Genealogical Tree Study as Screening Method in the Lynch Syndrome Prior to Genetic Test

e17119 Background: Universal tumor testing for defective DNA mismatch repair (MMR) is recommended for all women diagnosed with endometrial cancer (EC) to identify those with underlying Lynch syndrome (LS). However, since its implementation in 2013, the effectiveness of this screening method on identifying individuals with LS across the population has not been well studied. The aim of this study was to evaluate outcomes of MMR immunohistochemistry (IHC), MLH1 methylation, and microsatellite instability (MSI) analysis among EC patients. Methods: We conducted a complete systematic search of online databases PubMed, Embase, Medline, and Cochrane Library between 1990-2018. A DerSimonian–Laird random-effects model meta-analysis was utilized to estimate the weighted prevalence of LS diagnoses. Results: The comprehensive search produced 3,427 publications. 29 peer-review studies met the inclusion criteria. 6,649 EC patients were identified, 206 (3%) were confirmed to have LS following positive universal tumor molecular screening.5,917 patients underwent tumor IHC, 28% had abnormal staining. 3,140 patients underwent MSI analysis, 31% had MSI instability. Among EC patients with deficient IHC staining or positive MSI analysis, the weighted prevalence of LS was 15% and 19% respectively. 1159 patients exhibited loss of MLH1 staining, 143 (13.7%) were found to be MLH1 methylation negative, 32 demonstrated a germline MLH1 mutation (2.8% of all MLH1 absent staining; 22.4% of all MLH1 methylation negative). 43% of EC patients diagnosed with LS via tumor typing would have been missed by family history-based screening alone. Conclusions: Despite widespread implementation of universal tumor testing in EC, data regarding results have previously been limited. For the first time, this study provides large-scale predictive values that will help practitioners evaluate abnormal results in the context of LS and aid in patient counseling. [Table: see text]

Download Full-text

Sharing Genetic Test Results in Lynch Syndrome: Communication With Close and Distant Relatives

Clinical Gastroenterology and Hepatology ◽

10.1016/j.cgh.2007.12.014 ◽

2008 ◽

Vol 6 (3) ◽

pp. 333-338 ◽

Cited By ~ 64

Author(s):

Elena M. Stoffel ◽

Beth Ford ◽

Rowena C. Mercado ◽

Darashana Punglia ◽

Wendy Kohlmann ◽

...

Keyword(s):

Lynch Syndrome ◽

Genetic Test ◽

Test Results ◽

Genetic Test Results

Download Full-text

Diagnostic Application ofhMLH1Methylation in Hereditary Non-Polyposis Colorectal Cancer

Disease Markers ◽

10.1155/2004/371941 ◽

2004 ◽

Vol 20 (4-5) ◽

pp. 277-282 ◽

Cited By ~ 5

Author(s):

Nagahide Matsubara

Keyword(s):

Colorectal Cancer ◽

Lynch Syndrome ◽

Genetic Test ◽

Screening Program ◽

Immunohistochemical Analysis ◽

Germline Mutations ◽

Clinical Criteria ◽

Pathological Analysis ◽

Mmr Genes ◽

New Strategy

Colorectal cancer (CRC) due to mismatch repair (MMR) defect has distinct characteristics among unselected CRCs. These CRCs are biologically less aggressive and, thus, showing better prognosis but less sensitive to the 5FU-based chemotherapy. CRCs with MMR defect derive from both hereditary and sporadic reasons. Germline inactivation of MMR genes (hMLH1, hMSH2, hMSH6, andhPMS2) underlies the hereditary CRC with MMR defect (Lynch syndrome) and epigenetic silencing ofhMLH1gene causes the sporadic CRC with MMR defect. Hereditary and sporadic CRC with MMR defect can be detectable by microsatellite instability (MSI) test or immunohistochemical analysis among general CRCs. Lynch syndrome can be diagnosed by the clinical criteria or by genetic test to detect pathogenic germline mutations in MMR genes. However, both clinical criteria and genetic test are inadequate for the diagnosis of Lynch syndrome. Since genetic test for the diagnosis of the Lynch syndrome is expensive and not always identify pathogenic germline mutations, effective and inexpensive screening program is desirable. Here we propose a possible application of methylation test combined with MSI or pathological analysis as an effective and a cost-saving new strategy for screening of Lynch syndrome.

Download Full-text

Long-term psychosocial and behavioral adjustment in individuals receiving genetic test results in Lynch syndrome

Clinical Genetics ◽

10.1111/cge.12509 ◽

2014 ◽

Vol 87 (6) ◽

pp. 525-532 ◽

Cited By ~ 6

Author(s):

M.J. Esplen ◽

J. Wong ◽

M. Aronson ◽

K. Butler ◽

H. Rothenmund ◽

...

Keyword(s):

Lynch Syndrome ◽

Genetic Test ◽

Behavioral Adjustment ◽

Test Results ◽

Genetic Test Results

Download Full-text

New genetic test for Lynch syndrome

The Lancet Oncology ◽

10.1016/s1470-2045(06)70923-8 ◽

2006 ◽

Vol 7 (11) ◽

pp. 892

Author(s):

Cathel Kerr

Keyword(s):

Lynch Syndrome ◽

Genetic Test

Download Full-text

POST-GENETIC TEST RESULT ANXIETY AND DEPRESSION IN ONCOLOGIC PATIENTS SUSPECTED FOR HEREDITARY BREAST AND OVARY CANCER (HBOC) OR LYNCH SYNDROME (LS)

10.22533/at.ed.64521081024 ◽

2021 ◽

pp. 179-181

Author(s):

Francisca Fernanda Barbosa Oliveira ◽

Maria Júlia Barbosa Bezerra ◽

Isabelle Joyce de Lima Silva-Fernandes ◽

Deysi Viviana Tenazoa Wong ◽

Paulo Goberlânio de Barros Silva ◽

...

Keyword(s):

Lynch Syndrome ◽

Genetic Test ◽

Anxiety And Depression ◽

Genetic Test Result ◽

Ovary Cancer ◽

Oncologic Patients ◽

Test Result

Download Full-text

Colorectal Cancer Risk Perception on the Basis of Genetic Test Results in Individuals at Risk for Lynch Syndrome

Journal of Clinical Oncology ◽

10.1200/jco.2008.18.6940 ◽

2009 ◽

Vol 27 (24) ◽

pp. 3981-3986 ◽

Cited By ~ 16

Author(s):

Shilpa Grover ◽

Elena M. Stoffel ◽

Rowena C. Mercado ◽

Beth M. Ford ◽

Wendy K. Kohlman ◽

...

Keyword(s):

Colorectal Cancer ◽

Genetic Testing ◽

Risk Perception ◽

Cancer Risk ◽

Lynch Syndrome ◽

Genetic Test ◽

Genetic Test Result ◽

Test Results ◽

Genetic Test Results ◽

Test Result

Purpose Lynch syndrome is associated with inherited germline mutations in mismatch repair (MMR) genes. Genetic testing in high-risk individuals may yield indeterminate results if no mutation is found or if a mutation of unclear pathogenic significance is observed. There are limited data regarding how well patients with Lynch syndrome understand the clinical implications of genetic test results. This study examines colorectal cancer (CRC) risk perception in individuals tested for MMR mutations and identifies the factors associated with an appropriate interpretation of their cancer risk. Patients and Methods A total of 159 individuals who met the Revised Bethesda Guidelines and had previously undergone genetic testing completed a questionnaire eliciting demographic data, cancer history, genetic test results, and an estimate of their CRC risk. Associations between clinical factors, genetic test results, and CRC risk perception were explored using multivariable analyses. Results Of the 100 individuals with a pathogenic mutation (true positive), 90 (90%) correctly estimated their CRC risk as “high” or “very high” compared with other individuals their age. However, only 23 (62%) of 37 individuals with an indeterminate genetic test result correctly estimated their risk. Individuals with a history of Lynch syndrome–associated cancer (odds ratio [OR], 0.1; 95% CI, 0.1 to 0.6) or indeterminate genetic test results (OR, 0.2; 95% CI, 0.1 to 0.6) were significantly less likely to estimate their CRC risk as increased. Conclusion Patients at risk for Lynch syndrome with an indeterminate genetic test result may be falsely reassured. It is important that health care providers continue to discuss the implications of uninformative results on lifetime cancer risk.

Download Full-text

“Left in limbo”: Exploring how patients with colorectal cancer interpret and respond to a suspected Lynch syndrome diagnosis

Hereditary Cancer in Clinical Practice ◽

10.1186/s13053-021-00201-1 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Nicole den Elzen ◽

Sharelle L. Joseland ◽

Sibel Saya ◽

Sowmya Jonnagadla ◽

Joanne Isbister ◽

...

Keyword(s):

Risk Management ◽

Cancer Risk ◽

Lynch Syndrome ◽

Genetic Test ◽

Cancer Genetics ◽

Test Results ◽

Genetic Test Results ◽

Genetics Services ◽

Management Advice ◽

Cancer Risk Management

Abstract Background A diagnosis of suspected Lynch syndrome (SLS) is given when a tumour displays characteristics consistent with Lynch syndrome (LS), but no germline pathogenic variant is identified. This inconclusive diagnosis results in uncertainty around appropriate cancer risk management. This qualitative study explored how patients with CRC interpret and respond to an SLS diagnosis. Methods Semi-structured telephone interviews were conducted with 15 patients with CRC who received an SLS diagnosis, recruited from cancer genetics services across Australia. Interviews were transcribed verbatim and analysed using thematic analysis. Participant responses were compared with appointment summary letters from cancer genetics services. Results Participants’ interpretations of genetic test results were found to vary widely. While this variation often aligned with variation in interpretations by cancer genetics services, participants also had difficulties with the complexity and recall of genetic test results. Participants had a range of psychological responses to the uncertainty that their results presented, from relief to disappointment and doubt. Cancer risk perceptions also varied widely, with participants’ interpretations of their genetic test results just one of several influencing factors. Despite this variability, almost all participants adhered to cancer risk management advice, although different participants received different advice. All participants also communicated any cancer risk management advice to first-degree relatives, motivated by protecting them, but information communicated was not always consistent with advice received. Conclusions Our study findings highlight the variability in patients’ interpretations of their diagnosis, cancer risk management and family communication when a diagnosis of SLS is received, and provide novel insights into how healthcare professionals can better support patients with SLS.

Download Full-text

An integrated screening method for evaluating the pulmonary toxicity of inhaled particulates: Role of microscopic techniques in assessing pulmonary macrophage clearance functions

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100161692 ◽

1990 ◽

Vol 48 (3) ◽

pp. 826-827

Author(s):

David B. Warheit ◽

Lena Achinko ◽

Mark A. Hartsky

Keyword(s):

Bronchoalveolar Lavage ◽

Pulmonary Toxicity ◽

Screening Method ◽

Pulmonary Response ◽

Inhaled Particles ◽

Cytochemical Analysis ◽

Pulmonary Macrophages ◽

Integrated Screening

There is a great need for the development of a rapid and reliable bioassay to evaluate the pulmonary toxicity of inhaled particles. A number of methods have been proposed, including lung clearance studies, bronchoalveolar lavage analysis, and in vitro cytotoxicity tests. These methods are often limited in scope inasmuch as they measure only one dimension of the pulmonary response to inhaled, instilled or incubated dusts. Accordingly, a comprehensive approach to lung toxicity studies has been developed.To validate the method, rats were exposed for 6 hours or 3 days to various concentrations of either aerosolized alpha quartz silica (Si) or carbonyl iron (CI) particles. Cells and fluids from groups of sham and dust-exposed animals were recovered by bronchoalveolar lavage (BAL). Alkaline phosphatase, LDH and protein values were measured in BAL fluids at several time points postexposure. Cells were counted and evaluated for viability, as well as differential and cytochemical analysis. In addition, pulmonary macrophages (PM) were cultured and studied for morphology, chemotaxis, and phagocytosis by scanning electron microscopy.

Download Full-text