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1.  Strategies to Identify the Lynch Syndrome Among Patients With Colorectal Cancer 
Annals of internal medicine  2011;155(2):69-79.
Testing has been advocated for all persons with newly diagnosed colorectal cancer to identify families with the Lynch syndrome, an autosomal dominant cancer-predisposition syndrome that is a paradigm for personalized medicine.
To estimate the effectiveness and cost-effectiveness of strategies to identify the Lynch syndrome, with attention to sex, age at screening, and differential effects for probands and relatives.
Markov model that incorporated risk for colorectal, endometrial, and ovarian cancers.
Data Sources
Published literature.
Target Population
All persons with newly diagnosed colorectal cancer and their relatives.
Time Horizon
Third-party payer.
Strategies based on clinical criteria, prediction algorithms, tumor testing, or up-front germline mutation testing, followed by tailored screening and risk-reducing surgery.
Outcome Measures
Life-years, cancer cases and deaths, costs, and incremental cost-effectiveness ratios.
Results of Base-Case Analysis
The benefit of all strategies accrued primarily to relatives with a mutation associated with the Lynch syndrome, particularly women, whose life expectancy could increase by approximately 4 years with hysterectomy and salpingo-oophorectomy and adherence to colorectal cancer screening recommendations. At current rates of germline testing, screening, and prophylactic surgery, the strategies reduced deaths from colorectal cancer by 7% to 42% and deaths from endometrial and ovarian cancer by 1% to 6%. Among tumor-testing strategies, immunohistochemistry followed by BRAF mutation testing was preferred, with an incremental cost-effectiveness ratio of $36 200 per life-year gained.
Results of Sensitivity Analysis
The number of relatives tested per proband was a critical determinant of both effectiveness and cost-effectiveness, with testing of 3 to 4 relatives required for most strategies to meet a threshold of $50 000 per life-year gained. Immunohistochemistry followed by BRAF mutation testing was preferred in 59% of iterations in probabilistic sensitivity analysis at a threshold of $100 000 per life-year gained. Screening for the Lynch syndrome with immunohistochemistry followed by BRAF mutation testing only up to age 70 years cost $44 000 per incremental life-year gained compared with screening only up to age 60 years, and screening without an upper age limit cost $88 700 per incremental life-year gained compared with screening only up to age 70 years.
Other types of cancer, uncertain family pedigrees, and genetic variants of unknown significance were not considered.
Widespread colorectal tumor testing to identify families with the Lynch syndrome could yield substantial benefits at acceptable costs, particularly for women with a mutation associated with the Lynch syndrome who begin regular screening and have risk-reducing surgery. The cost-effectiveness of such testing depends on the participation rate among relatives at risk for the Lynch syndrome.
Primary Funding Source
National Institutes of Health.
PMCID: PMC3793257  PMID: 21768580
2.  Clinical guidelines versus universal molecular testing: are we ready to choose an optimal strategy for Lynch Syndrome identification? 
Lynch Syndrome, also known as hereditary non-polyposis colorectal cancer (HNPCC), is the most common form of inherited colorectal cancer, however, its identification still presents a challenge for health care providers. Clinically-based guidelines have been used as the basis for Lynch Syndrome screening in colorectal cancer patient populations. More recently, it has been argued that universal molecular testing strategies should be implemented to increase the selection of patients who should get germline testing for Lynch Syndrome. In this issue of AJG, Julie et al compare the performance of clinical guidelines with a molecular strategy based on universal microsatellite instability (MSI) testing for identifying patients with Lynch Syndrome from among 214 unselected, newly diagnosed CRC patients. The study highlights the need for a systematic approach to identify patients with Lynch Syndrome so that they and their relatives can be targeted for appropriate clinical management.
PMCID: PMC3584336  PMID: 19032469
3.  Genetic Testing Strategies in Newly Diagnosed Endometrial Cancer Patients Aimed at Reducing Morbidity or Mortality from Lynch Syndrome in the Index Case or Her Relatives 
PLoS Currents  2013;5:ecurrents.eogt.b59a6e84f27c536e50db4e46aa26309c.
Endometrial cancer is the first malignancy in 50% of women with Lynch syndrome, an autosomal dominant cancer-prone syndrome caused by germline mutations in genes encoding components of the DNA mismatch repair (MMR) pathway. These women (2-4% of all those with endometrial cancer) are at risk of metachronous colorectal cancer and other Lynch syndrome-associated cancers, and their first-degree relatives are at 50% risk of Lynch syndrome. Testing all women newly diagnosed with endometrial cancer for Lynch syndrome may have clinical utility for the index case and her relatives by alerting them to the benefits of surveillance and preventive options, primarily for colorectal cancer. The strategy involves offering germline DNA mutation testing to those whose tumour shows loss-of-function of MMR protein(s) when analysed for microsatellite instability (MSI) and/or by immunohistochemisty (IHC). In endometrial tumours from unselected patients, MSI and IHC have a sensitivity of 80-100% and specificity of 60-80% for detecting a mutation in an MMR gene, though the number of suitable studies for determining clinical validity is small. The clinical validity of strategies to exclude those with false-positive tumour test results due to somatic hypermethylation of the MLH1 gene promoter has not been determined. Options include direct methylation testing, and excluding those over the age of 60 who have no concerning family history or clinical features. The clinical utility of Lynch syndrome testing for the index case depends on her age and the MMR gene mutated: the net benefit is lower for those diagnosed at older ages and with less-penetrant MSH6 mutations. To date, women with these features are the majority of those diagnosed through screening unselected endometrial cancer patients but the number of studies is small. Similarly, clinical utility to relatives of the index case is higher if the family’s mutation is in MLH1 or MSH2 than for MSH6 or PMS2. Gaps in current evidence include a need for large, prospective studies on unselected endometrial cancer patients, and for health-economic analysis based on appropriate assumptions.
PMCID: PMC3775889  PMID: 24056992
4.  Genetic Testing for Lynch Syndrome in Individuals Newly Diagnosed with Colorectal Cancer to Reduce Morbidity and Mortality from Colorectal Cancer in Their Relatives 
PLoS Currents  2011;3:RRN1246.
Individuals with Lynch syndrome, sometimes referred to as hereditary non-polyposis colorectal cancer (HNPCC), have an increased risk of developing colorectal cancer (CRC) as well as other cancers. The increased risk is due to inherited mutations in mismatch repair (MMR) genes, which reduce the ability of cells to repair DNA damage. Screening for Lynch syndrome in individuals newly diagnosed with colorectal cancer has been proposed as part of a strategy that combines tests and interventions to reduce the risk of colorectal cancer in the relatives of the colorectal cancer patients with Lynch Syndrome.
PMCID: PMC3130897  PMID: 21743847
5.  Impact of Age Cutoffs on a Lynch Syndrome Screening Program 
Journal of Oncology Practice  2012;9(4):175-179.
Applying an age cutoff to a Lynch syndrome screening program has considerable potential for decreasing total screening costs and increasing efficiency, but at a loss of effectiveness.
To determine the impact of applying an age cutoff to tumor-based Lynch syndrome (LS) screening, specifically focusing on changes in relative effectiveness, efficiency, and cost. The project was undertaken to answer questions about implementation of the LS screening program in an integrated health care delivery system.
Patients and Methods:
Clinical data extracted from an internal cancer registry, previous modeling efforts, published literature, and gray data were used to populate decision models designed to answer questions about the impact of age cutoffs in LS screening. Patients with colorectal cancer (CRC) were stratified at 10-year intervals from ages 50 to 80 years and compared with no age cutoff. Outcomes are reported for a cohort of 325 patients screened and includes total cost to screen, LS cases present in the cutoff category, number of LS cases expected to be identified by screening, cost per LS case detected, and total number and percentage of LS cases missed.
Applying an age cutoff to an LS screening program has considerable potential for decreasing total screening costs and increasing efficiency, but at a loss of effectiveness. Imposing an age cutoff of 50 years reduces the cost of the screening program to 16% of a program with no age cutoff, but at the expense of missing more than half of the cases. Failure to identify LS cases is magnified by a cascade effect in family members. The results of this analysis influenced the final policy in our system.
PMCID: PMC3710164  PMID: 23942916
6.  The Search for Unaffected Individuals with Lynch Syndrome: Do the Ends Justify the Means? 
Lynch syndrome is the most common cause of inherited colorectal and endometrial cancers yet it is under-recognized in clinical practice. The relative merits of screening for Lynch syndrome among healthy adults without cancer versus among adults with colorectal or endometrial cancer are discussed in this Perspectives article. Newly diagnosed colorectal cancer patients are a much easier target population for screening and leads to more informative genetic test results, at a lower cost in most cases.
PMCID: PMC3076593  PMID: 21205737
Lynch syndrome; population screening; genetic testing; mismatch repair genes
7.  Identification of Lynch Syndrome Among Patients With Colorectal Cancer 
JAMA : the journal of the American Medical Association  2012;308(15):10.1001/jama.2012.13088.
Lynch syndrome is the most common form of hereditary colorectal cancer (CRC) and is caused by germline mutations in DNA mismatch repair (MMR) genes. Identification of gene carriers currently relies on germline analysis in patients with MMR-deficient tumors, but criteria to select individuals in whom tumor MMR testing should be performed are unclear.
To establish a highly sensitive and efficient strategy for the identification of MMR gene mutation carriers among CRC probands.
Design, Setting, and Patients
Pooled-data analysis of 4 large cohorts of newly diagnosed CRC probands recruited between 1994 and 2010 (n = 10 206) from the Colon Cancer Family Registry, the EPICOLON project, the Ohio State University, and the University of Helsinki examining personal, tumor-related, and family characteristics, as well as microsatellite instability, tumor MMR immunostaining, and germline MMR mutational status data.
Main Outcome Measures
Performance characteristics of selected strategies (Bethesda guidelines, Jerusalem recommendations, and those derived from a bivariate/multivariate analysis of variables associated with Lynch syndrome) were compared with tumor MMR testing of all CRC patients (universal screening).
Of 10 206 informative, unrelated CRC probands, 312 (3.1%) were MMR gene mutation carriers. In the population-based cohorts (n=3671 probands), the universal screening approach (sensitivity, 100%;95% CI, 99.3%–100%; specificity, 93.0%; 95% CI, 92.0%–93.7%; diagnostic yield, 2.2%; 95% CI, 1.7%–2.7%) was superior to the use of Bethesda guidelines (sensitivity, 87.8%; 95% CI, 78.9%–93.2%; specificity, 97.5%; 95% CI, 96.9%–98.0%; diagnostic yield, 2.0%; 95% CI, 1.5%–2.4%; P <.001), Jerusalem recommendations (sensitivity, 85.4%; 95% CI, 77.1%–93.6%; specificity, 96.7%; 95% CI, 96.0%–97.2%; diagnostic yield, 1.9%; 95% CI, 1.4%–2.3%; P < .001), and a selective strategy based on tumor MMR testing of cases with CRC diagnosed at age 70 years or younger and in older patients fulfilling the Bethesda guidelines (sensitivity, 95.1%; 95% CI, 89.8%–99.0%; specificity, 95.5%; 95% CI, 94.7%–96.1%; diagnostic yield, 2.1%; 95% CI, 1.6%–2.6%; P <.001). This selective strategy missed 4.9% of Lynch syndrome cases but resulted in 34.8% fewer cases requiring tumor MMR testing and 28.6% fewer cases undergoing germline mutational analysis than the universal approach.
Universal tumor MMR testing among CRC probands had a greater sensitivity for the identification of Lynch syndrome compared with multiple alternative strategies, although the increase in the diagnostic yield was modest.
PMCID: PMC3873721  PMID: 23073952
8.  Screening of the DNA mismatch repair genes MLH1, MSH2 and MSH6 in a Greek cohort of Lynch syndrome suspected families 
BMC Cancer  2010;10:544.
Germline mutations in the DNA mismatch repair genes predispose to Lynch syndrome, thus conferring a high relative risk of colorectal and endometrial cancer. The MLH1, MSH2 and MSH6 mutational spectrum reported so far involves minor alterations scattered throughout their coding regions as well as large genomic rearrangements. Therefore, a combination of complete sequencing and a specialized technique for the detection of genomic rearrangements should be conducted during a proper DNA-testing procedure. Our main goal was to successfully identify Lynch syndrome families and determine the spectrum of MLH1, MSH2 and MSH6 mutations in Greek Lynch families in order to develop an efficient screening protocol for the Greek colorectal cancer patients' cohort.
Forty-two samples from twenty-four families, out of which twenty two of Greek, one of Cypriot and one of Serbian origin, were screened for the presence of germline mutations in the major mismatch repair genes through direct sequencing and MLPA. Families were selected upon Amsterdam criteria or revised Bethesda guidelines.
Ten deleterious alterations were detected in twelve out of the twenty-four families subjected to genetic testing, thus our detection rate is 50%. Four of the pathogenic point mutations, namely two nonsense, one missense and one splice site change, are novel, whereas the detected genomic deletion encompassing exon 6 of the MLH1 gene has been described repeatedly in the LOVD database. The average age of onset for the development of both colorectal and endometrial cancer among mutation positive families is 43.2 years.
The mutational spectrum of the MMR genes investigated as it has been shaped by our analysis is quite heterogeneous without any strong indication for the presence of a founder effect.
PMCID: PMC2976752  PMID: 20937110
9.  Endometrial Cancer and Lynch Syndrome: Clinical and Pathologic Considerations 
Approximately 2% to 5% of endometrial cancers may be due to an inherited susceptibility. Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, an autosomal-dominant inherited cancer susceptibility syndrome caused by a germline mutation in one of the DNA mismatch repair genes, accounts for the majority of inherited cases. Lynch syndrome is associated with early onset of cancer and the development of multiple cancer types, particularly colon and endometrial cancer.
The current status of knowledge regarding Lynch syndrome-associated endometrial cancer and methods for diagnosis, screening and prevention of cancers are reviewed.
The lifetime cumulative risk of endometrial cancer for women with Lynch syndrome is 40% to 60%, which equals or exceeds their risk of colorectal cancer. No current evidence suggests either a survival advantage or disadvantage to endometrial cancer that is associated with Lynch syndrome when these cases are compared with sporadic cases. A combination of family and personal medical history and tumor testing provides an efficient combination for diagnosing Lynch syndrome in women with endometrial cancer. Current gynecologic cancer screening guidelines for women with Lynch syndrome include annual endometrial sampling and transvaginal ultrasonography beginning at age 30 to 35 years.
Diagnosing endometrial cancer patients with Lynch syndrome has important clinical implications for the individual and family members. Screening and prevention practices can decrease the likelihood of developing additional cancers.
PMCID: PMC3693757  PMID: 19078925
10.  Health Behaviors in Patients and Families with Hereditary Colorectal Cancer 
It is estimated that 5 to 10% of all colorectal cancer (CRC) cases are attributed to a hereditary cause. The primary hereditary cancer syndromes that confer an increased risk for colorectal cancers are Lynch syndrome/hereditary nonpolyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP). Through genetic testing, health care providers can identify patients and families who carry gene mutations and subsequently are at a substantially greater risk for developing colorectal cancer than the general population. Genetic testing provides risk information not only about an individual patient, but also his or her biological relatives. A variety of risk-reduction behaviors (including screening, surgery, and health and lifestyle behaviors) have been examined in Lynch syndrome and FAP populations. The research indicates that screening behaviors are less than optimal, although the rates vary from study to study. Prophylactic colectomy is the primary course of treatment for individuals who test positive for a FAP mutation, but the results are inconclusive for cancer-unaffected Lynch syndrome mutation carriers. Although research suggests that the adoption of healthy lifestyles and behaviors (e.g., diet, physical activity, weight control, smoking cessation, limited alcohol consumption) could have a favorable impact on colon cancer burden, there is minimal data on how these behaviors may moderate cancer risk among those at risk of hereditary colon cancer. To date, we know very little about the actual health and lifestyle behaviors of those at risk of hereditary colon cancer. Genetic testing and counseling at risk individuals may resolve uncertainty about their personal and familial cancer risk and provide information to guide and personalize decisions about their future health care.
PMCID: PMC3423885  PMID: 23730226
hereditary nonpolyposis colorectal cancer (HNPCC); Lynch syndrome; familial adenomatous polyposis (FAP); genetic counseling and testing; decision making
11.  Application of molecular diagnostics for the detection of Lynch syndrome 
Lynch syndrome (LS), or hereditary nonpolyposis colorectal cancer, is the most common hereditary colorectal cancer (CRC) syndrome, accounting for approximately 2–5% of all newly diagnosed cases of CRC. Patients with LS have an increased lifetime risk of colorectal (52.2% in women and 68.7% in men) and endometrial cancer (15–70%), as well as certain extra-colonic cancers. Germline mutations in one of several DNA mismatch repair genes underlie LS. Molecular testing has emerged as an indispensable strategy for the diagnosis of LS. The diagnostic work-up of at-risk individuals includes a careful family history evaluation, microsatellite instability, immunohistochemistry and germline DNA analysis. A positive test result can guide clinicians in formulating the appropriate screening, surveillance and management strategies. However, because of the absence of an overt phenotype, such as a diffuse polyposis, it is not always straightforward to recognize LS clinically.
PMCID: PMC2929365  PMID: 20629513
genetic testing; immunohistochemistry; Lynch syndrome; microsatellite instability; mismatch repair genes
12.  Current and emerging trends in Lynch syndrome identification in women with endometrial cancer 
Gynecologic oncology  2009;114(1):128-134.
Lynch syndrome is a heritable, cancer susceptibility syndrome. This study aims to review current and emerging trends in the identification of Lynch syndrome in the endometrial cancer patient population.
We performed a comprehensive review of past and present screening algorithms for Lynch syndrome, including a review of the utility of both the Amsterdam criteria and Bethesda guidelines. Because non-colon cancers have historically not been the focus of Lynch syndrome research, current literature is ripe with questions regarding screening among this patient population. Low BMI, age less than 50, positive family history and pathologic features have all been identified as risk factors in endometrial cancer patients who might benefit from Lynch screening. Additionally, based on experience at our own institution we offer a feasible screening algorithm for these patients.
A comprehensive review of the data demonstrated that immunohistochemistry is becoming an efficient, inexpensive way to screen tumors at risk for mismatch repair deficiency. The sensitivity and specificity of immunohistochemistry for predicting Lynch syndrome approaches 100%. Ideally, prospective screening of all endometrial cancer patients with IHC is a feasible, cost-efficient way to detect Lynch in this patient population given the limitations of using personal/family history of malignancy as well as pathologic risk factors.
It is imperative that clinicians be mindful of the risk of Lynch syndrome in women with endometrial cancer. Given the opportunity for colon cancer screening and prevention strategies to be initiated, the identification of probands with endometrial cancer as a result of Lynch syndrome will lead to a reduction in morbidity and mortality for these patients and their families.
PMCID: PMC2841434  PMID: 19375789
Lynch syndrome; Endometrial cancer; Screening
13.  Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives 
Genetics in Medicine  2009;11(1):35-41.
Summary of Recommendations
The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group found sufficient evidence to recommend offering genetic testing for Lynch syndrome to individuals with newly diagnosed colorectal cancer to reduce morbidity and mortality in relatives. We found insufficient evidence to recommend a specific genetic testing strategy among the several examined.
Genetic testing to detect Lynch syndrome in individuals with newly diagnosed colorectal cancer (CRC) is proposed as a strategy to reduce CRC morbidity and mortality in their relatives (see Clinical Considerations section for definition of Lynch syndrome). The EGAPP Working Group (EWG) constructed a chain of evidence that linked genetic testing for Lynch syndrome in patients with newly diagnosed CRC with improved health outcomes in their relatives. We found that assessing patients who have newly diagnosed CRC with a series of genetic tests could lead to the identification of Lynch syndrome. Relatives of patients with Lynch syndrome could then be offered genetic testing, and, where indicated, colorectal, and possibly endometrial, cancer surveillance, with the expectation of improved health outcome. The EWG concluded that there is moderate certainty that such a testing strategy would provide moderate population benefit.
Analytic Validity
The EWG found adequate evidence to conclude that the analytic sensitivity and specificity for preliminary and diagnostic tests were high.
Clinical Validity
After accounting for the specific technologies and numbers of markers used, the EWG found at least adequate evidence to describe the clinical sensitivity and specificity for three preliminary tests, and for four selected testing strategies. These measures of clinical validity varied with each test and each strategy (see Clinical Considerations section).
Clinical Utility
The EWG found adequate evidence for testing uptake rates, adherence to recommended surveillance activities, number of relatives approachable, harms associated with additional follow-up, and effectiveness of routine colonoscopy. This chain of evidence supported the use of genetic testing strategies to reduce morbidity/mortality in relatives with Lynch syndrome. Several genetic testing strategies were potentially effective, but none was clearly superior. The evidence for or against effectiveness of identifying mismatch repair (MMR) gene mutations in reducing endometrial cancer morbidity or mortality was inadequate.
Contextual Issues
CRC is a common disease responsible for an estimated 52,000 deaths in the United States in 2007. In about 3% of newly diagnosed CRC, the underlying cause is a mutation in a MMR gene (Lynch syndrome) that can be reliably identified with existing laboratory tests. Relatives inheriting the mutation have a high (about 45% by age 70) risk of developing CRC. Evidence suggests these relatives will often accept testing and increased surveillance.
PMCID: PMC2743612  PMID: 19125126
colorectal cancer; Lynch syndrome; HNPCC
14.  Prediction of Germline Mutations and Cancer Risk in the Lynch Syndrome 
Identifying families at high risk for the Lynch syndrome (ie, hereditary non-polyposis colorectal cancer) is critical for both genetic counseling and cancer prevention. Current clinical guidelines are effective but limited by applicability and cost.
To develop and validate a genetic counseling and risk prediction tool that estimates the probability of carrying a deleterious mutation in mismatch repair genes MLH1, MSH2, or MSH6 and the probability of developing colorectal or endometrial cancer.
Design, Setting, and Patients
External validation of the MMRpro model was conducted on 279 individuals from 226 clinic-based families in the United States, Canada, and Australia (referred between 1993–2005) by comparing model predictions with results of highly sensitive germline mutation detection techniques. MMRpro models the autosomal dominant inheritance of mismatch repair mutations, with parameters based on meta-analyses of the penetrance and prevalence of mutations and of the predictive values of tumor characteristics. The model’s prediction is tailored to each individual’s detailed family history information on colorectal and endometrial cancer and to tumor characteristics including microsatellite instability.
Main Outcome Measure
Ability of MMRpro to correctly predict mutation carrier status, as measured by operating characteristics, calibration, and overall accuracy.
In the independent validation, MMRpro provided a concordance index of 0.83 (95% confidence interval, 0.78–0.88) and a ratio of observed to predicted cases of 0.94 (95% confidence interval, 0.84–1.05). This results in higher accuracy than existing alternatives and current clinical guidelines.
MMRpro is a broadly applicable, accurate prediction model that can contribute to current screening and genetic counseling practices in a high-risk population. It is more sensitive and more specific than existing clinical guidelines for identifying individuals who may benefit from MMR germline testing. It is applicable to individuals for whom tumor samples are not available and to individuals in whom germline testing finds no mutation.
PMCID: PMC2538673  PMID: 17003396
15.  Oncologic Management of Hereditary Colorectal Cancer 
Colorectal cancer (CRC) is the second most common cancer in females and the third most common cancer diagnosed in males. Familial CRC comprises ~20 to 30% of all CRC cases. Lynch syndrome (LS), previously called hereditary nonpolyposis CRC (HNPCC), is the most common of the hereditary CRC syndromes. In this review, the oncological management of hereditary colorectal cancer from the medical oncologist perspective is discussed with special emphasis on Lynch syndrome. Lynch syndrome is characterized by the presence of germline mutations in the mismatch repair genes (MMR)-MSH2, MLH1, MSH6, and PMS2. The available data regarding the prognostic role of mismatch repair genes (MMR), the predictive role of MMR genes, and the implications of that in the management of patients with deficient MMR genes (dMMR/MSI-H) tumors including Lynch syndrome patients are also discussed.
PMCID: PMC3423879  PMID: 23730227
hereditary colorectal cancer; Lynch syndrome; microsatellite instability; chemotherapy
16.  Implementing screening for Lynch syndrome among patients with newly diagnosed colorectal cancer: summary of a public health/clinical collaborative meeting 
Lynch syndrome is the most common cause of inherited colorectal cancer, accounting for approximately 3% of all colorectal cancer cases in the United States. In 2009, an evidence-based review process conducted by the independent Evaluation of Genomic Applications in Practice and Prevention Working Group resulted in a recommendation to offer genetic testing for Lynch syndrome to all individuals with newly diagnosed colorectal cancer, with the intent of reducing morbidity and mortality in family members. To explore issues surrounding implementation of this recommendation, the Centers for Disease Control and Prevention convened a multidisciplinary working group meeting in September 2010. This article reviews background information regarding screening for Lynch syndrome and summarizes existing clinical paradigms, potential implementation strategies, and conclusions which emerged from the meeting. It was recognized that widespread implementation will present substantial challenges, and additional data from pilot studies will be needed. However, evidence of feasibility and population health benefits and the advantages of considering a public health approach were acknowledged. Lynch syndrome can potentially serve as a model to facilitate the development and implementation of population-level programs for evidence-based genomic medicine applications involving follow-up testing of at-risk relatives. Such endeavors will require multilevel and multidisciplinary approaches building on collaborative public health and clinical partnerships.
PMCID: PMC3762677  PMID: 22237445
colorectal cancer; genetic screening; genetic testing; HNPCC; Lynch syndrome
17.  Genetic testing for young-onset colorectal cancer: case report and evidence-based clinical guidelines 
Radiology and Oncology  2010;44(1):57-61.
Young-onset colorectal cancer is clinicopathologically different from older-onset colorectal cancer and tends to occur in patients with hereditary germline conditions such as Lynch syndrome and familial adenomatous polyposis.
Case report.
We describe the case of a 44-year-old man with a paternal history of colon polyps, a personal 2-year history of hematochezia, and a diagnosis of rectal cancer. Further clinical evaluation of the patient at our institution determined the cancer to be stage IIIA. The patient underwent genetic counseling and testing, which indicated he was negative for the most common familial cancer syndromes. After treatment with neoadjuvant chemoradiotherapy, surgery, and adjuvant chemotherapy, the patient has done well. We review the hereditary cancer syndromes and genetic tests to consider for patients with early-onset colorectal cancer.
This case underscores the importance of following cancer-screening guidelines.
PMCID: PMC3423677  PMID: 22933892
adenomatous polyposis coli; attenuated familial adenomatous polyposis; colorectal cancer; familial adenomatous polyposis; microsatellite instability; MYH-associated polyposis
18.  Hereditary Colon Cancer: Lynch Syndrome 
Gut and Liver  2010;4(2):151-160.
Lynch syndrome is the most common familial colorectal cancer syndrome. It is linked to germline mutations in one of four DNA mismatch repair (MMR) genes. A comprehensive family history is one important way to identify at-risk individuals. The elucidation of the molecular genetics of this syndrome has made it possible to screen for the disorder with molecular tests. Microsatellite instability and/or immunohistochemistry followed by germline testing for mutations in MMR genes is now a standard approach for clinically suspected cases. Correctly recognizing Lynch syndrome is essential for the application of appropriate screening and surveillance measures. Close surveillance and risk-reducing operations can decrease cancer-related mortality. In addition, counseling is an important component of the management of any family with Lynch syndrome.
PMCID: PMC2886941  PMID: 20559516
Lynch syndrome; Mismatch repair gene; Microsatellite instability; Immunohistochemistry; Hereditary nonpolyposis colon cancer; Colon cancer
19.  Is breast cancer a part of Lynch syndrome? 
A long-standing question is whether breast cancer is an integral part of Lynch syndrome, also known as hereditary non-polyposis colorectal cancer. A recent study by Lotsari and colleagues analyzes molecular features of breast cancers from families with Lynch syndrome, including germline mutation carriers and their non-mutation carrier siblings, and controls with sporadic breast cancer. The study finds microsatellite instability and loss of mismatch DNA repair protein expression in one third and two thirds of Lynch syndrome samples, respectively, but in none of the non-mutation carriers or controls. Overall, the age of diagnosis of breast cancer in Lynch syndrome mutation carriers is no different than that in non-carriers, but diagnosis age was lower in those carriers whose breast tumors exhibited defects in mismatch repair. These results have important implications for genetic counseling and genetic testing of families with breast cancer and other tumors associated with Lynch syndrome, such as colorectal and endometrial cancers.
PMCID: PMC3680925  PMID: 22913763
20.  Identification of Patients at Risk for Hereditary Colorectal Cancer 
Diagnosis of hereditary colorectal cancer syndromes requires clinical suspicion and knowledge of such syndromes. Lynch syndrome is the most common cause of hereditary colorectal cancer. Other less common causes include familial adenomatous polyposis (FAP), Peutz-Jeghers syndrome (PJS), juvenile polyposis syndrome, and others. There have been a growing number of clinical and molecular tools used to screen and test at risk individuals. Screening tools include diagnostic clinical criteria, family history, genetic prediction models, and tumor testing. Patients who are high risk based on screening should be referred for genetic testing.
PMCID: PMC3423884  PMID: 23730221
Lynch syndrome; familial adenomatous polyposis; Peutz-Jeghers syndrome
21.  Health Benefits and Cost-Effectiveness of Primary Genetic Screening for Lynch Syndrome in the General Population 
In current clinical practice, genetic testing to detect Lynch syndrome mutations ideally begins with diagnostic testing of an individual affected with cancer before offering predictive testing to at-risk relatives. An alternative strategy that warrants exploration involves screening unaffected individuals via demographic and family histories, and offering genetic testing to those individuals whose risks for carrying a mutation exceed a selected threshold. Whether this approach would improve health outcomes in a manner that is cost-effective relative to current standards of care has yet to be demonstrated. To do so, we developed a simulation framework that integrated models of colorectal and endometrial cancers with a 5-generation family history model to predict health and economic outcomes of 20 primary screening strategies (at a wide range of compliance levels) aimed at detecting individuals with mismatch repair gene mutations and their at-risk relatives. These strategies were characterized by (i) different screening ages for starting risk assessment and (ii) different risk thresholds above which to implement genetic testing. For each strategy, 100,000 simulated individuals, representative of the U.S. population, were followed from the age of 20, and the outcomes were compared with current practice. Findings indicated that risk assessment starting at ages 25, 30, or 35, followed by genetic testing of those with mutation risks exceeding 5%, reduced colorectal and endometrial cancer incidence in mutation carriers by approximately 12.4% and 8.8%, respectively. For a population of 100,000 individuals containing 392 mutation carriers, this strategy increased quality-adjusted life-years (QALY) by approximately 135 with an average cost-effectiveness ratio of $26,000 per QALY. The cost-effectiveness of screening for mismatch repair gene mutations is comparable to that of accepted cancer screening activities in the general population such as colorectal cancer screening, cervical cancer screening, and breast cancer screening. These results suggest that primary screening of individuals for mismatch repair gene mutations, starting with risk assessment between the ages of 25 and 35, followed by genetic testing of those whose risk exceeds 5%, is a strategy that could improve health outcomes in a cost-effective manner relative to current practice.
PMCID: PMC3793254  PMID: 21088223
22.  Patient-reported disease knowledge and educational needs in Lynch syndrome: findings of an interactive multidisciplinary patient conference 
Patients with Lynch Syndrome, the most common hereditary colorectal cancer syndrome, benefit from genetic education and family counseling regarding diagnostic testing and cancer surveillance/prevention recommendations. Although genetic counseling is currently the most common venue where such education and counseling takes place, little is known about the level of disease knowledge and education needs as directly reported by patients and families with Lynch Syndrome. Furthermore, experiences with forums for larger-scale knowledge transfer have been limited in the current literature.
We conducted a one-day interactive multidisciplinary patient conference, designed to complement individual genetic counseling for updating disease knowledge, supportive networking and needs assessment among Lynch Syndrome patients and their family members. The patient conference was designed utilizing the conceptual framework of action research. Paired pre- and post-conference surveys were administered to 44 conference participants anonymously to assess patient-reported disease knowledge and education needs.
A multidisciplinary team of expert providers utilized a variety of educational formats during the one-day conference. Four main focus areas were: genetic testing, surveillance/prevention, living with Lynch Syndrome, and update on research. Thirty-two participants (73%) completed the pre-conference, and 28 (64%) participants completed the post-conference surveys. Nineteen respondents were affected and the remaining were unaffected. The scores of the disease-knowledge items significantly increased from 84% pre- to 92% post-conference (p = 0.012). Patients reported a high level of satisfaction and identified further knowledge needs in nutrition (71%), surveillance/prevention options (71%), support groups (36%), cancer risk assessment (32%), active role in medical care (32%), and research opportunities (5%).
Our experience with a dedicated patient education conference focused on Lynch Syndrome demonstrated that such an educational format is effective for updating or reinforcing disease knowledge, for identifying patient-reported unmet educational needs, as well as for peer-support.
PMCID: PMC3922108  PMID: 24499499
Hereditary nonpolyposis colorectal cancer (HNPCC); Genetic counseling; Patient education; Health education; Cancer surveillance; Lynch syndrome
23.  Current Hypotheses on How Microsatellite Instability Leads to Enhanced Survival of Lynch Syndrome Patients 
High levels of microsatellite instability (MSI-high) are a cardinal feature of colorectal tumors from patients with Lynch Syndrome. Other key characteristics of Lynch Syndrome are that these patients experience fewer metastases and have enhanced survival when compared to patients diagnosed with microsatellite stable (MSS) colorectal cancer. Many of the characteristics associated with Lynch Syndrome including enhanced survival are also observed in patients with sporadic MSI-high colorectal cancer. In this review we will present the current state of knowledge regarding the mechanisms that are utilized by the host to control colorectal cancer in Lynch Syndrome and why these same mechanisms fail in MSS colorectal cancers.
PMCID: PMC2901607  PMID: 20631828
24.  Germline deletions in the EPCAM gene as a cause of Lynch syndrome – literature review 
Lynch syndrome (clinically referred to as HNPCC – Hereditary Non-Polyposis Colorectal Cancer) is a frequent, autosomal, dominantly-inherited cancer predisposition syndrome caused by various germline alterations that affect DNA mismatch repair genes, mainly MLH1 and MSH2. Patients inheriting this predisposition are susceptible to colorectal, endometrial and other extracolonic tumors. It has recently been shown that germline deletions of the last few exons of the EPCAM gene are involved in the etiology of Lynch syndrome. Such constitutional mutations lead to subsequent epigenetic silencing of a neighbouring gene, here, MSH2, causing Lynch syndrome. Thus, deletions of the last few exons of EPCAM constitute a distinct class of mutations associated with HNPCC. Worldwide, several investigators have reported families with EPCAM 3’end deletions. The risk of colorectal cancer in carriers of EPCAM deletions is comparable to situations when patients are MSH2 mutation carriers, and is associated with high expression levels of EPCAM in colorectal cancer stem cells. A lower risk of endometrial cancer was also reported. Until now the standard diagnostic tests for Lynch syndrome have contained analyses such as immunohistochemistry and tests for microsatellite instability of mismatch repair genes. The identification of EPCAM deletions or larger EPCAM-MSH2 deletions should be included in routine mutation screening, as this has implications for cancer predisposition.
PMCID: PMC3765447  PMID: 23938213
Lynch syndrome; EPCAM gene; Colon cancer; MSH2 hypermethylation
25.  A Mononucleotide Markers Panel to Identify hMLH1/hMSH2 Germline Mutations 
Disease Markers  2007;23(3):179-187.
Hereditary NonPolyposis Colorectal Cancer (Lynch syndrome) is an autosomal dominant disease caused by germline mutations in a class of genes deputed to maintain genomic integrity during cell replication, mutations result in a generalized genomic instability, particularly evident at microsatellite loci (Microsatellite Instability, MSI). MSI is present in 85–90% of colorectal cancers that occur in Lynch Syndrome. To standardize the molecular diagnosis of MSI, a panel of 5 microsatellite markers was proposed (known as the “Bethesda panel”). Aim of our study is to evaluate if MSI testing with two mononucleotide markers, such as BAT25 and BAT26, was sufficient to identify patients with hMLH1/hMSH2 germline mutations. We tested 105 tumours for MSI using both the Bethesda markers and the two mononucleotide markers BAT25 and BAT26. Moreover, immunohistochemical evaluation of MLH1 and MSH2 proteins was executed on the tumours with at least one unstable microsatellite, whereas germline hMLH1/hMSH2 mutations were searched for all cases showing two or more unstable microsatellites.
The Bethesda panel detected more MSI(+) tumors than the mononucleotide panel (49.5% and 28.6%, respectively). However, the mononucleotide panel was more efficient to detect MSI(+) tumours with lack of expression of Mismatch Repair proteins (93% vs 54%). Germline mutations were detected in almost all patients whose tumours showed MSI and no expression of MLH1/MSH2 proteins. No germline mutations were found in patients with MSI(+) tumour defined only through dinucleotide markers. In conclusion, the proposed mononucleotide markers panel seems to have a higher predictive value to identify hMLH1 and hMSH2 mutation-positive patients with Lynch syndrome. Moreover, this panel showed increased specificity, thus improving the cost/effectiveness ratio of the biomolecular analyses.
PMCID: PMC3850839  PMID: 17473388
MSI; HNPCC; colorectal cancer; MLH1; MSH2

Results 1-25 (1004763)