skin cancers in these hereditary populations can include diagnosis at extremely early ages and/or multiple primary cancers, as well as tumors at less common sites. Awareness of baseline skin cancer risks for these individuals is important, particularly in the setting of treatments that may compromise the immune system and further increase risk of cutaneous malignancies. Additionally, diagnosis of these disorders and management of non-cutaneous manifestations of these diseases have profound implications for both the patient and their family. This review highlights the current literature on the diagnosis, features, and non-melanoma skin cancer risks associated with lesser-known cancer predisposition syndromes, including bone marrow failure disorders, genomic instability disorders, and base excision repair disorders.
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Affiliation(s)
- Jennie Vagher
- Family Cancer Assessment Clinic, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States
| | - Amanda Gammon
- Family Cancer Assessment Clinic, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States
| | - Wendy Kohlmann
- Family Cancer Assessment Clinic, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States
| | - Joanne Jeter
- Family Cancer Assessment Clinic, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States
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Sarki M, Ming C, Aissaoui S, Bürki N, Caiata-Zufferey M, Erlanger TE, Graffeo-Galbiati R, Heinimann K, Heinzelmann-Schwarz V, Monnerat C, Probst-Hensch N, Rabaglio M, Zürrer-Härdi U, Chappuis PO, Katapodi MC. Intention to Inform Relatives, Rates of Cascade Testing, and Preference for Patient-Mediated Communication in Families Concerned with Hereditary Breast and Ovarian Cancer and Lynch Syndrome: The Swiss CASCADE Cohort. Cancers (Basel) 2022; 14:cancers14071636. [PMID: 35406409 PMCID: PMC8997156 DOI: 10.3390/cancers14071636] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/16/2022] [Accepted: 03/21/2022] [Indexed: 12/30/2022] Open
Abstract
Cascade screening for Tier 1 cancer genetic conditions is a significant public health intervention because it identifies untested relatives of individuals known to carry pathogenic variants associated with hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS). The Swiss CASCADE is a family-based, open-ended cohort, including carriers of HBOC- and LS-associated pathogenic variants and their relatives. This paper describes rates of cascade screening in relatives from HBOC- and LS- harboring families, examines carriers' preferences for communication of testing results, and describes theory-based predictors of intention to invite relatives to a cascade screening program. Information has been provided by 304 index cases and 115 relatives recruited from September 2017 to December 2021. On average, 10 relatives per index case were potentially eligible for cascade screening. Approximately 65% of respondents wanted to invite relatives to the cohort, and approximately 50% indicated a preference for patient-mediated communication of testing results, possibly with the assistance of digital technology. Intention to invite relatives was higher for first- compared to second- and third-degree relatives, but was not different between syndromes or based on relatives' gender. The family environment and carrying pathogenic variants predicts intention to invite relatives. Information helps optimize delivery of tailored genetic services.
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Affiliation(s)
- Mahesh Sarki
- Department of Clinical Research, University of Basel, 4055 Basel, Switzerland; (M.S.); (C.M.)
| | - Chang Ming
- Department of Clinical Research, University of Basel, 4055 Basel, Switzerland; (M.S.); (C.M.)
| | - Souria Aissaoui
- Breast Center, Cantonal Hospital Fribourg, 1752 Fribourg, Switzerland;
- GENESUPPORT, The Breast Centre, Hirslanden Clinique de Grangettes, 1224 Geneva, Switzerland
| | - Nicole Bürki
- Women’s Clinic, University Hospital Basel, 4031 Basel, Switzerland; (N.B.); (V.H.-S.)
| | - Maria Caiata-Zufferey
- Department of Business Economics, Health and Social Care, University of Applied Sciences and Arts of Southern Switzerland, 6928 Manno, Switzerland;
| | | | | | - Karl Heinimann
- Institute for Medical Genetics and Pathology, University Hospital Basel, 4031 Basel, Switzerland;
- Research Group Human Genomics, Department of Biomedicine, University of Basel, 4031 Basel, Switzerland
| | | | - Christian Monnerat
- Department of Medical Oncology, Hospital of Jura, 2800 Delemont, Switzerland;
| | - Nicole Probst-Hensch
- Swiss Tropical and Public Health Institute, University of Basel, 4123 Allschwil, Switzerland;
| | - Manuela Rabaglio
- Department of Medical Oncology, Inselspital, Bern University Hospital, 3010 Bern, Switzerland;
| | - Ursina Zürrer-Härdi
- Department of Medical Oncology, Cantonal Hospital Winterthur, 8400 Winterthur, Switzerland;
| | - Pierre Olivier Chappuis
- Unit of Oncogenetics, Division of Oncology, University Hospitals of Geneva, 1205 Geneva, Switzerland;
- Division of Genetic Medicine, University Hospitals of Geneva, 1205 Geneva, Switzerland
| | - Maria C. Katapodi
- Department of Clinical Research, University of Basel, 4055 Basel, Switzerland; (M.S.); (C.M.)
- Correspondence: ; Tel.: +41-61-207-04-30
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Parsa FG, Nobili S, Karimpour M, Aghdaei HA, Nazemalhosseini-Mojarad E, Mini E. Fanconi Anemia Pathway in Colorectal Cancer: A Novel Opportunity for Diagnosis, Prognosis and Therapy. J Pers Med 2022; 12:396. [PMID: 35330396 PMCID: PMC8950345 DOI: 10.3390/jpm12030396] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 03/01/2022] [Accepted: 03/02/2022] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and has the second highest mortality rate globally. Thanks to the advent of next-generation sequencing technologies, several novel candidate genes have been proposed for CRC susceptibility. Germline biallelic mutations in one or more of the 22 currently recognized Fanconi anemia (FA) genes have been associated with Fanconi anemia disease, while germline monoallelic mutations, somatic mutations, or the promoter hypermethylation of some FANC genes increases the risk of cancer development, including CRC. The FA pathway is a substantial part of the DNA damage response system that participates in the repair of DNA inter-strand crosslinks through homologous recombination (HR) and protects genome stability via replication fork stabilization, respectively. Recent studies revealed associations between FA gene/protein tumor expression levels (i.e., FANC genes) and CRC progression and drug resistance. Moreover, the FA pathway represents a potential target in the CRC treatment. In fact, FANC gene characteristics may contribute to chemosensitize tumor cells to DNA crosslinking agents such as oxaliplatin and cisplatin besides exploiting the synthetic lethal approach for selective targeting of tumor cells. Hence, this review summarizes the current knowledge on the function of the FA pathway in DNA repair and genomic integrity with a focus on the FANC genes as potential predisposition factors to CRC. We then introduce recent literature that highlights the importance of FANC genes in CRC as promising prognostic and predictive biomarkers for disease management and treatment. Finally, we represent a brief overview of the current knowledge around the FANC genes as synthetic lethal therapeutic targets for precision cancer medicine.
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Affiliation(s)
- Fatemeh Ghorbani Parsa
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 19857-17413, Iran; (F.G.P.); (H.A.A.)
| | - Stefania Nobili
- Department of Neurosciences, Imaging and Clinical Sciences, University “G. D’Annunzio” Chieti-Pescara, 66100 Chieti, Italy;
- Center for Advanced Studies and Technology (CAST), University “G. D’Annunzio” Chieti-Pescara, 66100 Chieti, Italy
| | - Mina Karimpour
- Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran 14115-154, Iran;
| | - Hamid Asadzadeh Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 19857-17413, Iran; (F.G.P.); (H.A.A.)
| | - Ehsan Nazemalhosseini-Mojarad
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 19857-17413, Iran
| | - Enrico Mini
- Department of Health Sciences, University of Florence, 50139 Florence, Italy
- DENOTHE Excellence Center, University of Florence, 50139 Florence, Italy
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Fanale D, Corsini LR, Brando C, Dimino A, Filorizzo C, Magrin L, Sciacchitano R, Fiorino A, Bazan Russo TD, Calò V, Iovanna JL, Francini E, Russo A, Bazan V. Impact of Different Selection Approaches for Identifying Lynch Syndrome-Related Colorectal Cancer Patients: Unity Is Strength. Front Oncol 2022; 12:827822. [PMID: 35223509 PMCID: PMC8864140 DOI: 10.3389/fonc.2022.827822] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 01/18/2022] [Indexed: 12/11/2022] Open
Abstract
Lynch syndrome (LS) is an inherited genetic condition associated with increased predisposition to colorectal cancer (CRC) and other tumors and is caused by germline mutations in Mismatch Repair (MMR) or EPCAM genes. The identification of LS carriers is currently based on germline testing of subjects with MMR-deficient (dMMR) tumors or fulfilling clinical criteria, but the most efficient strategies to select patients who should be offered genetic testing are yet not well defined. In order to assess the most suitable selection mode to identify LS-related CRC patients, we retrospectively collected and analyzed all clinical and molecular information of 854 CRC patients, recruited from 2013 to 2021 at the University Hospital Policlinico "P. Giaccone" of Palermo (Italy), 100 of which were selected based on revised Bethesda guidelines, Amsterdam criteria II, or tissue MMR deficiency, and genetically tested for germline variants in LS-susceptibility genes. Our study showed that 32 out of 100 CRC patients harbored germline likely pathogenic/pathogenic variants in MMR genes. The analysis of tissue microsatellite instability (MSI) status according to the revised Bethesda guidelines has been to be the best selection approach. However, using different selection approaches as complementary strategies is useful to identify LS carriers, reducing underdiagnosis of this syndrome.
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Affiliation(s)
- Daniele Fanale
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy
| | - Lidia Rita Corsini
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy
| | - Chiara Brando
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy
| | - Alessandra Dimino
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy
| | - Clarissa Filorizzo
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy
| | - Luigi Magrin
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy
| | - Roberta Sciacchitano
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy
| | - Alessia Fiorino
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy
| | - Tancredi Didier Bazan Russo
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy
| | - Valentina Calò
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy
| | - Juan Lucio Iovanna
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France
| | - Edoardo Francini
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Antonio Russo
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy
| | - Viviana Bazan
- Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D.), Section of Medical Oncology, University of Palermo, Palermo, Italy
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Shahani SA, Marcotte EL. Landscape of germline cancer predisposition mutations testing and management in pediatrics: Implications for research and clinical care. Front Pediatr 2022; 10:1011873. [PMID: 36225340 PMCID: PMC9548803 DOI: 10.3389/fped.2022.1011873] [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: 08/04/2022] [Accepted: 09/05/2022] [Indexed: 11/13/2022] Open
Abstract
As germline genetic testing capacities have improved over the last two decades, increasingly more people are newly diagnosed with germline cancer susceptibility mutations. In the wake of this growth, there remain limitations in both testing strategies and translation of these results into morbidity- and mortality-reducing practices, with pediatric populations remaining especially vulnerable. To face the challenges evoked by an expanding diversity of germline cancer mutations, we can draw upon a model cancer-associated genetic condition for which we have developed a breadth of expertise in managing, Trisomy 21. We can additionally apply advances in other disciplines, such as oncofertility and pharmacogenomics, to enhance care delivery. Herein, we describe the history of germline mutation testing, epidemiology of known germline cancer mutations and their associations with childhood cancer, testing limitations, and future directions for research and clinical care.
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Affiliation(s)
- Shilpa A Shahani
- Department of Pediatrics, City of Hope Comprehensive Cancer Center, Duarte, CA, United States
| | - Erin L Marcotte
- Division of Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis, MN, United States.,Masonic Cancer Center, University of Minnesota, Minneapolis, MN, United States
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