Comparison of Lynch predictive models for identification of MLH1/MSH2 mutation carriers in a Spanish multicentre clinic- based cohort

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e22077-e22077
Author(s):  
I. Valenzuela ◽  
J. Balmaña ◽  
M. Rue ◽  
I. Blanco ◽  
A. Torres ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Lynch Syndrome ◽  
Predictive Models ◽  
Carrier Status ◽  
Operating Characteristics ◽  
Comparative Performance ◽  
Large Rearrangement ◽  
Clinical Criteria ◽  
Msh2 Mutation ◽  
Mutation Carriers

e22077 Background: Different predictive models for Lynch syndrome have recently been developed and their comparative performance in a clinic-based cohort has not been assessed. We aimed to analyze the accuracy of the MMRpro, Barnetson, and PREMM1,2 models to predict MLH1/MSH2 mutation carrier status in 564 unrelated probands with clinical suspicion of hereditary colorectal cancer and compare it with Wijnen model and clinical criteria. Methods: Overall, 538 individuals (95%) underwent mismatch repair (MMR) deficiency screening before germline genetic testing (sequencing with or without large rearrangement analysis) and 26 (5%) performed direct genetic testing. Prediction scores for all individuals were calculated by each model. Sensitivity, specificity, positive predictive value (PPV), and the areas under the receiver operating characteristics curves (AUC) for all models were calculated and compared with the Revised Bethesda Guidelines (RBG). Results: 114 individuals (20%) were mutation carriers (63 MLH1, 51 MSH2). The AUC was 0.95 (95% CI: 0.93–0.97) for MMRpro, 0.87 (95% CI 0.83–0.91) for the Barnetson model, 0.87 (95% CI 0.83–0.91) for PREMM1,2, and 0.75 (95% CI 0.69–0.80) for the Wijnen model (p<0.001). Testing thresholds and specificity at 100% and 90% sensitivity for each model were: 0.001/17% and 0.33/89% for MMRpro, 0.01/9% and 0.07/59% for Barnetson, 0.05/5% and 0.11/58% for PREMM1,2. Sensitivity and specificity of RBG were 86% and 14%, respectively. Calibration was 0.92, 1.05, 0.50, and 1.25 for PREMM1,2,Barnetson, Wijnen, and MMRpro, respectively. Conclusions: In a population of individuals at risk of Lynch syndrome, the MMRpro model has the largest AUC, although the Barnetson and PREMM1,2 model also show adequate discrimination. Any of the models perform better than the RBG and provide quantitative risk estimation of finding a MLH1/MSH2 mutation useful in genetic counselling. No significant financial relationships to disclose.

Characterization of family history profiles in a large series of Lynch syndrome carriers.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 414-414
Author(s):  
Devki Saraiya ◽  
Sara J. Wiyrick ◽  
Barry S. Tong ◽  
Kelsey Moyes ◽  
Elizabeth Garner
Keyword(s):  
Genetic Testing ◽  
Family History ◽  
Lynch Syndrome ◽  
Single Gene ◽  
Healthcare Providers ◽  
Degree Relative ◽  
Large Rearrangement ◽  
Full Sequence ◽  
Bethesda Criteria ◽  
Second Degree

414 Background: The identification of Lynch syndrome carriers is an unmet medical need. Large studies characterizing family history profiles of unaffected individuals diagnosed with Lynch syndrome in the absence of a known family mutation have not been reported. Methods: We queried our laboratory database for unaffected patients who underwent Lynch syndrome genetic testing between September 2010 and May 2013 and had a positive test result. All individuals underwent full sequence and large rearrangement analysis of MLH1 and MSH2, and full sequence analysis of MSH6. Some patients also underwent full sequence and large rearrangement analysis of PMS2 and large rearrangement analysis of MSH6 and EPCAM. Those being tested for a known mutation in the family and patients undergoing single gene testing were excluded. We assessed family history profiles in 200 unaffected patients with genetically confirmed Lynch syndrome. Results: Of the 200 patients, 162 female and 38 male Lynch syndrome carriers were identified. Mutations in MLH1 and MSH2 were the most common (30.0% and 32.5%) while mutations in MSH6, PMS2, and EPCAM accounted for 21.0%, 13.5%, and 3.0% of all deleterious mutations, respectively. Eighteen patients did not have a first or second degree relative with colorectal cancer. Only 37.8% (73/193) of individuals had a first- or second-degree relative meeting the Amsterdam II criteria and 76.8 % (149/194) of individuals had a first or second degree relative meeting the Revised Bethesda criteria. The average PREMM1,2,6 score was 10.0% with 43.5% (87/200) falling below 5%. In this large cohort, 15.5% (31/200) had neither a first or second degree relative who met the Amsterdam II or Revised Bethesda criteria nor a PREMM1,2,6 score of 5% or greater. Conclusions: In order to improve detection of Lynch syndrome in the population, it is important to consider genetic testing in unaffected individuals even in the absence of a known family mutation. Development of guidelines that include having a single affected relative and extra-colonic cancers is needed to support healthcare providers in identifying appropriate patients for testing.

scholarly journals Contribution of Lynch syndrome to early onset malignancy in Ireland.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 586-586
Author(s):  
Alice Talbot ◽  
David James Gallagher
Keyword(s):  
Lynch Syndrome ◽  
Cancer Diagnosis ◽  
Early Onset ◽  
Cancer Genetics ◽  
Statistical Significance ◽  
Hereditary Cancer Syndrome ◽  
Carrier Status ◽  
Mutation Carriers ◽  
Significant Difference ◽  
First Diagnosis

586 Background: Lynch syndrome (LS) is an autosomal dominant hereditary cancer syndrome responsible for 2 -6% of hereditary colorectal cancers. LS is caused by germ-line mutations in mismatch repair genes (MMR): MLH1, MSH2, MSH6, PMS2 or EPCAM. This results in microsatellite instability, a phenotypic hallmark of LS-associated colorectal cancer. The aim of this study was to construct and analyse a database of Irish MMR mutation carriers. Methods: Records were from two of the three existing cancer genetics clinics in Ireland. Clinicopathological data of all probands (n=57) including names, dates of birth and death, carrier status and phenotype were recorded. Death certificates were used to confirm information regarding deceased mutation carriers. An ANOVA test was used to establish statistical significance of variations in age by gene. Length of survival based on stage was assessed using Kaplain Meier curves. Results: 345 affected individuals were identified. The most common cancers recorded were colorectal (53%), breast (12%) and endometrial (10%). 138 confirmed carriers were identified: 65 MLH1 (47%), 43 MSH2 (31%), 11 MSH6 (8%), 17 PMS2 (12%), and 2 EPCAM (1%). 22 patients have died since confirmation of Lynch Syndrome, 50% of whom died within 2.5 years of first diagnosis. All deceased carriers had at least one cancer diagnosis and 50% had developed multiple cancers. 59% of deaths were directly related to cancer. 7 of these patients had Stage 4 cancer at diagnosis. There was a significant difference in length of survival based on stage. (p=.048) Phenotype frequencies varied significantly by gene. (see table 1) Median age of first diagnosis of any cancer was 44.5 years (range 23-81). There was no difference in age at presentation by gene mutated. Conclusions: Under-diagnosis of LS misses a powerful preventive and therapeutic opportunity. LS causes early onset cancer diagnosis with substantial societal impact. A significant number of Lynch Syndrome cases have poor clinical outcomes. Genotype/Phenotype frequencies. [Table: see text]

Gastrointestinal cancer risk in Irish hereditary breast ovarian cancer families.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 413-413
Author(s):  
Darragh S Gogarty ◽  
Tomas Lyons ◽  
Michael P. Farrell ◽  
Naoise Maria Dorman ◽  
Andrew J Green ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Cancer Risk ◽  
Lynch Syndrome ◽  
Early Onset ◽  
Carrier Status ◽  
Hereditary Breast Ovarian Cancer ◽  
Mutation Carriers ◽  
Increased Risk ◽  
Age Of Diagnosis

413 Background: Colorectal and breast cancer are linked in certain predisposition syndromes such as Cowden and Peutz-Jegers syndrome. Breast cancer risk also appears increased in certain Lynch syndrome kindreds. Original reports suggested an increased risk of colorectal malignancies in BRCA1/2 mutation carriers. Two large studies in Ashkenazi Jewish populations subsequently contradicted this early evidence, although neither study was powered to address effects if each gene independently, or other modifier effects in certain families. We report the Irish experience of colorectal and gastro-esophageal (GE) cancer in hereditary breast ovarian cancer (HBOC) families. Methods: 97 HBOC families at two tertiary referral centres were reviewed for the presence of early onset GE malignancies. The medical records of individuals with GE cancer were reviewed to determine carrier status. Clinical data including age of diagnosis, stage, treatment and outcome were extracted. Median age of diagnosis and outcome were compared among BRCA1/2 mutation carriers and non-carriers. Results: We identified 30 individuals with GE malignancies in 97 HBOC families (19 with colorectal, 11 with gastric). Two families were excluded as Lynch syndrome was also diagnosed in these families. Definitive carrier status was available on 8 individuals. Additional 7 individuals were obligate carriers. Age at diagnosis ranged from 27-84 years (median=60). Median age of CRC diagnosis among carriers was 54 compared with 61 among non-carriers (p=0.20). Median age of gastric diagnosis among carriers was 66 compared with 53 among non-carriers. Conclusions: Early onset colorectal cancer occurs in certain HBOC families and may be related to mutation status. No genotype-phenotype association was identified in this study. An additional 150 Irish HBOC families are being screened for early onset GI malignancies and updated data will be presented at the meeting.

T2027 Comparison of Predictive Models and Clinical Criteria for the Identification of Patients with Lynch Syndrome in a Population-Based Cohort of Colorectal Cancer (CRC) Patients

2008 ◽  
Vol 134 (4) ◽  
pp. A-603
Author(s):  
Judith Balmaña ◽  
Francesc Balaguer ◽  
Sergi Castellvi-Bel ◽  
Ewout W Steyerberg ◽  
Montserrat Andreu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lynch Syndrome ◽  
Predictive Models ◽  
Population Based ◽  
Clinical Criteria

scholarly journals Uptake and predictors of colonoscopy use in family members not participating in cascade genetic testing for Lynch syndrome

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Donald W. Hadley ◽  
Dina Eliezer ◽  
Yonit Addissie ◽  
Andrea Goergen ◽  
Sato Ashida ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Lynch Syndrome ◽  
Health Care Providers ◽  
Perceived Risk ◽  
Risk Perceptions ◽  
Family Members ◽  
The United States ◽  
Carrier Status ◽  
Care Providers ◽  
Cross Sectional Survey

Abstract Cascade genetic testing provides a method to appropriately focus colonoscopy use in families with Lynch syndrome (LS). However, research suggests that up to two-thirds at risk to inherit LS don’t participate. Within the United States, no studies have assessed colonoscopy use within this elusive and high-risk subset. We set forth to (1) document colonoscopy use within those not undergoing genetic testing (NGT) and (2) identify factors associated with completing colonoscopy. Data came from a cross sectional survey of families with molecularly confirmed LS. One hundred seventy-six (176) adults participated; 47 of unknown variant status and 129 with variant status known (59 carriers/70 non-carriers). Despite a high level of awareness of LS (85%) and identical recommendations for colonoscopy, NGT reported significantly lower use of colonoscopy than carriers (47% vs. 73%; p = 0.003). Our results show that perceived risk to develop colon cancer (AOR = 1.99, p < 0.05) and physician recommendations (AOR = 7.64, p < 0.01) are significant predictors of colonoscopy use across all family members controlling for carrier status. Given these findings, health care providers, should assess patients’ perceived risk to develop cancer, assist them in adjusting risk perceptions and discuss recommendations for colonoscopy with all members in families with LS. Trial Registration Clinical Trials.gov Identifier: NCT00004210.

scholarly journals A Systematic Review on the Impact of Genetic Testing for Familial Melanoma I: Primary and Secondary Preventative Behaviours

Dermatology ◽  
2021 ◽  
pp. 1-10
Author(s):  
Clare A. Primiero ◽  
Tatiane Yanes ◽  
Anna Finnane ◽  
H. Peter Soyer ◽  
Aideen M. McInerney-Leo
Keyword(s):  
Genetic Testing ◽  
Positive Impact ◽  
Cochrane Library ◽  
Original Research ◽  
Carrier Status ◽  
Familial Melanoma ◽  
Mutation Carriers ◽  
Increased Risk ◽  
The Impact ◽  
Preventative Behaviour

<b><i>Background:</i></b> Increasing availability of panel testing for known high-penetrance familial melanoma genes has made it possible to improve risk awareness in those at greatest risk. Prior to wider implementation, the role of genetic testing in preventing melanoma, through influencing primary and secondary preventative behaviours, requires clarification. <b><i>Methods:</i></b> Database searches of PubMed, Embase, CINAHL, PsycINFO and the Cochrane Library were conducted for studies describing preventative behaviour outcomes in response to genetic testing for melanoma risk. Publications describing original research of any study type were screened for eligibility. <b><i>Results:</i></b> Eighteen publications describing 11 unique studies were reviewed. Outcomes assessed are based on health behaviour recommendations for those at increased risk: adherence to sun-protective behaviour (SPB); clinical skin examinations (CSE); skin self-examinations (SSE); and family discussion of risk. Overall, modest increases in adherence to primary prevention strategies of SPB were observed following genetic testing. Importantly, there were no net decreases in SPB found amongst non-carriers. For secondary preventative behaviour outcomes, including CSE and SSE, increases in post-test intentions and long-term adherence were reported across several subgroups in approximately half of the studies. While this increase reached significance in mutation carriers in some studies, one study reported a significant decline in annual CSE adherence of non-mutation carriers. <b><i>Conclusions:</i></b> Evidence reviewed suggests that genetic testing has a modestly positive impact on preventative behaviour in high-risk individuals. Furthermore, improvements are observed regardless of mutation carrier status, although greater adherence is found in carriers. While additional studies of more diverse cohorts would be needed to inform clinical recommendations, the findings are encouraging and suggest that genetic testing for melanoma has a positive impact on preventative behaviours.

Genotype-Phenotype Comparison of German MLH1 and MSH2 Mutation Carriers Clinically Affected With Lynch Syndrome: A Report by the German HNPCC Consortium

2006 ◽  
Vol 24 (26) ◽  
pp. 4285-4292 ◽  
Author(s):  
Timm Goecke ◽  
Karsten Schulmann ◽  
Christoph Engel ◽  
Elke Holinski-Feder ◽  
Constanze Pagenstecher ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lynch Syndrome ◽  
Germline Mutations ◽  
Time Span ◽  
Msh2 Mutation ◽  
Mutation Carriers ◽  
Phenotype Comparison ◽  
Rectal Cancers ◽  
Prostate Cancers ◽  
Colorectal Cancer Patients

Purpose Lynch syndrome is linked to germline mutations in mismatch repair genes. We analyzed the genotype-phenotype correlations in the largest cohort so far reported. Patients and Methods Following standard algorithms, we identified 281 of 574 unrelated families with deleterious germline mutations in MLH1 (n = 124) or MSH2 (n = 157). A total of 988 patients with 1,381 cancers were included in this analysis. Results We identified 181 and 259 individuals with proven or obligatory and 254 and 294 with assumed MLH1 and MSH2 mutations, respectively. Age at diagnosis was younger both in regard to first cancer (40 v 43 years; P < .009) and to first colorectal cancer (CRC; 41 v 44 years; P = .004) in MLH1 (n = 435) versus MSH2 (n = 553) mutation carriers. In both groups, rectal cancers were remarkably frequent, and the time span between first and second CRC was smaller if the first primary occurred left sided. Gastric cancer was the third most frequent malignancy occurring without a similarly affected relative in most cases. All prostate cancers occurred in MSH2 mutation carriers. Conclusion The proportion of rectal cancers and shorter time span to metachronous cancers indicates the need for a defined treatment strategy for primary rectal cancers in hereditary nonpolyposis colorectal cancer patients. Male MLH1 mutation carriers require earlier colonoscopy beginning at age 20 years. We propose regular gastric surveillance starting at age 35 years, regardless of the familial occurrence of this cancer. The association of prostate cancer with MSH2 mutations should be taken into consideration both for clinical and genetic counseling practice.

scholarly journals Underdiagnosis of Hereditary Colorectal Cancers Among Medicare Patients: Genetic Testing Criteria for Lynch Syndrome Miss the Mark

2021 ◽  
pp. 1103-1111
Author(s):  
Charles Muller ◽  
Sarah M. Nielsen ◽  
Kathryn E. Hatchell ◽  
Shan Yang ◽  
Scott T. Michalski ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Lynch Syndrome ◽  
Hereditary Cancer ◽  
Medicare Beneficiaries ◽  
Cancer Genes ◽  
Hereditary Cancer Syndromes ◽  
Clinical Criteria ◽  
Cancer Syndromes ◽  
Testing Criteria ◽  
Variant Identification

PURPOSE Strict clinical criteria used by Medicare for germline testing for Lynch syndrome (LS) could lead to missed diagnoses of hereditary cancer syndromes given variable individual and family phenotypes. The aim of this study was to compare rates and spectrum of pathogenic or likely pathogenic (P/LP) variants in LS and other hereditary cancer genes on the basis of meeting Medicare LS testing criteria. METHODS Retrospective review of Medicare beneficiaries who had multigene panel testing with an indication of personal or family history of colorectal cancer (CRC) was performed. Ordering providers determined if Medicare LS criteria were met. The results of genetic testing were compared on the basis of whether or not Medicare testing criteria were met. RESULTS Among 639 Medicare beneficiaries, 495 (77.5%) met testing criteria. Overall rates of P/LP variant identification were similar between those meeting and not meeting testing criteria (18.4% v 11.8%; P = .06). LS was diagnosed more frequently among those meeting testing criteria (10.1% v 4.9%; P = .05). No statistical differences were found in rates of P/LP variant identification for non-LS CRC genes (5.3% v 5.6%; P = .89) or non-CRC genes (4.2% v 2.1%; P = .23). PMS2, MUTYH, and ATM P/LP variants were found at higher rates among those outside of criteria. CONCLUSION Among Medicare beneficiaries undergoing genetic testing for suspected LS, rates of P/LP variants in actionable cancer genes were similar regardless of whether testing criteria were met. Current testing criteria fail to identify individuals with P/LP variants in PMS2 and other actionable cancer genes. Relaxing LS testing criteria could improve identification of individuals with hereditary cancer syndromes among Medicare beneficiaries.

Validation of the PREMM1,2 model for the prediction of MLH1/MSH2 germline mutation carriers in a population- based cohort of colorectal cancer (CRC) patients

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 10545-10545
Author(s):  
J. Balmaña ◽  
F. Balaguer ◽  
E. W. Steyerberg ◽  
E. M. Stoffel ◽  
S. Castellví-Bel ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lynch Syndrome ◽  
Population Based ◽  
Receiver Operating Characteristics ◽  
Deleterious Mutations ◽  
Operating Characteristics ◽  
Mutation Carriers ◽  
Bethesda Guidelines ◽  
Revised Bethesda Guidelines ◽  
Molecular Evaluation

10545 Background: PREMM1,2 is a predictive model for estimating the likelihood of finding a mutation in the MLH1 and MSH2 genes developed in a population at risk of Lynch syndrome (Balmaña et al. JAMA 2006). The EPICOLON cohort is a Spanish population-based series of 1222 patients with CRC (Piñol et al. JAMA 2005). Methods: All 1222 individuals underwent microsatellite instability (MSI) and immunohistochemistry (IHC) analysis for MLH1/MSH2. Patients whose tumours exhibited MSI or altered IHC underwent MLH1/MSH2 analysis (n=91). Sensitivity (Se), specificity, positive predictive value (PPV), and the areas under the receiver operating characteristics curves (AUC) for the PREMM1,2 model were calculated and compared with the Edinburgh model (Barnetson et al. NEJM 2006) and the Revised Bethesda guidelines (RBG). Results: Three-hundred and ninety six individuals (32%) had a PREMM1,2 score =5%, 287 (23%) fulfilled the RBG, and 75 (6%) had a Barnetson score =5%. A PREMM1,2 score =5% and the RBG identified all carriers with deleterious mutations (n=8, Se=100%), while a Barnetson score =5% missed 2 mutation carriers (Se= 75%). For PREMM1,2 and Barnetson scores =5% and fulfilment of the RBG, specificities were 68%, 94%, and 77%, respectively; and PPV were 2%, 8%, and 2.8%, respectively. The AUC was 0.93 (95% CI: 0.86–0.99) for the PREMM1,2 model and 0.86 (95% CI: 0.66–1.04) for the Barnetson model. The predictions of carrying a mutation stratified into five groups based on PREMM1,2 scores (<5%, 5–9%, 10–19%, 20–39%, =40%) correlated reasonably with the presence of mutations (0%, 1%, 1%, 13%, and 22%, respectively). Conclusions: In a population of CRC patients, the PREMM1,2 model identifies all mutation carriers of MSH2 and MLH1 using a cutoff of =5%. In addition, it provides quantification of risk that is useful to decide the strategy used for molecular evaluation and risk counselling of patients. No significant financial relationships to disclose.

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