Publications by authors named "Elke Holinski-Feder"

135 Publications

Somatic mosaics in hereditary tumor predisposition syndromes.

Eur J Med Genet 2021 Dec 13;64(12):104360. Epub 2021 Oct 13.

Center for Medical Genetics, Ghent University Hospital, Belgium; CRIG (Cancer Research Institute Ghent) and Department of Biomolecular Medicine, Ghent University, Belgium.

Historically, it is estimated that 5-10% of cancer patients carry a causative genetic variant for a tumor predisposition syndrome. These conditions have high clinical relevance as they are actionable regarding risk-specific surveillance, predictive genetic testing, reproductive options, and - in some cases - risk reducing surgery or targeted therapy. Every individual is born with on average 0.5-1 exonic mosaic variants prevalent in single or multiple tissues. Depending on the tissues affected, mosaic conditions can abrogate the clinical phenotype of a tumor predisposition syndrome and can even go unrecognized, because it can be impossible or difficult to detect them with routine genetic testing in blood/leucocytes. On the other hand, it is estimated that at least 4% of presumed de novo variants are the result of low-level mosaicism (variant allele frequency <10%) in a parent, while around 7% are true mosaic variants with a higher variant allele frequency, which can sometimes be confused for heterozygous variants. Clonal hematopoiesis however can simulate a mosaic tumor predisposition in genetic diagnostics and has to be taken into account, especially for TP53 variants. Depending on the technique, variant allele frequencies of 2-3% can be detected for single nucleotide variants by next generation sequencing, copy number variants with variant allele frequencies of 5-30% can be detected by array-based technologies or MLPA. Mosaic tumor predisposition syndromes are more common than previously thought and may often remain undiagnosed. The clinical suspicion and diagnostic procedure for several cases with mosaic tumor predisposition syndromes are presented.
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http://dx.doi.org/10.1016/j.ejmg.2021.104360DOI Listing
December 2021

Adenoma and colorectal cancer risks in Lynch syndrome, Lynch-like syndrome and familial colorectal cancer type X.

Int J Cancer 2022 Jan 14;150(1):56-66. Epub 2021 Sep 14.

Institute for Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig, Leipzig, Germany.

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.
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http://dx.doi.org/10.1002/ijc.33790DOI Listing
January 2022

Liquid Biopsy Hotspot Variant Assays: Analytical Validation for Application in Residual Disease Detection and Treatment Monitoring.

Clin Chem 2021 Nov;67(11):1483-1491

MGZ - Medizinisch Genetisches Zentrum, Munich, Germany.

Background: Analysis of circulating tumor DNA (ctDNA) in plasma is a powerful approach to guide decisions in personalized cancer treatment. Given the low concentration of ctDNA in plasma, highly sensitive methods are required to reliably identify clinically relevant variants.

Methods: We evaluated the suitability of 5 droplet digital PCR (ddPCR) assays targeting KRAS, BRAF, and EGFR variants for ctDNA analysis in clinical use.

Results: We investigated assay performance characteristics for very low amounts of variants, showing that the assays had very low limits of blank (0% to 0.11% variant allele frequency, VAF) and limits of quantification (0.41% to 0.7% VAF). Nevertheless, striking differences in detection and quantification of low mutant VAFs between the 5 tested assays were observed, highlighting the need for assay-specific analytical validation. Besides in-depth evaluation, a guide for clinical interpretation of obtained VAFs in plasma was developed, depending on the limits of blank and limits of quantification values.

Conclusion: It is possible to provide comprehensive clinical reports on actionable variants, allowing minimal residual disease detection and treatment monitoring in liquid biopsy.
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http://dx.doi.org/10.1093/clinchem/hvab124DOI Listing
November 2021

Early detection of duodenal cancer by upper gastrointestinal-endoscopy in Lynch syndrome.

Int J Cancer 2021 12 7;149(12):2052-2062. Epub 2021 Aug 7.

Department of Medicine, Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany.

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.
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http://dx.doi.org/10.1002/ijc.33753DOI Listing
December 2021

No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in and : A Prospective Lynch Syndrome Database Study.

J Clin Med 2021 Jun 28;10(13). Epub 2021 Jun 28.

Medical Genetics, Institute for Medical Genetics and Pathology, University Hospital Basel, 4031 Basel, Switzerland.

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 and genes.

Methods: Carriers of pathogenic variants of () and () 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 and .
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http://dx.doi.org/10.3390/jcm10132856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269121PMC
June 2021

Mutations Are Linked to a Distinct Metastatic Pattern and a Favorable Outcome in Microsatellite-Unstable Stage IV Gastrointestinal Cancers.

Front Oncol 2021 8;11:669774. Epub 2021 Jun 8.

Department of Applied Tumor Biology, Heidelberg University Hospital, Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Centre (DKFZ), Heidelberg, Germany.

Immune checkpoint blockade (ICB) shows remarkable clinical effects in patients with metastatic microsatellite-unstable (MSI) cancer. However, markers identifying potential non-responders are missing. We examined the prevalence of ( 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 mutation status. mutations and loss of B2M expression were detected in 6 out of 25 stage IV MSI cancers. mutations were strongly associated with exclusively peritoneal/peritoneal and lymph node metastases (p=0.0055). However, no significant differences in therapy response (25% . 46.6%, p>0.99) and survival (median PFS: 19.5 33.0 months, p=0.74; median OS 39 months . not reached, p>0.99) were observed between -mutant and -wild type tumor patients. Among metastatic MSI GI cancers, -mutant tumors represent a biologically distinct disease with distinct metastatic patterns. To assess ICB response in -mutant MSI cancer patients, future studies need to account for the fact that baseline survival of patients with -mutant MSI cancer may be longer than of patients with -wild type MSI cancer.
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http://dx.doi.org/10.3389/fonc.2021.669774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219238PMC
June 2021

[Hereditary non-polyposis tumor risk syndromes].

MMW Fortschr Med 2021 06;163(11):41-44

- FÄ für Humangenetik -, Med.-Genetisches Zentrum \/MGZ, Bayerstraße 3 - 5, 80335, München, Deutschland.

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http://dx.doi.org/10.1007/s15006-021-9960-1DOI Listing
June 2021

Actionable secondary findings in arrhythmogenic right ventricle cardiomyopathy genes: impact and challenge of genetic counseling.

Cardiovasc Diagn Ther 2021 Apr;11(2):637-649

Medical Genetics Center, Munich, Germany.

Background: Comprehensive genetic analysis yields in a higher diagnostic rate but also in a higher number of secondary findings (SF). American College of Medical Genetics and Genomics (ACMG) published a list of 59 actionable genes for which disease causing sequence variants are recommended to be reported as SF including 27 genes linked to inherited cardiovascular disease (CVD) such as arrhythmia syndromes, cardiomyopathies and vascular and connective tissue disorders. One of the selected conditions represented in the actionable gene list is the arrhythmogenic right ventricle cardiomyopathy (ARVC), an inherited heart muscle disease with a particularly high risk of sudden cardiac death (SCD). Since clinical symptoms are frequently absent before SCD, a genetic finding is a promising option for early diagnosis and possible intervention. However, the variant interpretation and the decision to return a SF is still challenging.

Methods: To determine the frequency of medically actionable SF linked to CVD we analyzed data of 6,605 individuals who underwent high throughput sequencing for noncardiac diagnostic requests. In particular, we critically assessed and classified the variants in the ARVC genes: and and compared our findings with the population-based genome Aggregation Database (gnomAD) and ARVC-afflicted individuals listed in ClinVar and ARVC database.

Results: 1% (69/6,605) of tested individuals carried pathogenic SF in one of the 27 genes linked to CVD, of them 13 individuals (0.2%) carried a pathogenic SF in a ARVC gene. Overall, 582 rare variants were identified in all five ARVC genes, 96% of the variants were missense variants and 4% putative LoF variants (pLoF): frameshift, start/stop-gain/loss, splice-site. Finally, we selected 13 of the 24 pLoF variants as pathogenic SF by careful data interpretation.

Conclusions: Since SF in actionable ARVC genes can allow early detection and prevention of disease and SCD, detected variant must undergo rigorous clinical and laboratory evaluation before it can be described as pathogenic and returned to patients. Returning a SF to a patient should be interdisciplinary, it needs genetic counselling and clinicians experienced in inherited heart disease.
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http://dx.doi.org/10.21037/cdt-20-585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102260PMC
April 2021

HPO-driven virtual gene panel: a new efficient approach in molecular autopsy of sudden unexplained death.

BMC Med Genomics 2021 03 31;14(1):94. Epub 2021 Mar 31.

MGZ - Medical Genetics Center Munich, Munich, Germany.

Background: Molecular autopsy represents an efficient tool to save the diagnosis in up to one-third of sudden unexplained death (SUD). A defined gene panel is usually used for the examination. Alternatively, it is possible to carry out a comprehensive genetic assessment (whole exome sequencing, WES), which also identifies rare, previously unknown variants. The disadvantage is that a dramatic number of variants must be assessed to identify the causal variant. To improve the evaluation of WES, the human phenotype ontology (HPO) annotation is used internationally for deep phenotyping in the field of rare disease. However, a HPO-based evaluation of WES in SUD has not been described before.

Methods: We performed WES in tissue samples from 16 people after SUD. Instead of a fixed gene panel, we defined a set of HPO terms and thus created a flexible "virtual gene panel", with the advantage, that recently identified genes are automatically associated by HPO terms in the HPO database.

Results: We obtained a mean value of 68,947 variants per sample. Stringent filtering ended up in a mean value of 276 variants per sample. Using the HPO-driven virtual gene panel we developed an algorithm that prioritized 1.4% of the variants. Variant interpretation resulted in eleven potentially causative variants in 16 individuals.

Conclusion: Our data introduce an effective diagnostic procedure in molecular autopsy of SUD with a non-specific clinical phenotype.
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http://dx.doi.org/10.1186/s12920-021-00946-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011092PMC
March 2021

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

Eur J Cancer 2021 05 17;148:124-133. Epub 2021 Mar 17.

Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany; MGZ- Medical Genetics Center, Munich, Germany; The International Society for Gastrointestinal Hereditary Tumours (InSiGHT), The Polyposis Registry, St Mark's Hospital, Watford Road, Harrow, Middlesex, HA1 3UJ, UK; European Hereditary Tumour Group (EHTG), C/o Lindsays, Caledonian Exchange, 19A Canning Street, Edinburgh, EH3 8HE, United Kingdom.

Purpose: This study aimed to report the uptake of hysterectomy and/or bilateral salpingo-oophorectomy (BSO) to prevent gynaecological cancers (risk-reducing surgery [RRS]) in carriers of pathogenic MMR (path_MMR) variants.

Methods: The Prospective Lynch Syndrome Database (PLSD) was used to investigate RRS by a cross-sectional study in 2292 female path_MMR carriers aged 30-69 years.

Results: Overall, 144, 79, and 517 carriers underwent risk-reducing hysterectomy, BSO, or both combined, respectively. Two-thirds of procedures before 50 years of age were combined hysterectomy and BSO, and 81% of all procedures included BSO. Risk-reducing hysterectomy was performed before age 50 years in 28%, 25%, 15%, and 9%, and BSO in 26%, 25%, 14% and 13% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 carriers, respectively. Before 50 years of age, 107 of 188 (57%) BSO and 126 of 204 (62%) hysterectomies were performed in women without any prior cancer, and only 5% (20/392) were performed simultaneously with colorectal cancer (CRC) surgery.

Conclusion: Uptake of RRS before 50 years of age was low, and RRS was rarely undertaken in association with surgical treatment of CRC. Uptake of RRS aligned poorly with gene- and age-associated risk estimates for endometrial or ovarian cancer that were published recently from PLSD and did not correspond well with current clinical guidelines. The reasons should be clarified. Decision-making on opting for or against RRS and its timing should be better aligned with predicted risk and mortality for endometrial and ovarian cancer in Lynch syndrome to improve outcomes.
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http://dx.doi.org/10.1016/j.ejca.2021.02.022DOI Listing
May 2021

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

Genet Med 2021 04 1;23(4):705-712. Epub 2020 Dec 1.

Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany.

Purpose: To determine impact of risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) on gynecological cancer incidence and death in heterozygotes of pathogenic MMR (path_MMR) variants.

Methods: The Prospective Lynch Syndrome Database was used to investigate the effects of gynecological risk-reducing surgery (RRS) at different ages.

Results: Risk-reducing hysterectomy at 25 years of age prevents endometrial cancer before 50 years in 15%, 18%, 13%, and 0% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 heterozygotes and death in 2%, 2%, 1%, and 0%, respectively. Risk-reducing BSO at 25 years of age prevents ovarian cancer before 50 years in 6%, 11%, 2%, and 0% and death in 1%, 2%, 0%, and 0%, respectively. Risk-reducing hysterectomy at 40 years prevents endometrial cancer by 50 years in 13%, 16%, 11%, and 0% and death in 1%, 2%, 1%, and 0%, respectively. BSO at 40 years prevents ovarian cancer before 50 years in 4%, 8%, 0%, and 0%, and death in 1%, 1%, 0%, and 0%, respectively.

Conclusion: Little benefit is gained by performing RRS before 40 years of age and premenopausal BSO in path_MSH6 and path_PMS2 heterozygotes has no measurable benefit for mortality. These findings may aid decision making for women with LS who are considering RRS.
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http://dx.doi.org/10.1038/s41436-020-01029-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026395PMC
April 2021

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

Int J Cancer 2021 01 13;148(1):106-114. Epub 2020 Oct 13.

Department of Hematology and Oncology, Klinikum Hochsauerland, Meschede, Germany.

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.
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http://dx.doi.org/10.1002/ijc.33294DOI Listing
January 2021

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

Int J Cancer 2020 11 14;147(10):2801-2810. Epub 2020 Sep 14.

Department of Applied Tumor Biology, University Hospital Heidelberg, Cooperation Unit Applied Tumor Biology, German Cancer research Center (DKFZ), and Molecular Medicine Partnership Unit (MMPU), University Hospital Heidelberg, Heidelberg, Germany.

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.
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http://dx.doi.org/10.1002/ijc.33273DOI Listing
November 2020

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

J Clin Med 2020 Jul 18;9(7). Epub 2020 Jul 18.

Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, 80336 Munich, Germany.

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 _ and carriers in 20/21 (95%) contributing centers, to carriers in 19/21 (91%) and to 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 , and variants but less so for 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.
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http://dx.doi.org/10.3390/jcm9072290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408942PMC
July 2020

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

Int J Cancer 2021 02 3;148(4):800-811. Epub 2020 Aug 3.

Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.

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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http://dx.doi.org/10.1002/ijc.33224DOI Listing
February 2021

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

BMC Cancer 2020 May 24;20(1):460. Epub 2020 May 24.

Institute for Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig, Leipzig, Germany.

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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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http://dx.doi.org/10.1186/s12885-020-06926-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245918PMC
May 2020

Critical assessment of secondary findings in genes linked to primary arrhythmia syndromes.

Hum Mutat 2020 05 18;41(5):1025-1032. Epub 2020 Feb 18.

Department of Genomics, Medical Genetics Center Munich, Munich, Germany.

As comprehensive sequencing technologies gain widespread use, questions about so-called secondary findings (SF) require urgent consideration. The American College of Medical Genetics and Genomics has recommended to report SF in 59 genes (ACMG SF v2.0) including four actionable genes associated with inherited primary arrhythmia syndromes (IPAS) such as catecholaminergic polymorphic ventricular tachycardia, long QT syndrome, and Brugada syndrome. Databases provide conflicting results for the purpose of identifying pathogenic variants in SF associated with IPAS at a level of sufficient evidence for clinical return. As IPAS account for a significant proportion of sudden cardiac deaths (SCD) in young and apparently healthy individuals, variant interpretation has a great impact on diagnosis and prevention of disease. Of 6381 individuals, 0.4% carry pathogenic variants in one of the four actionable genes related to IPAS: RYR2, KCNQ1, KCNH2, and SCN5A. Comparison of the databases ClinVar, Leiden Open-source Variant Database, and Human Gene Mutation Database showed impactful differences (0.2% to 1.3%) in variant interpretation improvable by expert-curation depending on database and classification system used. These data further highlight the need for international consensus regarding the variant interpretation, and subsequently management of SF in particular with regard to treatable arrhythmic disorders with increased risk of SCD.
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http://dx.doi.org/10.1002/humu.23996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187207PMC
May 2020

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

Fam Cancer 2020 04;19(2):161-167

Medizinische Klinik Und Poliklinik IV, Campus Innenstadt, Klinikum Der Universität München, Ziemssenstr. 1, 80336, Munich, Germany.

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.
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http://dx.doi.org/10.1007/s10689-020-00159-4DOI Listing
April 2020

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.

Gastroenterology 2020 04 8;158(5):1326-1333. Epub 2020 Jan 8.

Department of Gastroenterology & Hepatology, Leiden University Medical Center, Leiden, The Netherlands.

Background & Aims: 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.

Methods: We combined clinical and molecular data from 3 studies. We obtained clinical data from 2747 patients with Lynch syndrome associated with variants in MLH1, MSH2, or MSH6 from Germany, the Netherlands, and Finland who received at least 2 surveillance colonoscopies and were followed for a median time of 7.8 years for development of adenomas or CRC. We performed DNA sequence analyses of 48 colorectal tumors (from 16 patients with mutations in MLH1, 29 patients with mutations in MSH2, and 3 with mutations in MSH6) for somatic mutations in APC and CTNNB1.

Results: Risk of advanced adenoma in 10 years was 17.8% in patients with pathogenic variants in MSH2 vs 7.7% in MLH1 (P < .001). Higher proportions of patients with pathogenic variants in MLH1 or MSH2 developed CRC in 10 years (11.3% and 11.4%) than patients with pathogenic variants in MSH6 (4.7%) (P = .001 and P = .003 for MLH1 and MSH2 vs MSH6, respectively). Somatic mutations in APC were found in 75% of tumors from patients with pathogenic variants in MSH2 vs 11% in MLH1 (P = .015). Somatic mutations in CTNNB1 were found in 50% of tumors from patients with pathogenic variants in MLH1 vs 7% in MSH2 (P = .002). None of the 3 tumors with pathogenic variants in MSH6 had a mutation in CTNNB1, but all had mutations in APC.

Conclusions: In an analysis of clinical and DNA sequence data from patients with Lynch syndrome from 3 countries, we associated pathogenic variants in MMR genes with risk of adenoma and CRC, and somatic mutations in APC and CTNNB1 in colorectal tumors. If these findings are confirmed, surveillance guidelines might be adjusted based on MMR gene variants.
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http://dx.doi.org/10.1053/j.gastro.2019.12.032DOI Listing
April 2020

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

Eur J Hum Genet 2020 05 10;28(5):597-608. Epub 2019 Dec 10.

Medizinisch Genetisches Zentrum-MGZ, Munich, Germany.

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.
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http://dx.doi.org/10.1038/s41431-019-0536-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170855PMC
May 2020

Results of multigene panel testing in familial cancer cases without genetic cause demonstrated by single gene testing.

Sci Rep 2019 12 6;9(1):18555. Epub 2019 Dec 6.

Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.

We have surveyed 191 prospectively sampled familial cancer patients with no previously detected pathogenic variant in the BRCA1/2, PTEN, TP53 or DNA mismatch repair genes. In all, 138 breast cancer (BC) cases, 34 colorectal cancer (CRC) and 19 multiple early-onset cancers were included. A panel of 44 cancer-predisposing genes identified 5% (9/191) pathogenic or likely pathogenic variants and 87 variants of uncertain significance (VUS). Pathogenic or likely pathogenic variants were identified mostly in familial BC individuals (7/9) and were located in 5 genes: ATM (3), BRCA2 (1), CHEK2 (1), MSH6 (1) and MUTYH (1), followed by multiple early-onset (2/9) individuals, affecting the CHEK2 and ATM genes. Eleven of the 87 VUS were tested, and 4/11 were found to have an impact on splicing by using a minigene splicing assay. We here report for the first time the splicing anomalies using this assay for the variants ATM c.3806A > G and BUB1 c.677C > T, whereas CHEK1 c.61G > A did not result in any detectable splicing anomaly. Our study confirms the presence of pathogenic or likely pathogenic variants in genes that are not routinely tested in the context of the above-mentioned clinical phenotypes. Interestingly, more than half of the pathogenic germline variants were found in the moderately penetrant ATM and CHEK2 genes, where only truncating variants from these genes are recommended to be reported in clinical genetic testing practice.
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http://dx.doi.org/10.1038/s41598-019-54517-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898579PMC
December 2019

[Current recommendations for surveillance, risk reduction and therapy in Lynch syndrome patients].

Z Gastroenterol 2019 Nov 18;57(11):1309-1320. Epub 2019 Nov 18.

Medizinische Klinik und Poliklinik I, Universitätsklinikum Bonn.

Introduction:  Lynch syndrome (LS) is the most common hereditary colorectal cancer syndrome and accounts for ~3 % of all CRCs. This autosomal dominant disorder is caused by germline mutations in DNA mismatch repair genes (, and ). One in 300 individuals of the general population are considered to be mutation carriers (300 000 individuals/Germany). Mutation carriers are at a high CRC risk of 15-46 % till the age of 75 years. LS also includes a variety of extracolonic malignancies such as endometrial, small bowel, gastric, urothelial, and other cancers.

Methods:  The German Consortium for Familial Intestinal Cancer consists of 14 university centers in Germany. The aim of the consortium is to develop and evaluate surveillance programs and to further translate the results in clinical care. We have revisited and updated the clinical management guidelines for LS patients in Germany.

Results:  A surveillance colonoscopy should be performed every 12-24 months starting at the age of 25 years. At diagnosis of first colorectal cancer, an oncological resection is advised, an extended resection (colectomy with ileorectal anastomosis) has to be discussed with the patient. The lifetime risk for gastric cancer is 0.2-13 %. Gastric cancers detected during surveillance have a lower tumor stage compared to symptom-driven detection. The lifetime risk for small bowel cancer is 4-8 %. About half of small bowel cancer is located in the duodenum and occurs before the age of 35 years in 10 % of all cases. Accordingly, patients are advised to undergo an esophagogastroduodenoscopy every 12-36 months starting by the age of 25 years.

Conclusion:  LS colonic and extracolonic clinical management, surveillance and therapy are complex and several aspects remain unclear. In the future, surveillance and clinical management need to be more tailored to gene and gender. Future prospective trials are needed.
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http://dx.doi.org/10.1055/a-1008-9827DOI Listing
November 2019

Survival by colon cancer stage and screening interval in Lynch syndrome: a prospective Lynch syndrome database report.

Hered Cancer Clin Pract 2019 14;17:28. Epub 2019 Oct 14.

23High Risk and GI Cancer prevention Clinic, Gatro-Oncology Unit, The Department of Gastroenterology, Sheba Medical Center, Ramat Gan, Israel.

Background: We previously reported that in pathogenic mismatch repair () variant carriers, the incidence of colorectal cancer (CRC) was not reduced when colonoscopy was undertaken more frequently than once every 3 years, and that CRC stage and interval since last colonoscopy were not correlated.

Methods: The Prospective Lynch Syndrome Database (PLSD) that records outcomes of surveillance was examined to determine survival after colon cancer in relation to the time since previous colonoscopy and pathological stage. Only variants scored by the InSiGHT variant database as class 4 or 5 (clinically actionable) were included in the analysis.

Results: Ninety-nine carriers had no cancer prior to or at first colonoscopy, but subsequently developed colon cancer. Among these, 96 were 65 years of age or younger at diagnosis, and included 77 , 17 and 2 carriers. The number of cancers detected within < 1.5, 1.5-2.5, 2.5-3.5 and at > 3.5 years after previous colonoscopy were 9, 43, 31 and 13, respectively. Of these, 2, 8, 4 and 3 were stage III, respectively, and only one stage IV (interval 2.5-3.5 years) disease. Ten-year crude survival after colon cancer were 93, 94 and 82% for stage I, II and III disease, respectively ( < 0.001). Ten-year crude survival when the last colonoscopy had been < 1.5, 1.5-2.5, 2.5-3.5 or > 3.5 years before diagnosis, was 89, 90, 90 and 92%, respectively ( = 0.91).

Conclusions: In and carriers, more advanced colon cancer stage was associated with poorer survival, whereas time since previous colonoscopy was not. Although the numbers are limited, together with our previously reported findings, these results may be in conflict with the view that follow-up of variant carriers with colonoscopy intervals of less than 3 years provides significant benefit.
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http://dx.doi.org/10.1186/s13053-019-0127-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6792227PMC
October 2019

Genetic Screening and Personalized Prevention in Colorectal Cancer.

Visc Med 2019 Aug 17;35(4):226-230. Epub 2019 Jul 17.

MGZ - Medizinisch Genetisches Zentrum, Munich, Germany.

Cancer per se is a genetic disease, either originating in germline mutations in cancer genes or in somatic mutations only present in the cancer cells. Therefore, personalized risk prediction, prevention, and treatment for cancer can be based on the results of genetic testing either in the germline or in the tumor. Surveillance regimens need to be based on appropriate risk assessment, which includes germline monogenic genetic testing - where appropriate - and in the future polygenic risk - possibly - for the general population. Treatment regimens should also include germline testing at least for cases suspicious of hereditary tumor diseases, followed by the analysis of somatic mutations within the tumor cell genome, raising a possible target for personalized therapy. Appropriate risk assessment is the key for suitable and, most importantly, individualized surveillance strategies especially in hereditary tumor syndromes. This concerns not only the patient but also the family members at risk. An overview about the different fields and aspects of genetic testing in colorectal cancer and its impact on personalized prevention will be given below.
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http://dx.doi.org/10.1159/000501941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738322PMC
August 2019

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

Genet Med 2020 01 24;22(1):15-25. Epub 2019 Jul 24.

Hereditary Cancer Program (PROCANHE), Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.

Purpose: 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.

Methods: 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.

Results: 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.

Conclusion: 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.
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http://dx.doi.org/10.1038/s41436-019-0596-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371626PMC
January 2020

Full-length transcript amplification and sequencing as universal method to test mRNA integrity and biallelic expression in mismatch repair genes.

Eur J Hum Genet 2019 12 22;27(12):1808-1820. Epub 2019 Jul 22.

Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Ziemssenstr. 1, 80336, Munich, Germany.

In pathogenicity assessment, RNA-based analyses are important for the correct classification of variants, and require gene-specific cut-offs for allelic representation and alternative/aberrant splicing. Beside this, the diagnostic yield of RNA-based techniques capable to detect aberrant splicing or allelic loss due to intronic/regulatory variants has to be elaborated. We established a cDNA analysis for full-length transcripts (FLT) of the four DNA mismatch repair (MMR) genes to investigate the splicing pattern and transcript integrity with active/inhibited nonsense-mediated mRNA-decay (NMD). Validation was based on results from normal controls, samples with premature termination codons (PTC), samples with splice-site defects (SSD), and samples with pathogenic putative missense variants. The method was applied to patients with variants of uncertain significance (VUS) or unexplained immunohistochemical MMR deficiency. We categorized the allelic representation into biallelic (50 ± 10%) or allelic loss (≤10%), and >10% and <40% as unclear. We defined isoforms up to 10% and exon-specific exceptions as alternative splicing, set the cut-off for SSD in cDNA + P to 30-50%, and regard >10% and <30% as unclear. FLT cDNA analyses designated 16% of all putative missense variants and 12% of VUS as SSD, detected MMR-defects in 19% of the unsolved patients, and re-classified >30% of VUS. Our method allows a standardized, systematic cDNA analysis of the MMR FLTs to assess the pathogenicity mechanism of VUS on RNA level, which will gain relevance for precision medicine and gene therapy. Diagnostic accuracy will be enhanced by detecting MMR defects in hitherto unsolved patients. The data generated will help to calibrate a high-throughput NGS-based mRNA-analysis and optimize prediction programs.
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http://dx.doi.org/10.1038/s41431-019-0472-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6870986PMC
December 2019

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

MMW Fortschr Med 2019 04;161(7):43-48

Medizinisch Genetisches Zentrum, München, Deutschland.

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http://dx.doi.org/10.1007/s15006-019-0407-xDOI Listing
April 2019

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.

Hered Cancer Clin Pract 2019 28;17. Epub 2019 Feb 28.

28Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, The Netherlands.

Background: Recent epidemiological evidence shows that colorectal cancer (CRC) continues to occur in carriers of pathogenic mismatch repair () 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 carriers, provided the screening interval is sufficiently short and colonoscopic practice is optimal.

Methods: To inform the debate, we examined, in the Prospective Lynch Syndrome Database (PLSD), whether the time since last colonoscopy was associated with the pathological stage at which CRC was diagnosed during prospective surveillance. carriers were recruited for prospective surveillance by colonoscopy. Only variants scored by the InSiGHT Variant Interpretation Committee as class 4 and 5 (clinically actionable) were included. CRCs detected at the first planned colonoscopy, or within one year of this, were excluded as prevalent cancers.

Results: Stage at diagnosis and interval between last prospective surveillance colonoscopy and diagnosis were available for 209 patients with 218 CRCs, including 162 , 45 _, 10 and 1 carriers. The numbers of cancers detected within < 1.5, 1.5-2.5, 2.5-3.5 and at > 3.5 years since last colonoscopy were 36, 93, 56 and 33, respectively. Among these, 16.7, 19.4, 9.9 and 15.1% were stage III-IV, respectively ( = 0.34). The cancers detected more than 2.5 years after the last colonoscopy were not more advanced than those diagnosed earlier ( = 0.14).

Conclusions: The CRC stage and interval since last colonoscopy were not correlated, which is in conflict with the accelerated adenoma-carcinoma paradigm. We have previously reported that more frequent colonoscopy is not associated with lower incidence of CRC in carriers as was expected. In contrast, point estimates showed a higher incidence with shorter intervals between examinations, a situation that may parallel to over-diagnosis in breast cancer screening. Our findings raise the possibility that some CRCs in carriers may spontaneously disappear: the host immune response may not only remove CRC precursor lesions in carriers, but may remove infiltrating cancers as well. If confirmed, our suggested interpretation will have a bearing on surveillance policy for carriers.
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http://dx.doi.org/10.1186/s13053-019-0106-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394091PMC
February 2019

HADHA and HADHB gene associated phenotypes - Identification of rare variants in a patient cohort by Next Generation Sequencing.

Mol Cell Probes 2019 04 22;44:14-20. Epub 2019 Jan 22.

Medical Genetics Center, Munich, Germany; Department of Neurology, Friedrich-Baur-Institute, Klinikum der Ludwig-Maximilians-University, Munich, Germany. Electronic address:

The heterooctameric mitochondrial trifunctional protein (MTP), composed of four α- and β-subunits harbours three enzymes that each perform a different function in mitochondrial fatty acid β-oxidation. Pathogenic variants in the MTP genes (HADHA and HADHB) cause MTP deficiency, a rare autosomal recessive metabolic disorder characterized by phenotypic heterogeneity ranging from severe, early-onset, cardiac disease to milder, later-onset, myopathy and neuropathy. Since metabolic myopathies and neuropathies are a group of rare genetic disorders and their associated muscle symptoms may be subtle, the diagnosis is often delayed. Here we evaluated data of 161 patients with myopathy and 242 patients with neuropathy via next generation sequencing (NGS) and report the diagnostic yield in three patients of this cohort by the detection of disease-causing variants in the HADHA or HADHB gene. The mitigated phenotypes of this treatable disease were missed by the newborn screening, highlighting the importance of phenotype-based NGS analysis in patients with rare and clinically very variable disorders such as MTP deficiency.
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http://dx.doi.org/10.1016/j.mcp.2019.01.003DOI Listing
April 2019
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