In our study, we evaluated the effectiveness of upper gastrointestinal (GI) endoscopy as an instrument for early gastric cancer (GC) detection in Lynch syndrome (LS) patients by analyzing data from ...the registry of the German Consortium for Familial Intestinal Cancer. In a prospective, multicenter cohort study, 1128 out of 2009 registered individuals with confirmed LS underwent 5176 upper GI endoscopies. Compliance was good since 77.6% of upper GI endoscopies were completed within the recommended interval of 1 to 3 years. Forty‐nine GC events were observed in 47 patients. MLH1 (n = 21) and MSH2 (n = 24) mutations were the most prevalent. GCs in patients undergoing regular surveillance were diagnosed significantly more often in an early‐stage disease (UICC I) than GCs detected through symptoms (83% vs 25%; P = .0231). Thirty‐two (68%) patients had a negative family history of GC. The median age at diagnosis was 51 years (range 28‐66). Of all GC patients, 13 were diagnosed at an age younger than 45. Our study supports the recommendation of regular upper GI endoscopy surveillance for LS patients beginning no later than at the age of 30.
What's new?
Risk of gastric cancer (GC) is significantly increased among patients with Lynch syndrome (LS). GC screening in LS patients, however, is fraught with uncertainty, particularly regarding the use of esophagogastroduodenoscopy (EGD). The authors of this study investigated the use of EGD for regular GC surveillance in a German cohort of LS patients. Regular surveillance by EGD resulted in more frequent diagnosis and significant down‐staging of GC, relative to detection via symptoms alone. In most cases, family history of GC was negative. This study supports recommendations for regular gastroscopic surveillance in LS patients starting by age 30.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
BRAF V600E mutations have been reported as a marker of sporadic microsatellite instability (MSI) colorectal cancer (CRC). Current international diagnostic guidelines recommend BRAF mutation testing ...in MSI CRC patients to predict low risk of Lynch syndrome (LS). We evaluated the age‐specific performance of BRAF testing in LS diagnostics. We systematically compared the prevalence of BRAF mutations in LS‐associated CRCs and unselected MSI CRCs in different age groups as available from published studies, databases and population‐based patient cohorts. Sensitivity/specificity analysis of BRAF testing for exclusion of LS and cost calculations were performed. Among 969 MSI CRCs from LS carriers in the literature and German HNPCC Consortium, 15 (1.6%) harbored BRAF mutations. Six of seven LS patients with BRAF‐mutant CRC and reported age were <50 years. Among 339 of 756 (44.8%) of BRAF mutations detected in unselected MSI CRC, only 2 of 339 (0.6%) BRAF mutations were detected in patients <50 years. The inclusion of BRAF testing led to high risk of missing LS patients and increased costs at age <50 years. BRAF testing in patients <50 years carries a high risk of missing a hereditary cancer predisposition and is cost‐inefficient. We suggest direct referral of MSI CRC patients <50 years to genetic counseling without BRAF testing.
What's new?
Lynch syndrome (LS) is the most common hereditary colorectal cancer. While these cancers usually show microsatellite instability (MSI), most MSI tumors are sporadic. Here, the authors evaluated the usefulness of testing for BRAF mutations as a way to distinguish LS cancers from sporadic cases. They found that the frequency of tumors carrying BRAF mutations in LS patients under age 50 is very similar to the frequency of those mutations in MSI cancers from that age group, suggesting that there's substantial overlap between the two groups. Thus, BRAF mutation status should not be used to exclude LS in patients under 50.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Small bowel cancer (SBC) is the malignancy with the highest standardized incidence ratio in Lynch syndrome (LS) patients. Of all SBCs, about 50% are duodenal cancers (DCs), therefore being accessible ...by esophago‐gastro‐duodenoscopy (EGD) for surveillance. We asked whether early detection of DC is possible for LS patients undergoing surveillance by EGD and if surveillance should be limited to specific subgroups. Data for LS patients with DC were retrieved from the registry of the German Consortium for Familial Intestinal Cancer. Patients undergoing active surveillance by EGDs (surveillance group) were compared to those who did not (nonsurveillance group) regarding tumor stage at diagnosis. Union for International Cancer Control stages I‐IIA were defined as early stage disease and IIB‐IV as advanced stage disease. Statistical analysis was performed using Fisher's exact test. Among 2015 patients with pathogenic variants in any mismatch‐repair‐gene, 47 patients with 49 DCs were identified. In 10% of cases, patients were under 35 years at diagnosis; family and personal tumor history did not correlate with DC diagnosis. Pathogenic germline variants in MSH6, PMS2 or EPCAM were present in 10% of patients. Statistical analysis could be performed on 13 DC patients in the surveillance group and 14 in the nonsurveillance group. Early detection was possible for 71% of patients in the surveillance group and 29% of patients in the nonsurveillance group (P = .021). Early detection of DC by EGD in LS patients is feasible regardless of family history, mutational status and should start no later than 25 years of age.
What's new?
Although rare in the general population, duodenal cancer is among the malignancies with the highest standardised incidence ratio in patients with Lynch syndrome. Primary tumours in the duodenum are accessible by esophagogastroduodenoscopy, thus offering a surveillance option. However, surveillance data in this patient population is scarce and guideline recommendations are vague and inconsistent across the world. This retrospective analysis of the German Consortium for Familial Intestinal Cancer registry reveals that early detection of duodenal cancer in Lynch syndrome patients by upper gastrointestinal endoscopy is feasible and potentially beneficial regardless of age, personal tumour history, and family history.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Lynch syndrome (LS), Lynch‐like syndrome (LLS) and familial colorectal cancer type X (FCCX) are different entities of familial cancer predisposition leading to an increased risk of colorectal cancer ...(CRC). The aim of this prospective study was to characterise and to compare the risks for adenoma and CRC in these three risk groups. Data was taken from the registry of the German Consortium for Familial Intestinal Cancer. Patients were prospectively followed up in an intensified colonoscopic surveillance programme that included annual examinations. Cumulative risks for adenoma and CRC were calculated separately for LS, LLS and FCCX, and then for males and females. Multivariate Cox regression was used to analyse the independent contributions of risk group, mismatch repair gene (within LS), sex and previous adenoma. The study population comprised 1448 individuals (103 FCCX, 481 LLS and 864 LS). The risks were similar for colorectal adenomas, but different for first and metachronous CRC between the three risk groups. CRC risk was highest in LS, followed by LLS and lowest in FCCX. Male sex and a prevalent adenoma in the index colonoscopy were associated with a higher risk for incident adenoma and CRC. In patients with LS, CRC risks were particularly higher in female MSH2 than MLH1 carriers. Our study may support the development of risk‐adapted surveillance policies in LS, LLS and FCCX.
What's new?
While associations between colorectal cancer (CRC) risk and Lynch syndrome (LS) are well‐described, less is known about CRC risks linked to the closely related Lynch‐like syndrome (LLS) and familial colorectal cancer type X (FCCX). In this prospective follow‐up study of patients with LS, LLS, and FCCX, risks were similar for colorectal adenomas but considerably different for first and metachronous CRCs. In addition, LS females who carried MSH2 mutations had notably higher CRC risks than female MLH1 mutation carriers. The identification of variations in carcinogenic pathways between LS, LLS, and FCCX could enable risk‐adapted CRC surveillance for these syndromes.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
In many families with suspected Lynch syndrome (LS), no germline mutation in the causative mismatch repair (MMR) genes is detected during routine diagnostics. To identify novel causative genes for ...LS, the present study investigated 77 unrelated, mutation‐negative patients with clinically suspected LS and a loss of MSH2 in tumor tissue. An analysis for genomic copy number variants (CNV) was performed, with subsequent next generation sequencing (NGS) of selected candidate genes in a subgroup of the cohort. Genomic DNA was genotyped using Illumina's HumanOmniExpress Bead Array. After quality control and filtering, 25 deletions and 16 duplications encompassing 73 genes were identified in 28 patients. No recurrent CNV was detected, and none of the CNVs affected the regulatory regions of MSH2. A total of 49 candidate genes from genomic regions implicated by the present CNV analysis and 30 known or assumed risk genes for colorectal cancer (CRC) were then sequenced in a subset of 38 patients using a customized NGS gene panel and Sanger sequencing. Single nucleotide variants were identified in 14 candidate genes from the CNV analysis. The most promising of these candidate genes were: (i) PRKCA, PRKDC, and MCM4, as a functional relation to MSH2 is predicted by network analysis, and (ii) CSMD1, as this is commonly mutated in CRC. Furthermore, six patients harbored POLE variants outside the exonuclease domain, suggesting that these might be implicated in hereditary CRC. Analyses in larger cohorts of suspected LS patients recruited via international collaborations are warranted to verify the present findings.
What's new?
While several causal genetic factors for Lynch syndrome (LS), or hereditary non‐polyposis colorectal cancer, have been identified, in many families with suspected LS no germline mutation is detected during routine diagnostics. Here, a genome‐wide copy number variant (CNV) analysis in a large cohort of patients with suspected LS and MSH2 loss identified rare alterations in candidate genes (PRKCA, PRKDC, MCM4, and CSMD1) that may predispose to colorectal tumorigenesis. The study demonstrates that rare germline CNVs and point mutations are likely to contribute to the hereditary risk for colorectal tumors, and the underlying genetic factors are likely to be very heterogeneous.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Individuals with Lynch syndrome (LS), one of the most common inherited cancer syndromes, are at increased risk of developing malignancies, in particular colorectal cancer (CRC). Regular colonoscopy ...with polypectomy is recommended to reduce CRC risk in LS individuals. However, recent independent studies demonstrated that a substantial proportion of LS individuals develop CRC despite regular colonoscopy. The reasons for this surprising observation confirmed by large prospective studies are a matter of debate. In this review, we collect existing evidence from clinical, epidemiological and molecular studies and interpret them with regard to the origins and progression of LS‐associated CRC. Alongside with hypotheses addressing colonoscopy quality and pace of progression from adenoma to cancer, we discuss the role of alternative precursors and immune system in LS‐associated CRC. We also identify gaps in current knowledge and make suggestions for future studies aiming at improved CRC prevention for LS individuals.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Individuals with pathogenic germline variants in DNA mismatch repair (MMR) genes are at increased risk of developing colorectal, endometrial and other cancers (Lynch syndrome, LS). While previous ...studies have extensively described cancer risks in LS, cancer risks in individuals from families without detectable MMR gene defects despite MMR deficiency (Lynch-like syndrome, LLS), and in individuals from families fulfilling the Amsterdam-II criteria without any signs of MMR deficiency (familial colorectal cancer type X, FCCX) are less well studied. The aim of this prospective study was to characterise the risk for different cancer types in LS, LLS, and FCCX, and to compare these with the cancer risks in the general population.
Data was taken from the registry of the German Consortium for Familial Intestinal Cancer, where individuals were followed up prospectively within the framework of an intensified surveillance programme at recommended annual examination intervals. A total of 1120 LS, 594 LLS, and 116 FCCX individuals were analysed. From this total sample, eight different cohorts were defined, in which age-dependent cumulative risks and standardised incidence ratios were calculated regarding the first incident occurrence of any, colorectal, stomach, small bowel, urothelial, female breast, ovarian, and endometrial cancer, separately for LS, LLS, and FCCX.
The number of individuals at risk for first incident cancer ranged from 322 to 1102 in LS, 120 to 586 in LLS, and 40 to 116 in FCCX, depending on the cancer type of interest. For most cancer types, higher risks were observed in LS compared to LLS, FCCX, and the general population. Risks for any, colorectal, stomach, urothelial, and endometrial cancer were significantly higher in LLS compared to the general population. No significantly increased risks could be detected in FCCX compared to LLS patients, and the general population. Colorectal and endometrial cancer risks tended to be higher in LLS than in FCCX.
The characterisation of cancer risks in patients with LLS and FCCX is important to develop appropriate surveillance programmes for these specific intermediate risk groups. Larger prospective studies are needed to obtain more precise risk estimates.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background Analysis of circulating free DNA (cfDNA) is a promising tool for personalized management of colorectal cancer (CRC) patients. Untargeted cfDNA analysis using whole-genome sequencing (WGS) ...does not need a priori knowledge of the patient´s mutation profile. Methods Here we established LIquid biopsy Fragmentation, Epigenetic signature and Copy Number Alteration analysis (LIFE-CNA) using WGS with ~ 6x coverage for detection of circulating tumor DNA (ctDNA) in CRC patients as a marker for CRC detection and monitoring. Results We describe the analytical validity and a clinical proof-of-concept of LIFE-CNA using a total of 259 plasma samples collected from 50 patients with stage I-IV CRC and 61 healthy controls. To reliably distinguish CRC patients from healthy controls, we determined cutoffs for the detection of ctDNA based on global and regional cfDNA fragmentation patterns, transcriptionally active chromatin sites, and somatic copy number alterations. We further combined global and regional fragmentation pattern into a machine learning (ML) classifier to accurately predict ctDNA for cancer detection. By following individual patients throughout their course of disease, we show that LIFE-CNA enables the reliable prediction of response or resistance to treatment up to 3.5 months before commonly used CEA. Conclusion In summary, we developed and validated a sensitive and cost-effective method for untargeted ctDNA detection at diagnosis as well as for treatment monitoring of all CRC patients based on genetic as well as non-genetic tumor-specific cfDNA features. Thus, once sensitivity and specificity have been externally validated, LIFE-CNA has the potential to be implemented into clinical practice. To the best of our knowledge, this is the first study to consider multiple genetic and non-genetic cfDNA features in combination with ML classifiers and to evaluate their potential in both cancer detection and treatment monitoring. Trial registration DRKS00012890. Keywords: ctDNA, Colorectal cancer, Liquid biopsy, Whole-genome sequencing, Somatic copy number alterations, cfDNA fragmentation, Chromatin signatures
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Liquid biopsy (LB) is a promising complement to tissue biopsy for detection of clinically relevant genetic variants in cancer and mosaic diseases. A combined workflow to enable parallel tissue and LB ...analysis is required to maximize diagnostic yield for patients.
We developed and validated a cost-efficient combined next-generation sequencing (NGS) workflow for both tissue and LB samples, and applied Duplex sequencing technology for highly accurate detection of low frequency variants in plasma. Clinically relevant cutoffs for variant reporting and quantification were established.
We investigated assay performance characteristics for very low amounts of clinically relevant variants. In plasma, the assay achieved 100% sensitivity and 92.3% positive predictive value (PPV) for single nucleotide variants (SNVs) and 91.7% sensitivity and 100% PPV for insertions and deletions (InDel) in clinically relevant hotspots with 0.5-5% variant allele frequencies (VAFs). We further established a cutoff for reporting variants (i.e. Limit of Blank, LOB) at 0.25% VAF and a cutoff for quantification (i.e. Limit of Quantification, LOQ) at 5% VAF in plasma for accurate clinical interpretation of analysis results. With our LB approach, we were able to identify the molecular cause of a clinically confirmed asymmetric overgrowth syndrome in a 10-year old child that would have remained undetected with tissue analysis as well as other molecular diagnostic approaches.
Our flexible and cost-efficient workflow allows analysis of both tissue and LB samples and provides clinically relevant cutoffs for variant reporting and precise quantification. Complementing tissue analysis by LB is likely to increase diagnostic yield for patients with molecular diseases.
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