Lynch Syndrome Colorectal Cancer Research Articles

Role of microsatellite instability-low as a diagnostic biomarker of Lynch syndrome in colorectal cancer

Lynch syndrome is the most common Mendelian disorder predisposing persons to hereditary colorectal cancer. Carriers of MSH6 mutations constitute less than 10% of the total of cases with Lynch syndrome and present with a weaker clinical phenotype, including low levels of microsatellite instability (MSI-L) in colorectal tumors. The frequency of MSH6 mutation carriers among patients presenting with MSI-L colorectal cancer has yet to be determined, as has the appropriate genetic workup in this context. We have reviewed here the clinicopathologic characteristics, immunohistochemistry, and genetic testing results for 71 patients at a single institution diagnosed with MSI-L colorectal cancers. Of 71 patients with MSI-L tumors, 21 underwent genetic testing for MSH6 mutations, three of whom presented with loss of staining of MSH6 and only one of whom carried a pathogenic germline MSH6 mutation in exon 4 (c.2677_2678delCT; p.Leu893Alafs*6). This latter patient had a significant family history of cancer and had a rectal primary tumor that showed instability only in mononucleotide markers. In this cohort of MSI-L patients, we detected no notable clinicopathologic or molecular characteristic that would help to distinguish a group most likely to harbor germline MSH6 mutations. Therefore, we conclude that the prevalence of MSH6 mutations among patients with MSI-L tumors is very low. Microsatellite instability analysis combined with immunohistochemistry of mismatch repair proteins adequately detects potential MSH6 mutation carriers among MSI-L colorectal cancers.

Characterisation of Familial Colorectal Cancer Type X, Lynch syndrome, and non-familial colorectal cancer

Background:Familial Colorectal Cancer Type X (FCCTX) is defined as individuals with colorectal cancer (CRC) who families meet Amsterdam Criteria-1 (AC1), but whose tumours are DNA-mismatch-repair-proficient, unlike Lynch syndrome (LS). FCCTX does not have an increased risk of extra-colonic cancers. This analysis compares epidemiologic and clinicopathologic features among FCCTX, LS, and ‘non-familial' (non-AC1) CRC cases.Methods:From the Colon Cancer Family Registry, FCCTX (n=173), LS (n=303), and non-AC1 (n=9603) CRC cases were identified. Questionnaire-based epidemiologic information and CRC pathologic features were compared across case groups using polytomous logistic regression.Results:Compared with LS, FCCTX cases were less likely to be current (vs never) smokers; have a proximal subsite (vs rectal) tumour; or have mucinous histology, poor differentiation, or tumour-infiltrating lymphocytes. There were no observed differences in co-morbidities or medication usage.Conclusions:FCCTX were less likely to be current tobacco users; other exposures were similar between these groups. Histopathologic differences highly suggestive of LS CRCs do not appear to be shared by FCCTX.

Testing Women With Endometrial Cancer for Lynch Syndrome: Should We Test All?

Women with Lynch syndrome (LS) are at equal or higher risk for gynecologic cancers compared with their risk for colorectal cancer (CRC). Endometrial cancer (EC) often precedes CRC as patients' sentinel malignancy. Identifying these patients is believed to reduce their substantial risk for synchronous and metachronous tumors and has profound implications for reducing cancer-related morbidity and mortality in other family members. Routine screening of patients with CRC for LS has become increasingly common, but routine screening for LS in women with EC is rarely performed. Current screening guidelines for identifying LS in women with EC vary but rely heavily on patient age and personal/family history, with or without incorporation of tumor pathology. Because each of these strategies misses a significant proportion of women with LS, more inclusive screening strategies that make good economic and clinical sense are needed. In recent years, emerging medicoeconomic evidence supports the fact that screening EC patients for LS may be cost-effective. Implementation of such a strategy requires multidisciplinary collaboration and partnership.

Do lifestyle factors influence colorectal cancer risk in Lynch syndrome?

Lynch syndrome (LS) is one of the inherited colorectal cancer (CRC) syndromes and is due to germline mutations in one of the mismatch repair (MMR) genes. Within LS affected-families the expression of the syndrome varies, which suggests that other factors, such as lifestyle factors, have an influence on the LS phenotype. This review gives an overview of studies that assessed the role of lifestyle factors in the development of CRC in LS. Several published studies investigated smoking habits or body fatness (BMI) in relation to colorectal tumours. Those studies fairly consistently suggest that smoking and a high BMI markedly increase the risk of CRC in persons with LS. Other lifestyle factors, such as physical activity, alcohol or diet have not or only scarcely been studied. Lifestyle factors may indeed affect CRC risk in LS. However, more prospective studies with only confirmed MMR gene mutation carriers should be done to further elucidate the role of all lifestyle factors in CRC and in other types of cancer in persons with LS. Information on the role of lifestyle factors in the development of LS-associated cancers may help in establishing lifestyle and dietary recommendations with the ultimate goal of decreasing cancer risk in persons with LS.

107 Somatic MLH1 Promoter Hypermethylation Is a Frequent Event in Lynch Syndrome Colorectal Cancers

107 Somatic MLH1 Promoter Hypermethylation Is a Frequent Event in Lynch Syndrome Colorectal Cancers

Novel DNA Variants and Mutation Frequencies of hMLH1 and hMSH2 Genes in Colorectal Cancer in the Northeast China Population

Research on hMLH1 and hMSH2 mutations tend to focus on Lynch syndrome (LS) and LS-like colorectal cancer (CRC). No studies to date have assessed the role of hMLH1 and hMSH2 genes in mass sporadic CRC (without preselection by MSI or early age of onset). We aimed to identify novel hMLH1 and hMSH2 DNA variants, to determine the mutation frequencies and sites in both sporadic and LS CRC and their relationships with clinicopathological characteristics of CRC in Northeast of China. 452 sporadic and 21 LS CRC patients were screened for germline and somatic mutations in hMLH1 and hMSH2 genes with PCR–SSCP sequencing. We identified 11 hMLH1 and seven hMSH2 DNA variants in our study cohort. Six of them were novel: four in hMLH1 gene (IVS8-16 A>T, c.644 GAT>GTT, c.1529 CAG>CGG and c.1831 ATT>TTT) and two in hMSH2 gene (−39 C>T, insertion AACAACA at c.1127 and deletion AAG at c.1129). In sporadic CRC, germline and somatic mutation frequencies of hMLH1/hMSH2 gene were 15.59% and 17.54%, respectively (p = 0.52). Germline mutations present in hMLH1 and hMSH2 genes were 5.28% and 10.78%, respectively (p<0.01). Somatic mutations in hMLH1 and hMSH2 genes were 6.73% and 11.70%, respectively (p = 0.02). In LS CRC, both germline and somatic mutation frequencies of hMLH1/hMSH2 gene were 28.57%. The most prevalent germline mutation site in hMSH2 gene was c.1168 CTT>TTT (3.90%), a polymorphism. Somatic mutation frequency of hMLH1/hMSH2 gene was significantly different in proximal, distal colon and rectal cancer (p = 0.03). Our findings elucidate the mutation spectrum and frequency of hMLH1 and hMSH2 genes in sporadic and LS CRC, and their relationships with clinicopathological characteristics of CRC.

Distinct gene expression signatures in Lynch syndrome and familial colorectal cancer type X

Distinct gene expression signatures in Lynch syndrome and familial colorectal cancer type X

MLH1 Promoter Methylation Frequency in Colorectal Cancer Patients and Related Clinicopathological and Molecular Features

PurposeTo describe the frequency of MLH1 promoter methylation in colorectal cancer (CRC); to explore the associations between MLH1 promoter methylation and clinicopathological and molecular factors using a systematic review and meta-analysis.MethodsA literature search of the PubMed and Embase databases was conducted to identify relevant articles published up to September 7, 2012 that described the frequency of MLH1 promoter methylation or its associations with clinicopathological and molecular factors in CRC. The pooled frequency, odds ratio (OR) and 95% confidence intervals (95% CI) were calculated.ResultsThe pooled frequency of MLH1 promoter methylation in unselected CRC was 20.3% (95% CI: 16.8–24.1%). They were 18.7% (95% CI: 14.7–23.6%) and 16.4% (95% CI: 11.9–22.0%) in sporadic and Lynch syndrome (LS) CRC, respectively. Significant associations were observed between MLH1 promoter methylation and gender (pooled OR = 1.641, 95% CI: 1.215–2.215; P = 0.001), tumor location (pooled OR = 3.804, 95% CI: 2.715–5.329; P<0.001), tumor differentiation (pooled OR = 2.131, 95% CI: 1.464–3.102; P<0.001), MSI (OR: 27.096, 95% CI: 13.717–53.526; P<0.001). Significant associations were also observed between MLH1 promoter methylation and MLH1 protein expression, BRAF mutation (OR = 14.919 (95% CI: 6.427–34.631; P<0.001) and 9.419 (95% CI: 2.613–33.953; P = 0.001), respectively).ConclusionThe frequency of MLH1 promoter methylation in unselected CRC was 20.3%. They were 18.7% in sporadic CRC and 16.4% in LS CRC, respectively. MLH1 promoter methylation may be significantly associated with gender, tumor location, tumor differentiation, MSI, MLH1 protein expression, and BRAF mutation.

Uptake of genetic testing by relatives in Lynch syndrome: A systematic review.

374 Background: Screening of persons with newly diagnosed colorectal cancer (CRC) for Lynch Syndrome (LS) can yield substantial population-level benefits at acceptable costs, presuming sufficient uptake of genetic testing by first-degree relatives (FDRs) of LS probands. We reviewed systematically the published literature addressing the frequency and predictors of uptake of genetic testing by FDRs of LS probands. Methods: A literature search was conducted in four electronic databases (CINAHL, PsycInfo, PUBMED, and SCOPUS) for articles published through May 2011 that reported the uptake of genetic testing by relatives of LS probands. Two investigators independently screened articles to determine whether they met inclusion criteria, and abstracted data inthree broad categories: study population, methodology, and uptake of genetic testing. A narrative, qualitative systematic review was performed. The data were not amenable to meta-analysis. Results: 1,258 potentially relevant articles were identified with 533 studies undergoing full text review. Eight articles met inclusion criteria. 52% or less of FDRs of LS probands underwent genetic testing. For each LS proband, 4.6 or fewer relatives underwent genetic testing. Demographic factors (age &lt;50 years, female gender, parenthood, education level, employment, participation in past medical studies), psychological factors (lack of depressive symptoms), and family history (greater number of relatives with cancer) were associated with uptake of genetic testing. Conclusions: Genetic testing may be underutilized by FDRs at risk for LS. The economic feasibility of screening persons with CRC for LS depends on optimizing family-wide uptake of genetic testing. Future research and clinical efforts should focus on ways to overcome barriers to genetic testing.

Cell cycle–related genes as modifiers of age of onset of colorectal cancer in Lynch syndrome: a large-scale study in non-Hispanic white patients

Heterogeneity in age of onset of colorectal cancer in individuals with mutations in DNA mismatch repair genes (Lynch syndrome) suggests the influence of other lifestyle and genetic modifiers. We hypothesized that genes regulating the cell cycle influence the observed heterogeneity as cell cycle-related genes respond to DNA damage by arresting the cell cycle to provide time for repair and induce transcription of genes that facilitate repair. We examined the association of 1456 single nucleotide polymorphisms (SNPs) in 128 cell cycle-related genes and 31 DNA repair-related genes in 485 non-Hispanic white participants with Lynch syndrome to determine whether there are SNPs associated with age of onset of colorectal cancer. Genotyping was performed on an Illumina GoldenGate platform, and data were analyzed using Kaplan-Meier survival analysis, Cox regression analysis and classification and regression tree (CART) methods. Ten SNPs were independently significant in a multivariable Cox proportional hazards regression model after correcting for multiple comparisons (P < 5 × 10(-4)). Furthermore, risk modeling using CART analysis defined combinations of genotypes for these SNPs with which subjects could be classified into low-risk, moderate-risk and high-risk groups that had median ages of colorectal cancer onset of 63, 50 and 42 years, respectively. The age-associated risk of colorectal cancer in the high-risk group was more than four times the risk in the low-risk group (hazard ratio = 4.67, 95% CI = 3.16-6.92). The additional genetic markers identified may help in refining risk groups for more tailored screening and follow-up of non-Hispanic white patients with Lynch syndrome.

Risks of Primary Extracolonic Cancers Following Colorectal Cancer in Lynch Syndrome

Lynch syndrome is a highly penetrant cancer predisposition syndrome caused by germline mutations in DNA mismatch repair (MMR) genes. We estimated the risks of primary cancers other than colorectal cancer following a diagnosis of colorectal cancer in mutation carriers. We obtained data from the Colon Cancer Family Registry for 764 carriers of an MMR gene mutation (316 MLH1, 357 MSH2, 49 MSH6, and 42 PMS2), who had a previous diagnosis of colorectal cancer. The Kaplan-Meier method was used to estimate their cumulative risk of cancers 10 and 20 years after colorectal cancer. We estimated the age-, sex-, country- and calendar period-specific standardized incidence ratios (SIRs) of cancers following colorectal cancer, compared with the general population. Following colorectal cancer, carriers of MMR gene mutations had the following 10-year risk of cancers in other organs: kidney, renal pelvis, ureter, and bladder (2%, 95% confidence interval [CI] = 1% to 3%); small intestine, stomach, and hepatobiliary tract (1%, 95% CI = 0.2% to 2%); prostate (3%, 95% CI = 1% to 5%); endometrium (12%, 95% CI = 8% to 17%); breast (2%, 95% CI = 1% to 4%); and ovary (1%, 95% CI = 0% to 2%). They were at elevated risk compared with the general population: cancers of the kidney, renal pelvis, and ureter (SIR = 12.54, 95% CI = 7.97 to 17.94), urinary bladder (SIR = 7.22, 95% CI = 4.08 to 10.99), small intestine (SIR = 72.68, 95% CI = 39.95 to 111.29), stomach (SIR = 5.65, 95% CI = 2.32 to 9.69), and hepatobiliary tract (SIR = 5.94, 95% CI = 1.81 to 10.94) for both sexes; cancer of the prostate (SIR = 2.05, 95% CI = 1.23 to 3.01), endometrium (SIR = 40.23, 95% CI = 27.91 to 56.06), breast (SIR = 1.76, 95% CI = 1.07 to 2.59), and ovary (SIR = 4.19, 95% CI = 1.28 to 7.97). Carriers of MMR gene mutations who have already had a colorectal cancer are at increased risk of a greater range of cancers than the recognized spectrum of Lynch syndrome cancers, including breast and prostate cancers.

Influence of Patient Preferences on the Cost-Effectiveness of Screening for Lynch Syndrome

Patients and relatives have varying preferences for genetic testing and interventions related to hereditary cancer syndromes. We examined how the impact of these services on quality of life (QoL) affects the cost-effectiveness of screening for Lynch syndrome among probands newly diagnosed with colorectal cancer and their relatives. We constructed a state-transition model comparing screening strategies (clinical criteria, prediction algorithms, tumor testing, and upfront germline testing) with no screening to identify Lynch syndrome. The model incorporated individuals' health state utilities after screening, germline testing, and risk-reducing surgeries, with utilities persisting for 12 months in the base case. Outcomes consisted of quality-adjusted life-years (QALYs), costs, and cost per QALY gained. Sensitivity analyses assessed how the duration and magnitude of changes in QoL influenced results. Multiple screening strategies yielded gains in QALYs at acceptable costs compared with no screening. The preferred strategy-immunohistochemistry of tumors followed by BRAF mutation testing (IHC/BRAF)-cost $59,700 per QALY gained in the base case. The duration and magnitude of decreases in QoL after decisions related to germline testing and surgeries were key determinants of the cost-effectiveness of screening. IHC/BRAF cost > $100,000 per QALY gained when decrements to QoL persisted for 21 months. Screening for Lynch syndrome in the population is likely to yield long-term gains in life expectancy that outweigh any short-term decreases in QoL, at acceptable costs. Counseling for individuals should aim to mitigate potential negative impact of genetic testing and risk-reducing interventions on QoL.

Abstract LB-439: Distinct tumorigenic pathways within the hereditary nonpolyposis colorectal cancer

Abstract Background Identification of families with hereditary nonpolyposis colorectal cancer (HNPCC) allows for surveillance that has been proved to reduce morbidity and mortality from colorectal cancer (CRC). The HNPCC subset can broadly be divided into tumors caused by germline mismatch-repair (MMR) gene mutations, referred to as Lynch syndrome (LS), and those with an undefined genetic background, designated as familial colorectal cancer type X (FCC-X). Recognition of FCC-X tumor is challenging due to the lack of MMR defect and limited information is available about the global gene expression patterns in FCC-X tumors. We aimed at comprehensive pathway mapping of the global gene expression profile in FCC-X tumors with comparison to LS and sporadic CRC as controls. Materials and methods Tumour specimens were obtained from the national Danish HNPCC Register. RNA was extracted from 3-5 10-µm sections using the High Pure RNA Paraffin Kit (Roche, Castle Hill, Australia). The Whole-genome cDNA-mediated annealing selection extension and ligation (DASL) assay (Illumina, San Diego, CA) containing &amp;gt;24,000 probes in &amp;gt;18,000 genes was used for whole genome expression analysis. Expression values were analysed using the GenomeStudio software (Illumina, San Diego, CA) and imported into MeV 4.6.02. Canonical pathways were identified using DAVID Bioinformatics Resources 6.7. Results RNA was obtained from 180 tumors (60 LS, 60 FCC-X, 30 sporadic MSI-CRC and 30 sporadic MSS-CRC. Samples with &amp;lt;7000 genes represented (n=48) were excluded. Expression data from the remaining 132 samples were cubic normalized and a presence filter of 80% was applied (detection p-values ≤0.01). Sequence Alignment and Modeling (SAM) system analysis identified 3873 genes that differed significantly between LS/sporadic MSI-CRC and FCC-X/sporadic MSS-CRC. Using DAVID Bioinformatics resources, we identified 5 significantly up-regulated pathways in FCC-X/MSS-CRC including vascular smooth muscle contraction, G-protein coupled receptor signaling, calcium signaling, Wnt signalling and integrin cell surface interactions. For LS/MSI-CRC, we also identified 5 up-regulated pathways related antigen processing and presentation, DNA replication, cell cycle progression, and telomere maintenance. Conclusions Gene expression profiling using the DASL technology from 132 CRC identified MSI status as the major discriminator. Our data indicates that vascular smooth muscle contraction, G-protein coupled receptor signaling, calcium signaling, Wnt signaling, and integrin cell surface interactions pathways are up-regulated in FCC-X and MSS-CRC. These data provide strong evidence that these pathways play a role in development of CRC in these families and FCC-X should be considered as different clinical entity. These data also identify key signaling pathways as potential therapeutic targets in FCC- X tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-439. doi:1538-7445.AM2012-LB-439

Abstract 2108: Prevalence of mutations in MSH6, PMS1 and PMS2 gene in Brazilian families with Lynch syndrome

Abstract Background: Lynch syndrome (LS) is an autosomal dominant disorder predisposing to colorectal cancer and increased risk for cancers of the stomach, small intestine, hepatobiliary system, kidney, ureter, ovary, and sebaceous tumors. Germline mutations in the MMR genes MutL homolog 1 (MLH1), MutS homolog 2 (MSH2), MutS homolog 6 (MSH6), post- meiotic segregation increased 1 (PMS1) or post- meiotic segregation increased 2 (PMS2), are known to cause LS. While mutations in MLH1 and MSH2 gene, account for 70% - 80% of all Lynch syndrome colorectal cancers, the involvement of the MSH6, PMS2 and PMS1 gene is continually rising. Altogether, MSH6, PMS1 and PMS2 mutations account for 5-20% of kindreds in which MSH2 and MLH1 mutations are excluded. Objective: The aim of the study was evaluate the frequency of mutations in MSH6, PMS1 and PMS2 gene. Methods: Seventy one unrelated patients without MLH1/MSH2 mutations were eligible for this study. Genomic DNA was obtained from peripheral blood and primers were designed within introns of all exons of MSH6, PMS1 gene. In order to avoid the amplification of pseudogenes for the PMS2 gene, a set of four primer pairs were design. Results: Out of 71 patients, 20 fulfilled the Amsterdam criteria and other 51 fulfilled the Bethesda guideline. Four novel pathogenic mutations were detected, three in MSH6 and 1 in PMS2. In addition, 7 variants of uncertain significance were encountered, in which two of them were previously described as pathogenic. No mutations were found in PMS1 gene. Conclusion: Our data shows that 8.5% (6/71) of the individuals have mutations in MSH6 and PMS2 gene and these results strongly suggest that MSH6 and PMS2 should not be excluded from the MMR screening in Brazilian families suspected for Lynch syndrome. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2108. doi:1538-7445.AM2012-2108

Simplified identification of Lynch syndrome: A prospective, multicenter study

BackgroundRecommended strategies to screen for Lynch syndrome in colorectal cancer are not applied in daily practice and most of Lynch cases remain undiagnosed. AimsWe investigated in routine conditions a strategy that uses simplified clinical criteria plus detection of MisMatch Repair deficiency in tumours to identify Lynch carriers. MethodsColorectal cancer patients that met at least one of three clinical criteria were included: (1) colorectal cancer before 50 years, (2) personal history of colorectal or endometrial cancer, (3) first-degree relative history of colorectal or endometrial cancer. All tumours underwent an MisMatch Repair test combining microsatellite instability analysis and MisMatch Repair immunohistochemistry. Patients with an MisMatch Repair-deficient tumour were offered germline testing. ResultsOf the 307 patients fulfilling the clinical criteria, 46 (15%) had a MisMatch Repair-deficient tumour. Amongst them 27 were identified as Lynch carriers (20 with germline mutation: 12 MLH1, 7 MSH2, 1 MSH6; 7 highly suspected cases despite failure of genetic testing). The simplified clinical criteria selected a population whose MisMatch Repair-deficient status was highly predictive (59%) of Lynch syndrome. ConclusionThis bio-clinical strategy based on simplified clinical criteria combined with an MisMatch Repair test efficiently detected LS cases and is easy to use in clinical practice, outside expert centres.

Diagnosing Lynch Syndrome: More Light at the End of the Tunnel

Since the recognition of Lynch syndrome, which confers a high risk of colorectal, uterine, and other cancers, approaches to its diagnosis have included a family history of associated cancers and web-based algorithms. Identification of causative genes now allows a precise diagnosis, thus focusing present efforts on who should have genetic testing. Testing for cancer tissue changes can determine who should have germline genetic testing. Indeed, such tumor testing is now generally recommended for all newly diagnosed colorectal cancer cases. As reported in this issue of the journal by Yurgelun and colleagues (beginning on page 574), large colorectal adenomatous polyps (≥10 mm) from patients with Lynch syndrome exhibit findings similar to those in Lynch syndrome colorectal cancer tissues. This finding indicates that testing larger adenomas in persons at a significant risk for Lynch syndrome can now determine the need for germline genetic testing. Although further study is needed for general application, the present study justifies large polyp testing in high-risk families when cancer tissue is unavailable, albeit negative polyp tissue would not rule out Lynch syndrome, as would negative cancer tissue.

Infiltration of Lynch Colorectal Cancers by Activated Immune Cells Associates with Early Staging of the Primary Tumor and Absence of Lymph Node Metastases

Lynch syndrome colorectal cancers often lose human leukocyte antigen (HLA) class I expression. The outgrowth of clones with immune evasive phenotypes is thought to be positively selected by the action of cytotoxic T cells that target HLA class I-positive cancer cells. To investigate this hypothesis, we related the type and density of tumor lymphocytic infiltrate in Lynch colorectal cancers with their HLA class I phenotype and clinicopathologic stage. HLA class I expression was assessed by means of immunohistochemistry. Characterization of tumor-infiltrating lymphocytes was carried out by using a triple immunofluorescence procedure that allowed the simultaneous detection of CD3-, CD8-, and granzyme B (GZMB)-positive cells. Additional markers were also used for further characterization of an elusive CD3(-)/CD8(-)/GZMB(+) cell population. We discovered that high tumor infiltration by activated CD8(+) T cells correlated with aberrant HLA class I expression and associated with early tumor stages (P < 0.05). CD8(+) T cells were most abundant in HLA class I heterogeneous tumors (P = 0.02) and frequent in HLA class I-negative cases (P = 0.04) when compared with HLA class I-positive carcinomas. An elusive immune cell population (CD45(+)/CD8(-)/CD56(-)/GZMB(+)) was characteristic for HLA class I-negative tumors lacking lymph node metastases (P < 0.01). The immune system assumes an important role in counteracting the progression of Lynch colorectal cancers and in selecting abnormal HLA class I phenotypes. Our findings support the development of clinical strategies that explore the natural antitumor immune responses occurring in Lynch syndrome carriers.

Screening Patients With Colorectal Cancer for Lynch Syndrome: What Are We Waiting For?

Screening Patients With Colorectal Cancer for Lynch Syndrome: What Are We Waiting For?

Comparison of the clinical prediction model PREMM1,2,6 and molecular testing for the systematic identification of Lynch syndrome in colorectal cancer

BackgroundLynch syndrome is caused by germline mismatch repair (MMR) gene mutations. The PREMM1,2,6 model predicts the likelihood of a MMR gene mutation based on personal and family cancer history.ObjectiveTo compare...

Cancer Risks for the Relatives of Colorectal Cancer Cases with a Methylated MLH1 Promoter Region: Data from the Colorectal Cancer Family Registry

Methylation of the MLH1 gene promoter region is an underlying cause of colorectal cancer (CRC) with high microsatellite instability (MSI-H) diagnosed in persons without a germ line mutation in a mismatch repair (MMR) gene (non-Lynch Syndrome CRC). It is unclear whether relatives of CRC cases with MLH1 methylation have an increased risk of colorectal or other cancers. In this retrospective cohort study, we assessed risk of CRC and other cancers for the first- and second-degree relatives of CRC cases with a methylated MLH1 gene, by comparing observed numbers of cases with those expected on the basis of age-, sex-, and country-specific cancer incidences (standardized incidence ratios). The cohort consisted of 3,128 first- and second-degree relatives of the 233 MLH1-methylated CRC cases with no MMR or MUTYH gene mutations. The standardized incidence ratio (SIR) for CRC was 1.60 [95% confidence interval (CI), 1.22-2.16] for first-degree relatives and 1.08 (0.74-1.60) for second-degree relatives. The SIR for gastric cancer was 2.58 (1.52-4.71) for first-degree relatives and 4.52 (2.23-10.61) for second-degree relatives and, for ovarian cancer, it was 2.16 (1.29-3.86) for first-degree relatives. The risk of liver cancer was also increased significantly in first-degree relatives but the estimate was on the basis of only two cases. These data imply that relatives of CRC cases with MLH1 methylation may be at increased risk of CRC and stomach cancer and possibly ovarian and liver cancer, suggesting that there may be a heritable factor for CRC and other cancers associated with MLH1 methylation in non-Lynch syndrome CRCs.