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Publikationen unter Beteiligung des Zentrums für erbliche Tumorerkrankungen

Im Rahmen der Forschung publizieren unsere Mitarbeiter ihre Ergebnisse. Im Folgenden finden Sie eine Liste an ausgewählten Publikationen von unseren Mitarbeitern im Zentrum für erbliche Tumorerkrankungen.

 

Aktuelle Publikationen

 

No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic

Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study 

„Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.“ 

  1. Dominguez-Valentin et al MDPI, 10 (2021) 2856. https://doi.org/10.3390/jcm10132856

 

Solve-RD: systematic pan-European data sharing and collaborative analysis to solve rare diseases  

„For the first time in Europe hundreds of rare disease (RD) experts team up to actively share and jointly analyse existing patient’s data. Solve-RD is a Horizon 2020-supported EU flagship project bringing together >300 clinicians, scientists, and patient representatives of 51 sites

from 15 countries. Solve-RD is built upon a core group of four European Reference Networks (ERNs; ERN-ITHACA, ERN-RND, ERN-Euro NMD, ERN-GENTURIS) which annually see more than 270,000 RD patients with respective pathologies. The main ambition is to solve unsolved rare diseases for which a molecular cause is not yet known. This is achieved through an innovative clinical research environment that introduces novel ways to organise expertise and data. Two major approaches are being pursued (i) massive data re-analysis of >19,000 unsolved rare disease patients and (ii) novel combined -omics approaches. The minimum requirement to be eligible for the analysis activities is an inconclusive exome that can be shared with controlled access. The first preliminary data re-analysis has already diagnosed 255 cases form 8393 exomes/genome datasets. This unprecedented degree of collaboration focused on sharing of data and expertise shall identify many new disease genes and enable diagnosis of many so far undiagnosed patients from all over Europe.“

  1. Zurek et al. European journal of human genetics: EJHG, (2021). https://doi.org/10.1038/s41431-021-00859-0.

 

A mosaic PIK3CA variant in a young adult with diffuse gastric cancer: case report.  

Hereditary diffuse gastric cancer (HDGC) is associated with germline deleterious variants in CDH1 and CTNNA1. The majority of HDGC-suspected patients are still genetically unresolved, raising the need for identification of novel HDGC predisposing genes. Under the collaborative environment of the SOLVE-RD consortium, re-analysis of whole-exome sequencing data from unresolved gastric cancer cases (n = 83) identified a mosaic missense variant in PIK3CA in a 25-year-old female with diffuse gastric cancer (DGC) without familial history for cancer. The variant, c.3140A>G p.(His1047Arg), a known cancer-related somatic hotspot, was present at a low variant allele frequency (18%) in leukocyte-derived DNA. Somatic variants in PIK3CA are usually associated with overgrowth, a phenotype that was not observed in this patient. This report highlights mosaicism as a potential, and understudied, mechanism in the etiology of DGC.

  1. A. W. Te Paske et al. European journal of human genetics: EJHG, (2021). https://doi.org/10.1038/s41431-021-00853-6

 

Variation in the risk of colorectal cancer in families with Lynch syndrome: a retrospective cohort study.  

Existing clinical practice guidelines for carriers of pathogenic variants of DNA mismatch repair genes (Lynch syndrome) are based on the mean age-specific cumulative risk

(penetrance) of colorectal cancer for all carriers of pathogenic variants in the same gene. We aimed to estimate the variation in the penetrance of colorectal cancer between carriers of pathogenic variants in the same gene by sex and continent of residence.

International Mismatch Repair Consortium. The Lancet. Oncology, (2021) S14702045(21)00189–3. https://doi.org/10.1016/S1470-2045(21)00189-3

 

Hereditary non-polyposis tumor risk syndromes  

  1. Steinke-Lange & E. Holinski-Feder. MMW Fortschritte der Medizin, 163 (2021) 41–44. https://doi.org/10.1007/s15006-021-9960-1

 

Uptake of hysterectomy and bilateral salpingo-oophorectomy in carriers of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report.  

„Lynch syndrome (LS) is a dominantly inherited cancer syndrome caused by germline pathogenic variants of mismatch repair (MMR) genes (path_MMR variants). In women with LS, gynaecological cancers are as common as gastrointestinal cancers.“

  1. T. Seppälä et al European Journal of Cancer (Oxford, England: 1990), 148 (2021) 124– 133. https://doi.org/10.1016/j.ejca.2021.02.022

 

Risk-reducing hysterectomy and bilateral salpingo-oophorectomy in female heterozygotes of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report.

„Lynch syndrome (LS) is a common hereditary cancer predisposition syndrome, present in an estimated 1 in 300 individuals, based on prevalence of the underlying genetic abnormalities in the general population. LS is caused by pathogenic variants in one of four DNA mismatch repair (MMR) genes (path_MMR): path_MLH1, path_MSH2, path_MSH6, and path_PMS2, each of which result in different risks for cancers, including colorectal, endometrial, ovarian, stomach, small bowel, bile duct, pancreas, urinary tract, brain, and prostate cancer. In women with LS, gynecological cancers are as common as gastrointestinal cancers. Until recently, clinical guidelines were similar for heterozygotes of all path_MMR genetic variants, endometrial cancer prognosis was assumed to be similar in heterozygotes and MMR variantnegative individuals, and the prognosis for ovarian cancer was assumed to be similar to ovarian cancer in path_BRCA1 heterozygotes. The recent Manchester International

Consensus Group publication described the risk for, and survival after, gynecological cancers in LS by genotype, as initially reported by the Prospective Lynch Syndrome Database (PLSD). Later, the PLSD reported findings in an additional independent cohort of path_MMR heterozygotes that validated the results from its original cohort and allowed merger of both cohorts to obtain more precise risk estimates and calculation of 5-year and 10-year crude survival after cancer.“

  1. Dominguez-Valentin et al Genetics in Medicine: Official Journal of the American College of Medical Genetics, 23 (2021) 705–712. https://doi.org/10.1038/s41436-020-01029-1 .

 

Value of upper gastrointestinal endoscopy for gastric cancer surveillance in patients with Lynch syndrome.  

„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. Fortynine 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.“

  1. Ladigan-Badura et al German Consortium for Familial Intestinal Cancer, International Journal of Cancer, 148 (2021) 106–114. https://doi.org/10.1002/ijc.33294

 

Beta-2-microglobulin Mutations Are Linked to a Distinct Metastatic Pattern and a Favorable

Outcome in Microsatellite-Unstable Stage IV Gastrointestinal Cancers  

„Immune checkpoint blockade (ICB) shows remarkable clinical effects in patients with metastatic microsatellite-unstable (MSI) cancer. However, markers identifying potential nonresponders are missing. We examined the prevalence of Beta-2-microglobulin (B2M) mutations, a common immune evasion mechanism, in stage IV MSI gastrointestinal cancer and its influence on metastatic pattern and patients’ survival under ICB. Twenty-five patients with metastatic, MSI gastrointestinal adenocarcinoma were included. Eighteen patients received ICB with pembrolizumab and one patient with nivolumab/ipilimumab. Sequencing was performed to determine B2M mutation status. B2M mutations and loss of B2M expression were detected in 6 out of 25 stage IV MSI cancers. B2M mutations were strongly associated with exclusively peritoneal/peritoneal and lymph node metastases (p=0.0055). However, no significant differences in therapy response (25% vs. 46.6%, p>0.99) and survival (median PFS: 19.5 vs 33.0 months, p=0.74; median OS 39 months vs. not reached, p>0.99) were observed between B2M-mutant and B2M-wild type tumor patients. Among metastatic MSI GI cancers, B2M-mutant tumors represent a biologically distinct disease with distinct metastatic patterns. To assess ICB response in B2M-mutant MSI cancer patients, future studies need to account for the fact that baseline survival of patients with B2M-mutant MSI cancer may be longer than of patients with B2M-wild type MSI cancer.“

  1. Busch et al Frontiers in Oncology, 11 (2021) 669774. https://doi.org/10.3389/fonc.2021.669774.

 

The “unnatural” history of colorectal cancer in Lynch syndrome: Lessons from colonoscopy surveillance.  

„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.“

Ahadova et al International Journal of Cancer, 148 (2021) 800–811. https://doi.org/10.1002/ijc.33224 .

 

Analysis in the Prospective Lynch Syndrome Database identifies sarcoma as part of the Lynch syndrome tumor spectrum.M.

Dominguez-Valentin et al International Journal of Cancer, 148 (2021) 512–513. https://doi.org/10.1002/ijc.33214

 

Associations of Pathogenic Variants in MLH1, MSH2, and MSH6 With Risk of Colorectal Adenomas and Tumors and With Somatic Mutations in Patients With Lynch Syndrome 

"Lynch syndrome is caused by variants in DNA mismatch repair (MMR) genes and associated with an increased risk of colorectal cancer (CRC). In patients with Lynch syndrome, CRCs can develop via different pathways. We studied associations between Lynch syndrome– associated variants in MMR genes and risks of adenoma and CRC and somatic mutations in APC and CTNNB1 in tumors in an international cohort of patients." 

Engel C et al. Gastroenterology. 2020;158(5):1326-1333. doi:10.1053/j.gastro.2019.12.032 

  

Prevalence of CNV-neutral structural genomic rearrangements in MLH1, MSH2, and PMS2 not detectable in routine NGS diagnostics 

"Routine diagnostics for colorectal cancer patients suspected of having Lynch-Syndrome (LS) currently uses Next-Generation-Sequencing (NGS) of targeted regions within the DNA mismatch repair (MMR) genes. This analysis can reliably detect nucleotide alterations and copy-number variations (CNVs); however, CNV-neutral rearrangements comprising gene inversions or large intronic insertions remain undetected because their breakpoints are usually not covered. As several founder mutations exist for LS, we established PCR-based screening methods for five known rearrangements in MLH1, MSH2, or PMS2, and investigated their prevalence in 98 German patients with suspicion of LS without a causative germline variant or CNV detectable in the four MMR genes. We found no recurrence of CNV-neutral structural rearrangements previously described: Neither for two inversions in MLH1 (exon 1 and exon 16-19) within 33 MLH1-deficient patients, nor for two inversions in MSH2 (exon 17 and exon 2-6) within 48 MSH2-deficient patients. The PMS2 insertion in intron 7 was detected in one of 17 PMS2-deficient patients. None of the four genomic inversions constitutes a founder event within the German population, but we advise to test the rare cases with unsolved PMS2-deficiency upon the known insertion. As a next diagnostic step, tumour tissue of the unsolved patients should be sequenced for somatic variants, and germline analysis of additional genes with an overlapping clinical phenotype should be considered. Alternatively, full-length cDNA analyses may detect concealed MMR-defects in cases with family history." 

Morak M et al. Fam Cancer. 2020;19(2):161-167. doi:10.1007/s10689-020-00159-4 

  

Analysis of 3297 individuals suggests that the pathogenic germline 5-UTR variant BRCA1 c.107A > T is not common in south-east Germany 

"In this study we aim to determine the prevalence of the recently identified pathogenic 

BRCA1 variant c.-107A > T in the south-east German population. This variant causes the epigenetic silencing of the BRCA1 promotor and has been detected in two independent families from the UK without a germline BRCA1 or BRCA2 pathogenic variant. A total of 3297 individuals with suspicion of hereditary breast and ovarian cancer and fulfilling the clinical criteria necessary for genetic testing in Germany were analyzed for presence of the variant by a Kompetitive Allele-Specific PCR (KASP) assay or direct Sanger sequencing. Since we did not detect an individual carrying the variant we conclude that BRCA1

c.107A > T is not a common variant in the south-east German population." 

Laner A et al. Fam Cancer. March 2020. doi:10.1007/s10689-020-00175-4 

  

Targeted deep-intronic sequencing in a cohort of unexplained cases of suspected Lynch syndrome.  

„Lynch syndrome (LS) is caused by germline defects in DNA mismatch repair (MMR) pathway, resulting in microsatellite instability (MSI-H) and loss of immunohistochemical staining (IHC) of the respective protein in tumor tissue. However, not in all clinically suspected LS patients with MSI-H tumors and IHC-loss, causative germline alterations in the MMR genes can be detected. Here, we investigated 128 of these patients to possibly define new pathomechanisms. A search for large genomic rearrangements and deep-intronic regulatory variants was performed via targeted next-generation sequencing (NGS) of exonic, intronic, and chromosomal regions upstream and downstream of MLH1, MSH2, MSH6, PMS2, MLH3, MSH3, PMS1, and EPCAM. Within this cohort, two different large rearrangements causative for LS were detected in three cases, belonging to two families (2.3%). The sensitivity to detect large rearrangements or copy number variations (CNV) was evaluated to be 50%. In 9 of the 128 patients (7%), previously overlooked pathogenic single-nucleotide variants (SNV) and two variants of uncertain significance (VUS) were identified in MLH1, MSH2, and MSH6. Pathogenic aberrations were not found in MLH3, MSH3, and PMS1. A potential effect on regulation was exerted for 19% of deep-intronic SNVs, predominantly located in chromosomal regions where the modification of histone proteins suggests an enhancer function. In conclusion, conventional variation analysis of coding regions is missing rare genomic rearrangements, nevertheless they should be analyzed. Assessment of deep-intronic SNVs is so far non-conclusive for medical questioning.“

Arnold AM et al Hum Genet. 2011 2020;28(5):597-608. doi:10.1038/s41431-019-0536-9

 

Prevalence of CNV-neutral structural genomic rearrangements in MLH1, MSH2, and PMS2 not detectable in routine NGS diagnostics.  

„Routine diagnostics for colorectal cancer patients suspected of having Lynch-Syndrome

(LS) currently uses Next-Generation-Sequencing (NGS) of targeted regions within the DNA mismatch repair (MMR) genes. This analysis can reliably detect nucleotide alterations and copy-number variations (CNVs); however, CNV-neutral rearrangements comprising gene inversions or large intronic insertions remain undetected because their breakpoints are usually not covered. As several founder mutations exist for LS, we established PCR-based screening methods for five known rearrangements in MLH1, MSH2, or PMS2, and investigated their prevalence in 98 German patients with suspicion of LS without a causative germline variant or CNV detectable in the four MMR genes. We found no recurrence of CNV-neutral structural rearrangements previously described: Neither for two inversions in MLH1 (exon 1 and exon 16–19) within 33 MLH1-deficient patients, nor for two inversions in MSH2 (exon 1–7 and exon 2–6) within 48 MSH2-deficient patients. The PMS2 insertion in intron 7 was detected in one of 17 PMS2-deficient patients. None of the four genomic inversions constitutes a founder event within the German population, but we advise to test the rare cases with unsolved PMS2-deficiency upon the known insertion. As a next diagnostic step, tumour tissue of the unsolved patients should be sequenced for somatic variants, and germline analysis of additional genes with an overlapping clinical phenotype should be considered. Alternatively, full-length cDNA analyses may detect concealed MMR-defects in cases with family history.“

Morak M et al Fam Cancer. 2020;19(2):161-167. doi:10.1007/s10689-020-00159-4

 

Cancer incidence and spectrum among children with genetically confirmed BeckwithWiedemann spectrum in Germany: a retrospective cohort study.  

„Beckwith-Wiedemann Syndrome (BWS; MIM 130650) is a multisystem human imprinting disorder. Characteristic features are macrosomia, macroglossia, visceromegaly, abdominal wall defects, neonatal hypoglycaemia and an increased occurrence of embryonal tumours.1 The prevalence is estimated to be 1:10,000 live births. BWS is caused by genetic or epigenetic defects of the Imprinting Centers (IC) in the chromosome 11p15.5 region. The IC1 (H19/IGF2:IG DMR) regulates the expression of the H19 and IGF2 genes, while the expression of CDKN1C, KCNQ10T1 and KCNQ1 is under the control of IC2 (KCNQ1OT1:TSS DMR). The term Beckwith-Wiedemann spectrum (BWSp) describes

“classical BWS without a molecular diagnosis and BWS-related phenotypes with an 11p15.5 molecular anomaly”.“

Cöktü S et al Br J Cancer. 2020;123(4):619-623. doi:10.1038/s41416-020-0911-x

 

Age-dependent performance of BRAF mutation testing in Lynch syndrome diagnostics.  

„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 LSassociated 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.“

Bläker H et al Int J Cancer. 2020;147(10):2801-2810. doi:10.1002/ijc.33273

 

Value of upper GI endoscopy for gastric cancer surveillance in patients with Lynch syndrome.  

„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.“

Ladigan-Badura S et al Int J Cancer. Published online September 15, 2020. doi:10.1002/ijc.33294

 

Rare tumors as leading symptom of hereditary tumor syndromes.  

„Monogenic hereditary tumor syndromes or tumor disposition syndromes (TDS) are based on germline/constitutional mutations in key genes of carcinogenesis. Early onset and a clustering of tumors belonging to a typical spectrum in the personal or family history are indicators for a hereditary form. In particular, rare specific tumors occur relatively frequently in the context of TDS. Based on a literature search the current article presents information on which TDS should be considered for differential diagnosis (DD) in the presence of a rare tumor. The identification of a causal germline mutation in the index patient is important for the DD, the evaluation of recurrence risks, and predictive testing of asymptomatic at-risk family members. In TDS with autosomal dominant inheritance, it is often possible to identify several high-risk individuals in the affected families. Early detection and correct classification are of high clinical relevance as the patients and persons at risk can often be offered effective preventive procedures (surveillance, prophylactic operations), and in some cases, special therapeutic options exist. TDS are paradigmatic for an extremely successful concept of preventive oncology and personalized medicine. The introduction of new methods of high-throughput sequencing (next generation sequencing) enables a more effective genetic diagnosis, but also poses a challenge for the interpretation of findings and counseling. Referral to multidisciplinary expert centers is useful for care of the families.“

Perne C et al Pathologe. 2020;41(5):535-549. doi:10.1007/s00292-020-00806-8

 

The “unnatural” history of colorectal cancer in Lynch syndrome: Lessons from colonoscopy surveillance.  

„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.“

Ahadova A et al Int J Cancer. Published online July 19, 2020. doi:10.1002/ijc.33224

 

Risk-Reducing Gynecological Surgery in Lynch Syndrome: Results of an International Survey from the Prospective Lynch Syndrome Database.  

„Purpose: To survey risk-reducing hysterectomy and bilateral salpingo-oophorectomy

(BSO) practice and advice regarding hormone replacement therapy (HRT) in women with

Lynch syndrome. Methods: We conducted a survey in 31 contributing centers from the Prospective Lynch Syndrome Database (PLSD), which incorporates 18 countries worldwide. The survey covered local policies for risk-reducing hysterectomy and BSO in Lynch syndrome, the timing when these measures are offered, the involvement of stakeholders and advice regarding HRT. Results: Risk-reducing hysterectomy and BSO are offered to path_MLH1 and path_MSH2 carriers in 20/21 (95%) contributing centers, to path_MSH6 carriers in 19/21 (91%) and to path_PMS2 carriers in 14/21 (67%). Regarding the involvement of stakeholders, there is global agreement (~90%) that risk-reducing surgery should be offered to women, and that this discussion may involve gynecologists, genetic counselors and/or medical geneticists. Prescription of estrogen-only HRT is offered by 15/21 (71%) centers to women of variable age range (35–55 years). Conclusions: Most centers offer risk-reducing gynecological surgery to carriers of path_MLH1, path_MSH2 and path_MSH6 variants but less so for path_PMS2 carriers. There is wide variation in how, when and to whom this is offered. The Manchester International Consensus Group developed recommendations to harmonize clinical practice across centers, but there is a clear need for more research.“

Dominguez-Valentin M et al J Clin Med. 2020;9(7). doi:10.3390/jcm9072290

 

Cancer risks in Lynch syndrome, Lynch-like syndrome, and familial colorectal cancer type X: a prospective cohort study.  

„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.“

Bucksch K et al BMC Cancer. 2020;20(1):460. doi:10.1186/s12885-020-06926-x

 

Associations of Pathogenic Variants in MLH1, MSH2, and MSH6 With Risk of Colorectal Adenomas and Tumors and With Somatic Mutations in Patients With Lynch Syndrome.  

„Lynch syndrome is caused by variants in DNA mismatch repair (MMR) genes and associated with an increased risk of colorectal cancer (CRC). In patients with Lynch syndrome, CRCs can develop via different pathways. We studied associations between Lynch syndrome–associated variants in MMR genes and risks of adenoma and CRC and somatic mutations in APC and CTNNB1 in tumors in an international cohort of patients.“

Engel C et al Gastroenterology. 2020;158(5):1326-1333. doi:10.1053/j.gastro.2019.12.032

 

Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database.  

„Pathogenic variants affecting MLH1, MSH2, MSH6, and PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organ-specific cancer risks according to gene and gender and to determine survival after cancer. We conducted an international, multicenter prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were merged providing 6350 participants and 51,646 follow-up years.

There were 1808 prospectively observed cancers. Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes sharing similar colorectal, endometrial, and ovarian cancer risks, but older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate. Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders. We did not demonstrate a significantly increased cancer risk in carriers of pathogenic PMS2 variants. Ten-year crude survival was over 80% following colon, endometrial, or ovarian cancer. Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers.“

Dominguez-Valentin M et al Genet Med. 2020;22(1):15-25. doi:10.1038/s41436-019-05969

 

Guidelines for the Li-Fraumeni and heritable TP53-related cancer syndromes.  

„Fifty years after the recognition of the Li–Fraumeni syndrome (LFS), our perception of cancers related to germline alterations of TP53 has drastically changed: (i) germline TP53 alterations are often identified among children with cancers, in particular soft-tissue sarcomas, adrenocortical carcinomas, central nervous system tumours, or among adult females with early breast cancers, without familial history. This justifies the expansion of the LFS concept to a wider cancer predisposition syndrome designated heritable TP53related cancer (hTP53rc) syndrome; (ii) the interpretation of germline TP53 variants remains challenging and should integrate epidemiological, phenotypical, bioinformatics prediction, and functional data; (iii) the penetrance of germline disease-causing TP53 variants is variable, depending both on the type of variant (dominant-negative variants being associated with a higher cancer risk) and on modifying factors; (iv) whole-body MRI (WBMRI) allows early detection of tumours in variant carriers and (v) in cancer patients with germline disease-causing TP53 variants, radiotherapy, and conventional genotoxic chemotherapy contribute to the development of subsequent primary tumours. It is critical to perform TP53 testing before the initiation of treatment in order to avoid in carriers, if possible, radiotherapy and genotoxic chemotherapies. In children, the recommendations are to perform clinical examination and abdominal ultrasound every 6 months, annual WBMRI and brain MRI from the first year of life, if the TP53 variant is known to be associated with childhood cancers. In adults, the surveillance should include every year clinical examination, WBMRI, breast MRI in females from 20 until 65 years and brain MRI until 50 years.“

  1. Frebourg et al European journal of human genetics: EJHG, 28 (2020) 1379–1386. https://doi.org/10.1038/s41431-020-0638-4.

 

Correction: Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database.  

  1. Dominguez-Valentin et al Genetics in Medicine: Official Journal of the American

College of Medical Genetics, 22 (2020) 1569. https://doi.org/10.1038/s41436-020-0892-4 

 

Value of upper GI endoscopy for gastric cancer surveillance in patients with Lynch syndrome.  

Ladigan-Badura S et al Int J Cancer. Published online September 15, 2020. https://10.1002/ijc.33294 

 

Contribution of mRNA Splicing to Mismatch Repair Gene Sequence Variant Interpretation.  

„Functional assays that assess mRNA splicing can be used in interpretation of the clinical significance of sequence variants, including the Lynch syndrome-associated mismatch repair (MMR) genes. The purpose of this study was to investigate the contribution of splicing assay data to the classification of MMR gene sequence variants. We assayed mRNA splicing for 24 sequence variants in MLH1, MSH2, and MSH6, including 12

missense variants that were also assessed using a cell-free in vitro MMR activity (CIMRA) assay. Multifactorial likelihood analysis was conducted for each variant, combining CIMRA outputs and clinical data where available. We collated these results with existing public data to provide a dataset of splicing assay results for a total of 671 MMR gene sequence variants (328 missense/in-frame indel), and published and unpublished repair activity measurements for 154 of these variants. There were 241 variants for which a splicing aberration was detected: 92 complete impact, 33 incomplete impact, and 116 where it was not possible to determine complete versus incomplete splicing impact. Splicing results mostly aided in the interpretation of intronic (72%) and silent (92%) variants and were the least useful for missense substitutions/in-frame indels (10%). MMR protein functional activity assays were more useful in the analysis of these exonic variants but by design they were not able to detect clinically important splicing aberrations identified by parallel mRNA assays. The development of high throughput assays that can quantitatively assess impact on mRNA transcript expression and protein function in parallel will streamline classification of MMR gene sequence variants.“

  1. A. Thompson et al Spurdle, & InSiGHT Variant Interpretation Committee, Frontiers in Genetics, 11 (2020) 798. https://doi.org/10.3389/fgene.2020.00798.

 

Früherkennung, Risikoreduktion, Überwachung und Therapie bei Patienten mit LynchSyndrom 

"Das Lynch-Syndrom(LS) ist die häufigste Form des erblichen Darmkrebses und verursacht ca. 3 % aller kolorektalen 

Karzinome (KRK). Ursächlich ist eine pathogene Sequenzvariante in einem Mismatch- Reparaturgen (MLH1, MSH2, 

MSH6, PMS2, EPCAM). Nach aktueller Schätzung ist ca. eine von 300 Personen Anlageträger für LS (ca. 300 000 Mutationsträger/Deutschland). Anlageträger haben ein erhöhtes Lebenszeitrisiko für ein KRK mit einer kumulativen Inzidenz von 15 bis 46 % bis zum 75. Lebensjahr. Weiterhin ist auch das Risiko für extrakolonische Tumoren wie Endometrium-, Dünndarm-, Magen-, Urothel- und andere Karzinome erhöht. 

Methoden Das Deutsche Konsortium Familiärer Darmkrebs besteht aus 14 universitären Zentren in Deutschland. Das 

Ziel des Konsortiums ist es, geeignete Vorsorgeprogramme zu entwickeln und zu evaluieren, damit diese später in die allgemeine Patientenversorgung übernommen werden können. 

Wir haben aktuell die Empfehlung zur klinischen Betreuung von LS-Patienten überarbeitet. 

Ergebnis Eine Koloskopie sollte ab dem 25. Lebensjahr alle 12–24 Monate erfolgen. Bei  Diagnose eines KRK ist eine onkologische 

Resektion notwendig, eine Kolektomie mit ileorektaler Anastomose sollte individuell mit dem Patienten besprochen  werden. Das Lebenszeitrisiko für ein Magenkarzinom liegt bei 0,2–13 %. Im Rahmen der endoskopischen Überwachung 

können signifikant mehr Magenkarzinome in früheren Tumorstadien entdeckt werden im 

Vergleich zur symptomgetriggerten Endoskopie. Das Lebenszeitrisiko für ein 

Dünndarmkarzinom iegt bei 4–8 %. Dünndarmkarzinome treten zur Hälfte im Duodenum auf, in 10% der Fälle vor dem 35. Lebensjahr. Eine ÖGD sollte deshalb ab dem 25. Lebensjahr alle 12–36 Monate erfolgen." 

Hüneburg R et al. Z Gastroenterol 2019; 57: 1–12. doi.org/10.1055/a-1008-9827 

  

Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database 

"Pathogenic variants affecting MLH1, MSH2, MSH6, and PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organ-specific cancer risks according to gene and gender and to determine survival after cancer." 

Dominguez-Valentin M et al. Genet Med. July 2019. doi:10.1038/s41436-019-0596-9 

  

Boosting care and knowledge about hereditary cancer: European Reference Network on Genetic Tumour Risk Syndromes 

"Approximately 27–36 million patients in Europe have one of the ~ 5.000–8.000 known rare diseases. These patients often do not receive the care they need or they have a substantial delay from diagnosis to treatment. In March 2017, twenty-four European Reference Networks (ERNs) were launched with the aim to improve the care for these patients through cross border healthcare, in a way that the medical knowledge and expertise travels across the borders, rather than the patients. It is expected that through the ERNs, European patients with a rare disease get access to expert care more often and more quickly, and that research and guideline development will be accelerated resulting in improved diagnostics and therapies. The ERN on Genetic Tumour Risk Syndromes (ERN GENTURIS) aims to improve the identification, genetic diagnostics, prevention of cancer, and treatment of European patients with a genetic predisposition for cancer. The ERN GENTURIS focuses on syndromes such as hereditary breast cancer, hereditary colorectal cancer and polyposis, neurofibromatosis and more rare syndromes e.g. PTEN Hamartoma Tumour Syndrome, Li Fraumeni Syndrome and hereditary diffuse gastric cancer." 

Vos JR et al. Fam Cancer. 2019;18(2):281-284. doi:10.1007/s10689-018-0110-6 

  

Colorectal cancer prevention and early detection: what is the best strategy? 

"Der gemeinsame Bundesausschuss (G-BA) hat eine Neuregelung der Darmkrebsvorsorge beschlossen. Ab voraussichtlich Juli 2019 werden anspruchsberechtige Personen schriftlich auf die Möglichkeit der Vorsorgeuntersuchungen hingewiesen. Darüber hinaus sollten Sie als Hausarzt Personen mit erhöhtem Risiko identifizieren können." 

Gross M & Holinski-Feder E. MMW Fortschr Med. 2019;161(7):43-48. doi:10.1007/s15006019-0407-x 

  

Lack of association between screening interval and cancer stage in Lynch syndrome may be accounted for by over-diagnosis; a prospective Lynch syndrome database report 

"Recent epidemiological evidence shows that colorectal cancer (CRC) continues to occur in carriers of pathogenic mismatch repair (path_MMR) variants despite frequent colonoscopy surveillance in expert centres. This observation conflicts with the paradigm that removal of all visible polyps should prevent the vast majority of CRC in path_MMR carriers, provided the screening interval is sufficiently short and colonoscopic practice is optimal." 

Seppala TT et al. Hered Cancer Clin Pract. 2019;17:8. doi:10.1186/s13053-019-0106-8 

  

No Difference in Colorectal Cancer Incidence or Stage at Detection by Colonoscopy Among 3

Countries With Different Lynch Syndrome Surveillance Policies 

"Patients with Lynch syndrome are at high risk for developing colorectal cancer (CRC). Regular colonoscopic surveillance is recommended, but there is no international consensus on the appropriate interval. We investigated whether shorter intervals are associated with lower CRC incidence and detection at earlier stages by comparing the surveillance policies in Germany, which evaluates patients by colonoscopy annually, in the Netherlands (patients evaluated at 1–2-year intervals), and Finland (patients evaluated at 2–3-year intervals)." 

Engel C et al. Gastroenterology. 2018;155(5):1400-1409.e2. doi:10.1053/j.gastro.2018.07.030 

  

Role of germline aberrations affecting CTNNA1, MAP3K6 and MYD88 in gastric cancer susceptibility 

"In familial or early-onset gastric cancer (GC) cases, a heritable germline aberration may underlie the development of GC. Elucidation of these germline defects is crucial to improve the clinical management of these patients and their relatives at risk. Pathogenic germline mutations in the CDH1 gene predispose to the development of hereditary diffuse gastric cancer (HDGC) with high GC risk of up to 70%, although the penetrance of CDH1 mutations identified in incident cases through gene panel testing for other reasons is not known. In more than 75% of the families that fulfil the CDH1 testing criteria, a causative germline mutation in CDH1 cannot be identified. In addition to these unexplained HDGC families, no heritable germline defects predisposing to the development of familial mixed-type and intestinal-type GC have been identified yet. Consequently, the putative causative germline aberration remains unknown for the majority of patients with GC." 

Weren R et al. J Med Genet. 2018;55(10):669-674. doi:10.1136/jmedgenet-2017-104962 

  

Haplotype analysis suggest that the MLH1 c.2059C > T mutation is a Swedish founder mutation 

"Lynch syndrome (LS) predisposes to a spectrum of cancers and increases the lifetime risk of developing colorectal- or endometrial cancer to over 50%. Lynch syndrome is dominantly inherited and is caused by defects in DNA mismatch-repair genes MLH1, MSH2, MSH6 or PMS2, with the vast majority detected in MLH1 and MSH2. Recurrent LS-associated variants observed in apparently unrelated individuals, have either arisen de novo in different families due to mutation hotspots, or are inherited from a founder (a common ancestor) that lived several generations back. There are variants that recur in some populations while also acting as founders in other ethnic groups. Testing for founder mutations can facilitate molecular diagnosis of Lynch Syndrome more efficiently and more cost effective than screening for all possible mutations. Here we report a study of the missense mutation MLH1 c.2059C > T (p.Arg687Trp), a potential founder mutation identified in eight Swedish families and one 

Finnish family with Swedish ancestors. Haplotype analysis confirmed that the Finnish and  Swedish families shared a haplotype of between 0.9 and 2.8 Mb. While MLH1 c.2059C > T exists worldwide, the Swedish haplotype was not found among mutation carriers from Germany or France, which indicates a common founder in the Swedish population. The geographic distribution of MLH1 c.2059C > T in Sweden suggests a single, ancient mutational event in the northern part of Sweden." von Salome J et al. Fam Cancer. 2018;17(4):531-537. doi:10.1007/s10689-017-0067-x 

  

Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database 

"Lynch syndrome (LS) is associated with a high probability of gastrointestinal, gynaecological and other cancers. It is caused by germline pathogenic variants in any of four DNA MMR genes referred to here as path_MSH2, path_MLH1, path_PMS2 or path_MSH6 and collectively as path_MMR. Deletions in the EPCAM gene, which lead to inherited methylation of the adjacent MSH2 promoter, are also referred to as path_MSH2. To date, most patients with LS have been identified following investigation because of their family or personal history of multiple and/or early onset cancers." 

Pål Mølle et. al. Gut. 2018;67(7):1306-1316. doi:10.1136/gutjnl-2017-314057 

  

Comprehensive analysis of the MLH1 promoter region in 480 patients with colorectal cancer and 1150 controls reveals new variants including one with a heritable constitutional MLH1 epimutation 

"We report the second promoter variant stably inducing a hereditary CEM. Concerning the classification of promoter variants, we discuss contradictory results from the literature for two variants, describe classification discrepancies between existing rules for five variants, suggest the (re-)classification of five promoter variants to (likely) benign and regard four variants as functionally unclear." 

Morak M et al. J Med Genet. 2018 Feb 22. pii: jmedgenet-2017-104744. doi: 

10.1136/jmedgenet-2017-104744. 

  

Identification of genetic variants for clinical management of familial colorectal tumors 

"Among 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." 

Dominguez-Valentin M et al. BMC Med Genet. 2018 Feb 20;19(1):26. doi:

10.1186/s12881018-0533-9. 

  

Genetic variants of prospectively demonstrated phenocopies in BRCA1/2 kindreds 

"We identified 48 women who were tested negative for their family's path_BRCA1 (n = 13) or path_BRCA2 (n = 35) variants. Pathogenic variants in the ATM, BRCA2, MSH6 and MUTYH genes were found in 10% (5/48) of the cases, of whom 15% (2/13) were from path_BRCA1 and 9% (3/35) from path_BRCA2 families. Out of the 26 unique VUS, 3 (12%) were predicted to affect RNA splicing (APC c.721G > A, MAP3K1 c.764A > G and MSH2 c.815C > T). However, by using a minigene, assay we here show that APC c.721G > A does not cause a splicing defect, similarly to what has been recently reported for the MAP3K1 c.764A > G. The MSH2 c.815C > T was previously described as causing partial exon skipping and it was identified in this work together with the path_BRCA2 c.9382C > T (p.R3128X). 

All women in breast or breast/ovarian cancer kindreds would benefit from being offered genetic testing irrespective of which causative genetic variants have been demonstrated in their relatives." 

Dominguez-Valentin M et al. Hered Cancer Clin Pract. 2018 Jan 15;16:4. doi:

10.1186/s13053018-0086-0. eCollection 2018. 

  

Role of germline aberrations affecting CTNNA1, MAP3K6 and MYD88 in gastric cancer susceptibility 

"Predicted deleterious germline variants were not encountered in MYD88, but recurrently observed in CTNNA1 (n=2) and MAP3K6 (n=3) in our cohort of patients with GC. In contrast to deleterious variants in CTNNA1, deleterious variants in MAP3K6 also occur frequently in the general population. 

Based on our results MAP3K6 should no longer be considered a GC predisposition gene, whereas deleterious CTNNA1 variants are confirmed as an infrequent cause of GC susceptibility. Biallelic MYD88 germline mutations are at most a very rare cause of GC susceptibility as no additional cases were identified." 

Weren RDA et al. J Med Genet. 2018 Jan 12. pii: jmedgenet-2017-104962. doi: 

10.1136/jmedgenet-2017-104962. 

  

 

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