Clinical Criteria For Lynch Syndrome Research Articles

Evaluation of the psychological state of patients suspected of Lynch syndrome after the germline genetic testing result.

e24201 Background: Lynch syndrome (LS) also known as Hereditary Non-Polyposis Colorectal Cancer (HNPCC) syndrome, is caused by a deficiency of Mismatch Repair Complex (MMR) enzymes. It is an autosomal dominant syndrome associated with an increased risk of developing colorectal cancer and other neoplasms, which can be confirmed using a germline molecular test. Psychological distress can be triggered regardless of the genetic test result. How the individual reacts emotionally and psychologically to the development can influence the processing of information and guidelines and adherence to preventive strategies. In this context, tracking anxiety symptoms provides opportunities for psychosocial follow-up planning. Objective: to evaluate levels of anxiety and depression in cancer patients suspected of having LS submitted to genetic testing. Methods: 84 patients with clinical criteria for LS were submitted to the germline genetic panel by NGS and immediately after the genetic test result, answered the Hospital Anxiety and Depression Scales (HADS). Data were expressed as mean±SD and compared using the Mann-Whitney, Kruskal-Wallis/Dunn, and Spearman correlation tests (SPSS v20.0, p < 0.05). Results: The mean levels of anxiety (5.59±3.31) were significantly higher than that of depression (4.63±3.58) ( p= 0.007), both domains were positively correlated ( p< 0.001, r= 0.447). Eighteen patients (21.4%) had pathogenic mutations in genes of the MMR complex. A positive diagnosis did not affect levels of anxiety or depression (pathogenic variant p= 0.617 and p= 0.478; Significance Uncertain-VUS p= 0.415 and p= 0.561, respectively). Females had higher levels of depression than males ( p= 0.047, with a relative risk of 1.65 times; CI95% = 1.05-13.19); however, other clinical and therapeutic characteristics did not significantly influence anxiety levels or depression. Conclusions: Colorectal cancer women are most sensitive to depression after germline genetic testing, despite the results. These findings reinforce the need for psychological screening of individuals undergoing genetic testing for LS and continuing psychological follow-up after receiving the genetic test.

Germline heterozygous exons 8–11 pathogenic BARD1 gene deletion reported for the first time in a family with suspicion of a hereditary colorectal cancer syndrome: more than an incidental finding?

BackgroundColorectal cancer (CRC) is a highly prevalent disease in developed countries. Inherited Mendelian causes account for approximately 5% of CRC cases, with Lynch syndrome and familial adenomatous polyposis being the most prevalent forms. Scientific efforts are focused on the discovery of new candidate genes associated with CRC and new associations of phenotypes with well-established cancer-related genes. BRCA1-associated ring domain (BARD1) gene deleterious germline variants are associated with a moderate increase in the relative risk of breast cancer, but their association with other neoplasms, such as CRC, remains unclear.Case presentationWe present the case of a 49-year-old male diagnosed with rectal adenocarcinoma whose maternal family fulfilled Amsterdam clinical criteria for Lynch syndrome. Genetic test confirmed the presence in heterozygosis of a germline pathogenic deletion of exons 8–11 in BARD1 gene. The predictive genetic study of the family revealed the presence of this pathogenic variant in his deceased cancer affected relatives, confirming co-segregation of the deletion with the disease.ConclusionsTo the best of our knowledge, this is the first published work in which this BARD1 deletion is detected in a family with familial colorectal cancer type X (FCCTX) syndrome, in which the clinical criteria for Lynch syndrome without alteration of the DNA mismatch repair (MMR) system are fulfilled. Whether this incidental germline finding is the cause of familial colorectal aggregation remains to be elucidated in scientific forums. Patients should be carefully assessed in specific cancer genetic counseling units to account for hypothetical casual findings in other genes, in principle unrelated to the initial clinical suspicion, but with potential impact on their health.

A prospective cohort study about the screening tests of mismatch repair protein and clinical criteria for Lynch syndrome associated endometrial carcinoma

Objectives: Currently, the commonly used screening methods for Lynch syndrome in patients with endometrial cancer (EC) are clinical diagnostic criteria and immunohistochemical testing. Our study compared the accuracy of the two methods in this prospective cohort study. Methods: Mismatch repair (MMR) protein was detected by immunohistochemical in the pathological tissues of newly diagnosed EC patients in Peking Union Medical College Hospital, during December 2015 and June 2018. Lynch syndrome related mutation gene was detected in patients with MMR protein deficiency. At the same time, all the patients were evaluated by the clinical diagnostic criteria (Amsterdam Criteria Ⅱ and the revised Bethesda criteria). Results: A total of 121 newly diagnosed EC patients were enrolled in this study, and 41 cases (33.9%) were MMR protein deficient. All of them received Lynch syndrome related mutation gene detection, and 7 cases were finally diagnosed with Lynch syndrome. Only 6 cases of Lynch syndrome, however, were diagnosed by the clinical diagnostic criteria, with 1 case misdiagnosed and 2 cases missed diagnosed. Conclusion: The incidence of Lynch syndrome in endometrial cancer patients is 5.8%. And the clinical diagnostic criteria for Lynch syndrome in patients with EC will result in miss diagnosis and misdiagnosis.

Novel genetic mutations detected by multigene panel are associated with hereditary colorectal cancer predisposition.

Half of the high-risk colorectal cancer families that fulfill the clinical criteria for Lynch syndrome lack germline mutations in the mismatch repair (MMR) genes and remain unexplained. Genetic testing for hereditary cancers is rapidly evolving due to the introduction of multigene panels, which may identify more mutations than the old screening methods. The aim of this study is the use of a Next Generation Sequencing panel in order to find the genes involved in the cancer predisposition of these families. For this study, 98 patients from these unexplained families were tested with a multigene panel targeting 94 genes involved in cancer predisposition. The mutations found were validated by Sanger sequencing and the segregation was studied when possible. We identified 19 likely pathogenic variants in 18 patients. Out of these, 8 were found in MMR genes (5 in MLH1, 1 in MSH6 and 2 in PMS2). In addition, 11 mutations were detected in other genes, including high penetrance genes (APC, SMAD4 and TP53) and moderate penetrance genes (BRIP1, CHEK2, MUTYH, HNF1A and XPC). Mutations c.1194G>A in SMAD4, c.714_720dup in PMS2, c.2050T>G in MLH1 and c.1635_1636del in MSH6 were novel. In conclusion, the detection of new pathogenic mutations in high and moderate penetrance genes could contribute to the explanation of the heritability of colorectal cancer, changing the individual clinical management. Multigene panel testing is a more effective method to identify germline variants in cancer patients compared to single-gene approaches and should be therefore included in clinical laboratories.

Identification of genetic variants for clinical management of familial colorectal tumors

BackgroundThe genetic mechanisms for families who meet the clinical criteria for Lynch syndrome (LS) but do not carry pathogenic variants in the mismatch repair (MMR) genes are still undetermined. We aimed to study the potential contribution of genes other than MMR genes to the biological and clinical characteristics of Norwegian families fulfilling Amsterdam (AMS) criteria or revised Bethesda guidelines.MethodsThe Hereditary Cancer Biobank of the Norwegian Radium Hospital was interrogated to identify individuals with a high risk of developing colorectal cancer (CRC) for whom no pathogenic variants in MMR genes had been found in routine diagnostic DNA sequencing. Forty-four cancer susceptibility genes were selected and analyzed by using our in-house designed TruSeq amplicon-based assay for targeted sequencing. RNA splicing- and protein-dedicated in silico analyses were performed for all variants of unknown significance (VUS). Variants predicted as likely to affect splicing were experimentally analyzed by resorting to minigene assays.ResultsWe identified a patient who met the revised Bethesda guidelines and carried a likely pathogenic variant in CHEK2 (c.470 T > C, p.I157T). In addition, 25 unique VUS were identified in 18 individuals, of which 2 exonic variants (MAP3K1 c.764A > G and NOTCH3 c.5854G >A) were analyzed in the minigene splicing assay and found not to have an effect on RNA splicing.ConclusionsAmong high-risk CRC patients that fulfill the AMS criteria or revised Bethesda guidelines, targeted gene sequencing identified likely pathogenic variant and VUS in other genes than the MMR genes (CHEK2, NOTCH3 and MAP3K1). Our study suggests that the analysis of genes currently excluded from routine molecular diagnostic screens may confer cancer susceptibility.

Use of multigene-panel identifies pathogenic variants in several CRC-predisposing genes in patients previously tested for Lynch Syndrome.

Many families with a high burden of colorectal cancer fulfil the clinical criteria for Lynch Syndrome. However, in about half of these families, no germline mutation in the mismatch repair genes known to be associated with this disease can be identified. The aim of this study was to find the genetic cause for the increased colorectal cancer risk in these unsolved cases. To reach the aim, we designed a gene panel targeting 112 previously known or candidate colorectal cancer susceptibility genes to screen 274 patient samples for mutations. Mutations were validated by Sanger sequencing and, where possible, segregation analysis was performed. We identified 73 interesting variants, of whom 17 were pathogenic and 19 were variants of unknown clinical significance in well-established cancer susceptibility genes. In addition, 37 potentially pathogenic variants in candidate colorectal cancer susceptibility genes were detected. In conclusion, we found a promising DNA variant in more than 25 % of the patients, which shows that gene panel testing is a more effective method to identify germline variants in CRC patients compared to a single gene approach.

Prevalence of pathogenic mismatch repair mutations in an Irish cohort after clinical and molecular pre-selection.

574 Background: Lynch syndrome (LS) is a highly penetrant, autosomal dominant multi-system disorder characterised by an inherited predisposition to a range of cancers. LS is caused by germline mutations in one of the mismatch repair (MMR) genes ( MSH2, MLH1, MSH2 and PMS2). Tumours from patients with LS have characteristic features resulting from the underlying molecular involvement of defective MMR, that is, the presence of microsatellite instability (MSI) and the absence of MMR protein expression by immunohistochemistry (IHC) corresponding to the mutated gene. MMR mutations are identified in approximately 60% of microsatellite instability-high (MSI-H) cancer patients fulfilling clinical criteria for LS. We sought to define the prevalence of pathogenic MMR mutations among an Irish cohort following molecular pre-selection with IHC/MSI and BRAF/MLH1 hypermethylation testing Methods: The results of diagnostic MMR genetic screening conducted on individuals following genetic counselling, in the Clinical Cancer Genetics Departments of the Mater Campus between January 2011 to September 2016, were correlated with ages at diagnoses and genetic test result. Results: This clinic-based cohort of affected individuals (n = 35) consisted of 22 females and 13 males. Median age at first cancer diagnosis was 44 years, range 23 to 86, standard deviation 12.3. Deleterious mutations were identified in 16 patients (45.7%), 6 in MLH1, 3 in MSH2, 2 in MSH6 and 5 in PMS2. Thirteen patients had a normal genetics test result (37.1%). Variants of uncertain significance (VUS) were identified in 6 patients (17.1%). With additional molecular testing and co-segregation studies in one family an MLH1 VUS was reclassified as likely pathogenic, facilitating pre-symptomatic testing for family members. This reclassification gives a revised prevalence of pathogenic mutation in this cohort of 48.5% and a VUS detection rate of 14.2%. Conclusions: We report a higher than expected VUS rate following molecular preselection of patients likely to have LS. No mutations were identified in 37% of patients supporting the presence of alternative negative regulators of the MMR pathway.

Systematic Immunohistochemistry Screening for Lynch Syndrome in Early Age-of-Onset Colorectal Cancer Patients Undergoing Surgical Resection

Lynch syndrome (LS), defined by a deleterious (pathogenic) germline mutation in a mismatch repair (MMR) gene, is characterized by early age-of-onset colorectal cancer (CRC). Because clinical criteria for LS, such as the Amsterdam II Criteria, may miss cases, reflex tumor tissue testing of all CRC patients for LS has been proposed. Our study describes the impact of routine immunohistochemistry (IHC) analysis of tumor tissue for loss of MMR protein expression in early age-of-onset CRC patients undergoing resection. A prospective institutional program was established to perform IHC analysis on all early age-of-onset (≤50 years) CRC patients undergoing resection. Patients with abnormal IHC analysis were referred to the Clinical Genetics Service for further evaluation. The study cohort excluded patients with other polyposis syndromes and inflammatory bowel disease. IHC was performed on 198 patients from July 2006 to June 2010. The median age was 42.8 years (range 23.1 to 50.6 years). Abnormal IHC was reported in 38 (19.1%) patients, and 22 (57.8%) with abnormal IHC analysis had germline genetic testing. Seventeen (77.2%) had an alteration detected in an MMR gene: 10 were known to be deleterious mutations and 7 were variants of uncertain significance. Overall, LS was detected in 5.1% of patients. Only 2 of the 10 (20%) with a deleterious mutation actually met the Amsterdam II Criteria. Reflex IHC testing for LS on early age-of-onset CRC patients undergoing resection is feasible at the institutional level. This strategy identifies a substantial number of LS patients who would have been missed if genetic testing was based on the Amsterdam II Criteria alone.

Factors affecting encouragement of relatives among families with Lynch syndrome to seek medical assessment

Lynch syndrome (HNPCC) is an autosomal dominant hereditary cancer syndrome, and members of affected families are at-risk for developing colorectal and other associated tumors. Such individuals should disseminate familial genetic information, so they can seek specific medical assessment or genetic testing to reduce mortality and morbidity rates by early detection. Since published results have been encouraging, we explored which factors influence the likelihood of good communication within families regarding medical assessment. We studied 40 individuals from 33 families who satisfied the Japanese clinical criteria for Lynch syndrome and their relatives at our hospital. We determined the status of relatives of the 40 individuals after genetic counseling and testing using questionnaires and semi-structured interviews based on pedigree charts. We also examined their knowledge or perception of colorectal cancer syndrome, levels of intimacy and whether or not they encouraged their relatives to have specific medical assessments. We found that 75% of the individuals advised their relatives to seek medical assessment, and any significant background factors that promoted such encouragement were observed. They tended to encourage first degree relatives and discuss the issue with other family members such as spouses before undertaking such attempts at encouragement. The reasons and methods of imparting encouragement were essentially identical. We also found that genetic testing for at-risk or more distant relatives was not encouraged so often. Therefore, providing individuals who have been tested for Lynch syndrome with opportunities for disseminating familial genetic information through appropriate genetic counseling is important.

Pacientes con criterios clínicos de síndrome de Lynch con y sin mutación en genes reparadores del ADN ( MLH1 y MSH2). Un reto para el clínico

Background and objectives The objective was to study the clinicopathologic characteristics of patients diagnosed of colorectal cancer (CRC) with clinical criteria for Lynch syndrome, in our region, in order to assess and improve the care of them and their families in the Genetic Counseling Unit of our hospital. Patients and methods This was an observational, transversal retrospective study. The studied sample was made up of all the patients with clinical criteria for Lynch syndrome, who underwent a molecular analysis test in the Genetic Counseling Unit of Salamanca, during the period 2004-2009. We included patient and tumor related variables and the presence or absence of mutations in MLH1 and MSH2. Results A total of 76 patients were included in the analysis. Fifteen of them carried a mutation either in MLH1 or in MSH2. The mean age at diagnosis of colorectal cancer was 51.2 and 54.3 years in the group with and without mutation respectively, with a similar gender distribution in both groups. A wide phenotypic heterogeneity was found in the sample. Conclusions Lynch syndrome is an entity difficult to categorize from a clinical point of view. Therefore, it is important to be alert for a better management of these patients and their families.

Current clinical criteria for Lynch syndrome are not sensitive enough to identify MSH6 mutation carriers

BackgroundReported prevalence, penetrance and expression of deleterious mutations in the mismatch repair (MMR) genes, MLH1, MSH2, MSH6 and PMS2, may reflect differences in the clinical criteria used to select families...

Report From the Jerusalem Workshop on Lynch Syndrome-Hereditary Nonpolyposis Colorectal Cancer

A Workshop was held in Jerusalem, Israel, on October 26 and 27, 2009 to discuss the management of Lynch syndrome-hereditary nonpolyposis colorectal cancer (CRC), with the primary goal to develop consensus for the optimal management of this disease. A second goal was to identify areas of research with the potential to advance the clinical management of Lynch syndrome. The perspectives and recommendations from the workshop are meant to be a platform for discussion and deliberation. The Workshop was organized by Moshe Shike (Memorial Sloan Kettering Cancer Center, New York) and sponsored by The Colon Cancer Foundation. More details of each presentation are available in an on-line supplement.

Epitope-positive truncating MLH1 mutation and loss of PMS2: implications for IHC-directed genetic testing for lynch syndrome

We assessed mismatch repair by immunohistochemistry (IHC) and microsatellite instability (MSI) analysis in an early onset endometrial cancer and a sister’s colon cancer. We demonstrated high-level MSI and normal expression for MLH1, MSH2 and MSH6. PMS2 failed to stain in both tumors, strongly implicating a PMS2 defect. This family did not meet clinical criteria for Lynch syndrome. However, early onset endometrial cancers in the proband and her sister, a metachronous colorectal cancer in the sister as well as MSI in endometrial and colonic tumors suggested a heritable mismatch repair defect. PCR-based direct exonic sequencing and multiplex ligation-dependent probe amplification (MLPA) were undertaken to search for PMS2 mutations in the germline DNA from the proband and her sister. No mutation was identified in the PMS2 gene. However, PMS2 exons 3, 4, 13, 14, 15 were not evaluated by MLPA and as such, rearrangements involving those exons cannot be excluded. Clinical testing for MLH1 and MSH2 mutation revealed a germline deletion of MLH1 exons 14 and 15. This MLH1 germline deletion leads to an immunodetectable stable C-terminal truncated MLH1 protein which based on the IHC staining must abrogate PMS2 stabilization. To the best of our knowledge, loss of PMS2 in MLH1 truncating mutation carriers that express MLH1 in their tumors has not been previously reported. This family points to a potential limitation of IHC-directed gene testing for suspected Lynch syndrome and the need to consider comprehensive MLH1 testing for individuals whose tumors lack PMS2 but for whom PMS2 mutations are not identified.

Prospective evaluation of DNA mismatch repair protein expression in primary endometrial cancer

Objectives Immunohistochemical (IHC) stains for mismatch repair (MMR) proteins help screen for Lynch syndrome and identify microsatellite unstable colorectal carcinomas, providing prognostic information. It has been suggested that colorectal and endometrial carcinomas should be screened routinely for a MMR defect, but data are lacking on the practical application of this policy. We report our experience with the prospective evaluation of MMR protein expression in endometrial cancer. Methods All cases of primary endometrial cancer at a single institution regardless of age, family history or histologic features were prospectively stained for the MMR proteins MLH1, MSH2, MSH6 and PMS2. Clinical and pathologic correlates were collected from the medical record. Results A total of 140 endometrial cancer cases were studied. Over 90% of cases were of endometrioid histology. 119 patients had stage I/II disease, and 21 stage III/IV. Nineteen percent of patients were < age 50. Overall, there was loss of 1 or more MMR proteins in 30 patients (21%), including MLH1 and PMS2 in 24, MSH2 and MSH6 in 4, and MSH6 in 2 patients. None of the patients met clinical criteria for Lynch syndrome. However, using MMR protein expression, age and family history, 11% of patients were referred for genetic counseling. Of these patients, three (20%) scheduled an appointment: one canceled and two tested negative. Conclusions Prospective staining for MMR proteins is feasible and allows for primary triage for the evaluation of Lynch syndrome in women with endometrial cancer. However, acceptance of genetic consultation and testing is surprisingly low and deserves further investigation.

Colorectal Adenomas in Young Patients: Microsatellite Instability is not a Useful Marker to Detect New Cases of Lynch Syndrome

Original Bethesda Guidelines proposed microsatellite instability analysis in colorectal adenomas from patients younger than aged 40 years to identify new cases of Lynch syndrome. We intended to evaluate the characteristics of colorectal adenomas from patients younger than aged 40 years to determine their microsatellite instability status and to correlate it with germline mutations in MLH1 and MSH2 genes. Seventy-two adenomas from 58 patients were analyzed. Family history of colorectal cancer, location, and histology of adenomas were evaluated. Microsatellite instability testing was performed with BAT26 only or with the complete Bethesda panel. Germline mutational analysis was performed in MLH1 and MSH2 genes. Thirty-five patients had a family history of colorectal cancer and 16 of them belonged to Amsterdam Criteria positive families. The remaining 23 presented with sporadic adenomas. Microsatellite instability was found in seven adenomas from seven different patients, all belonging to Amsterdam Criteria-positive families. In six of these patients, a pathogenic germline mutation was identified. Adenomas diagnosed before aged 40 years presented microsatellite instability only in patients from families with clinical criteria for Lynch syndrome. According to our results, to detect new cases of Lynch syndrome, family history is more important than microsatellite instability testing in adenomas from young patients.