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Peutz-Jeghers syndrome (PJS) is an autosomal dominant hereditary polyposis syndrome causing increased morbidity and mortality due to complications of polyposis and the development of cancer. STK11 is the only gene known to be associated with PJS, although in 10%-15% of patients fulfilling the diagnostic criteria no pathogenic variant (PV) is identified. The primary aim of this study was to identify the genetic etiology in all known PJS patients in Denmark and to estimate the risk of cancer, effect of surveillance and overall survival. We identified 56 patients (2-83 years old) with PJS. The detection rate of PVs was 96%, including three cases of mosaicism (6%). In two patients a variant was not detected. At the age of 40 years, the probabilities of cancer and death were 21% and 16%, respectively; at the age of 70 years these probabilities were 71% and 69%. Most cases of cancer (92%) were identified between the scheduled examinations in the surveillance program. These observations emphasize that PJS should be regarded as a general cancer predisposition syndrome, where improvement of clinical care is needed. Peutz-Jeghers syndrome (PJS) is an autosomal dominant hereditary polyposis syndrome causing increased morbidity and mortality due to complications of polyposis and the development of cancer. STK11 is the only gene known to be associated with PJS, although in 10%-15% of patients fulfilling the diagnostic criteria no pathogenic variant (PV) is identified. The primary aim of this study was to identify the genetic etiology in all known PJS patients in Denmark and to estimate the risk of cancer, effect of surveillance and overall survival. We identified 56 patients (2-83 years old) with PJS. The detection rate of PVs was 96%, including three cases of mosaicism (6%). In two patients a variant was not detected. At the age of 40 years, the probabilities of cancer and death were 21% and 16%, respectively; at the age of 70 years these probabilities were 71% and 69%. Most cases of cancer (92%) were identified between the scheduled examinations in the surveillance program. These observations emphasize that PJS should be regarded as a general cancer predisposition syndrome, where improvement of clinical care is needed.

Background: The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time.Methods: The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender.Findings: Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers.Interpretation: In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome. Background: The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time. Methods: The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender. Findings: Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers. Interpretation: In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome. Funding: We acknowledge funding from the Norwegian Cancer Society, contract 194751-2017.

Supplementary Methods, Tables 1-3, Figure 1 from Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Implications for Risk Prediction

Aim: Our goal was to describe a precision medicine program in a regional academic hospital, characterize features of included patients and present early data on clinical impact. Materials and methods: We prospectively included 163 eligible patients with late-stage cancer of any diagnosis from June 2020 to May 2022 in the Proseq Cancer trial. Molecular profiling of new or fresh frozen tumor biopsies was done by WES and RNAseq with parallel sequencing of non-tumoral DNA as individual reference. Cases were presented at a National Molecular Tumor Board (NMTB) for discussion of targeted treatment. Subsequently, patients were followed for at least 7 months. Results: 80% (N = 131) of patients had a successful analysis done, disclosing at least one pathogenic or likely pathogenic variant in 96%. A strongly or potentially druggable variant was found in 19% and 73% of patients, respectively. A germline variant was identified in 2.5%. Median time from trial inclusion to NMTB decision was one month. One third (N = 44) of patients who underwent molecularly profiling were matched with a targeted treatment, however, only 16% were either treated (N = 16) or are waiting for treatment (N = 5), deteriorating performance status being the primary cause of failure. A history of cancer among 1st degree relatives, and a diagnosis of lung or prostate cancer correlated with greater chance of targeted treatment being available. The response rate of targeted treatments was 40%, the clinical benefit rate 53%, and the median time on treatment was 3.8 months. 23% of patients presented at NMTB were recommended clinical trial participation, not dependent on biomarkers. Conclusions: Precision medicine in end-stage cancer patients is feasible in a regional academic hospital but should continue within the frame of clinical protocols as few patients benefit. Close collaboration with comprehensive cancer centers ensures expert evaluations and equality in access to early clinical trials and modern treatment.

We present a three-generation family with an AXIN2 variant and a family history of colorectal cancer (CRC), colon polyps and tooth agenesis. A likely pathogenic variant was detected in the AXIN2 gene (c.1994dup; p.(Asn666Glnfs*41)). This variant has previously been associated with tooth agenesis and polyposis, only. In this case report we describe eight carriers with tooth agenesis and variable clinical findings, including polyps and CRC. Our case provides additional knowledge to the sparse data on genotype-phenotype association related to AXIN2 associated cancer syndrome. Further, our case highlights the importance of analysing an extended CRC and oligodontia/ectodermal dysplasia gene panel including AXIN2 but also raises awareness and discussion about appropriate surveillance program.

Background and study aims In most patients with juvenile polyposis Syndrome, it is possible to detect a pathogenic germline variant in SMAD4 or BMPR1A. It is well known that patients with a pathogenic variant in SMAD4 have a higher risk of gastric polyposis and gastric cancer compared to BMPR1A carriers, but the natural history of gastric involvement is poorly described. We aimed to systematically review endoscopic and histopathological gastric findings in Danish patients with pathogenic variants in SMAD4. Patients and methods This was a retrospective, cross-sectional study including endoscopic and histological gastric findings in all known Danish patients with pathogenic variants in SMAD4. The patients were identified by data from various registries as well as from clinical genetic departments and laboratories. Results We identified 41 patients (2–72 years) with a pathogenic SMAD4 variant. In 31 patients, we were able to retrieve information on upper gastrointestinal endoscopy. Eighty-seven percent had at least one gastric abnormality including erythema (72 %) and edema (72 %). Half of the patients also had vulnerability of the mucosa and 68 % had gastric polyposis. An increasing frequency of abnormalities were observed with increasing age. Gastric cancer was diagnosed in 5 % of the cases and 22 % had a gastrectomy mainly because of massive polyposis. Conclusions This study showed that most patients with pathogenic SMAD4 variants have a distinct phenotype of the gastric mucosa, and with an increasing severity in the elderly patients. These findings provide new insights into the natural history of gastric manifestations in patients with pathogenic SMAD4 variants.

Phenomenon The morning report is one of the longest surviving hospital practices. Most studies of the morning report focus on the effectiveness of formal medical training, while focus on social and communicative aspects is rarer. This study explores the social interactions and communication in morning reports, examining the ways in which they contribute to the construction of professional identity and socialization into the community of the clinical department. Approach We used a qualitative explorative design with video observations of morning reports. Our data consisted of 43 video-recorded observations (in all, 15.5 hours) from four different hospital departments in Denmark. These were analyzed using the theoretical framework of positioning theory. Findings A key finding was that each department followed its own individual structure. This order was not articulated as such but played out implictly. Two alternative storylines unfolded in the elements of the morning report: 1) being equal members of the specialty and department, and 2) preserving the hierarchical community and its inherent positions. Insights The morning report can be seen as playing an important role in community making. It unfolds as a “dance” of repeated elements in a complex collegial space. Within this complexity, the morning report is a space for positioning oneself and others as a collegial “we”, i.e., equal members of a department and specialty, at the same time as “having a place” in a hierarchal community. Thus, morning reports contribute to developing professional identity and socialization into the medical community.

PURPOSE: The aim of the study is to investigate presence and role of the gene encoding the maternally contributed nucleotide-binding oligomerization domain (NOD)-like receptors with a pyrin domain (PYD)-containing protein 9 (NLRP9) in human and mouse ovaries, respectively, and in preimplantation mouse embryo development by knocking down Nlrp9b.METHODS: Expression levels of NLRP9 mRNA in human follicles were extracted from RNA sequencing data from previous studies. In this study, we performed a qPCR analysis of Nlpr9b mRNA in mouse oocytes and found it present. Intracellular ovarian distribution of NLRP9B protein was accomplished using immunohistochemistry. The distribution of NLRP9B was explored using a reporter gene approach, fusing NLRP9B to green fluorescent protein and microinjection of in vitro-generated mRNA. Nlrp9b mRNA function was knocked down by microinjection of short interference (si) RNA targeting Nlrp9b, into mouse pronuclear zygotes. Knockdown of the Nlrp9b mRNA transcript was confirmed by qPCR.RESULT: We found that the human NLRP9 gene and its corresponding protein are highly expressed in human primordial and primary follicles. The NLRP9B protein is localized to the cytoplasm in the blastomeres of a 2-cell embryo in mice. SiRNA-mediated knockdown of Nlrp9b caused rapid elimination of endogenous Nlrp9b mRNA and premature embryo arrest at the 2- to 4-cell stages compared with that of the siRNA-scrambled control group.CONCLUSIONS: These results suggest that mouse Nlrp9b, as a maternal effect gene, could contribute to mouse preimplantation embryo development. It remains to investigate whether NLRP9 have a crucial role in human preimplantation embryo and infertility.

Background and aim Gestational trophoblastic disease (GTD) is a heterogeneous group of disorders characterised by abnormal proliferation of trophoblastic tissue. Since GTD and its malignant sequel gestational trophoblastic neoplasia (GTN) are rare diseases, little evidence is available from randomised controlled trials on optimal treatment and follow-up. Treatment protocols vary within Europe, and even between different centres within countries. One of the goals of the ‘European Organisation for Treatment of Trophoblastic Diseases’ (EOTTD) is to harmonise treatment in Europe. To provide a basis for European standardisation of definitions, treatment and follow-up protocols in GTD, we composed a set of guidelines for minimal requirements and optimal management of GTD. Methods Members from each EOTTD country attended multiple workshops during annual EOTTD meetings. Clinical guidelines were formulated by consensus and evidence where available. The following guidelines were discussed: diagnostics of GTD and GTN, treatment of low-risk GTN, high-risk GTN, ultra-high-risk GTN, placental site and epithelioid trophoblastic tumours and follow-up. Results Between 40 and 65 EOTTD members from 17 European countries and 7 non-European countries attended the clinical workshops held on 6 occasions. Flow diagrams for patient management were composed to display minimum and best practice for most treatment situations. New agreed definitions of recurrence and chemotherapy resistance were formulated. Conclusions Despite the many differences between and within the participating countries, an important step in uniform treatment of GTD and GTN within Europe was made by the Clinical Working Party of the EOTTD. This is an example on how guidelines and harmonisation can be achieved within international networks.

Background Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the progressive growth of cysts and a decline of renal function. The clinical feasibility of the number of potential disease-modifying drugs is limited by systemic adverse effects. We hypothesize that megalin, a multiligand endocytic receptor expressed in the proximal tubule, may be used to facilitate drug uptake into cysts, thereby allowing for greater efficacy and fewer side effects. Methods The cyst expression of various tubular markers, including megalin and aquaporin 2 (AQP2), was analysed by immunohistochemistry (IHC) of kidney sections from the ADPKD mouse model (PKD1RC/RC) at different post-natal ages. The endocytic function of megalin in cysts was examined by IHC of kidney tissue from mice injected with the megalin ligand aprotinin. Results Cyst lining epithelial cells expressing megalin were observed at all ages; however, the proportion decreased with age. Concomitantly, an increasing proportion of cysts revealed expression of AQP2, partial expression of megalin and/or AQP2 or no expression of the examined markers. Endocytic uptake of aprotinin was evident in megalin-positive cysts, but only in those that remained connected to the renal tubular system. Conclusions Megalin-expressing cysts were observed at all ages, but the proportion decreased with age, possibly due to a switch in tubular origin, a merging of cysts of different tubular origin and/or a change in the expression pattern of cyst lining cells. Megalin expressed in cysts was functional, suggesting that megalin-mediated endocytosis is a potential mechanism for drug targeting in ADPKD if initiated early in the disease.

Hereditary Polyposis Syndromes are a group of rare, inherited syndromes characterized by the presence of histopathologically specific or numerous intestinal polyps and an increased risk of cancer. Some polyposis syndromes have been known for decades, but the development in genetic technologies has allowed the identification of new syndromes.. The diagnosis entails surveillance from an early age, but universal guideline on how to manage and surveille these new syndromes are lacking. This paper represents a condensed version of the recent guideline (2020) from a working group appointed by the Danish Society of Medical Genetics and the Danish Society of Surgery on recommendations for the surveillance of patients with hereditary polyposis syndromes, including rare polyposis syndromes. Supplementary Information The online version contains supplementary material available at 10.1186/s13053-021-00197-8.

Hereditary polyposis syndromes (HPS) are a group of rare, inherited syndromes characterised by the presence of histopathological specific or numerous intestinal polyps and a high risk of intestinal and extraintestinal cancer. During the last decade, several new HPS have been discovered, as it is possible to detect pathogenic germline variants in genes not previously known to be associated with polyposis. This review summarises the current knowledge on the syndromes and discusses genetic testing as part of the diagnostic pipeline when suspecting a polyposis syndrome.

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.

Findings 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (p 0 center dot 0001 for each of the three three continents). These familial risk factors resulted in a wide within-gene variation in the risk of colorectal cancer for men and women from each continent who all carried pathogenic variants in the same gene or the MSH2 c.942+3A T variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and onlyBackground 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. Methods In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero. Findings 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (pT variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and only 10-19% having a penetrance of 40-60%. Interpretation Our study findings highlight the important role of risk modifiers, which could lead to personalised risk assessments for precision prevention and early detection of colorectal cancer for people with Lynch syndrome. Funding National Health and Medical Research Council, Australia. Copyright (c) 2021 Elsevier Ltd. All rights reserved.Methods In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero.

von Hippel Lindau disease (vHL) is caused by a hereditary predisposition to multiple neoplasms, especially hemangioblastomas in the retina and CNS, renal cell carcinomas (RCC), pheochromocytomas, neuroendocrine pancreatic tumours (PNET) and endolymphatic sac tumours. Evidence based approaches are needed to ensure an optimal clinical care, while minimizing the burden for the patients and their families. This guideline is based on evidence from the international vHL literature and extensive research of geno- and phenotypic characteristics, disease progression and surveillance effect in the national Danish vHL cohort. We included the views and preferences of the Danish vHL patients, ensured consensus among Danish experts and compared with international recommendations. Recommendations: vHL can be diagnosed on clinical criteria, only; however, in most cases the diagnosis can be supported by identification of a pathogenic or likely pathogenic variant in VHL. Surveillance should be initiated in childhood in persons with, or at risk of, vHL, and include regular examination of the retina, CNS, inner ear, kidneys, neuroendocrine glands, and pancreas. Treatment of vHL manifestations should be planned to optimize the chance of cure, without unnecessary sequelae. Most manifestations are currently treated by surgery. However, belzutifan, that targets HIF-2α was recently approved by the U.S. Food and Drug Administration (FDA) for adult patients with vHL-associated RCC, CNS hemangioblastomas, or PNETs, not requiring immediate surgery. Diagnostics, surveillance, and treatment of vHL can be undertaken successfully by experts collaborating in multidisciplinary teams. Systematic registration, collaboration with patient organisations, and research are fundamental for the continuous improvement of clinical care and optimization of outcome with minimal patient inconvenience.

We present a three-generation family with an AXIN2 variant and a family history of colorectal cancer (CRC), colon polyps and tooth agenesis. A likely pathogenic variant was detected in the AXIN2 gene (c.1994dup; p.(Asn666Glnfs*41)). This variant has previously been associated with tooth agenesis and polyposis, only. In this case report we describe eight carriers with tooth agenesis and variable clinical findings, including polyps and CRC. Our case provides additional knowledge to the sparse data on genotype-phenotype association related to AXIN2 associated cancer syndrome. Further, our case highlights the importance of analysing an extended CRC and oligodontia/ectodermal dysplasia gene panel including AXIN2 but also raises awareness and discussion about appropriate surveillance program.

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 syn-drome to improve outcomes. (C) 2021 The Author(s). Published by Elsevier Ltd.

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.

Supplemental Digital Content is available in the text., The protein p57 is encoded by CDKN1C. This gene is known to be paternally imprinted and maternally expressed in cytotrophoblasts and villous stromal cells. We present a method for evaluating p57 antibodies (Abs) in hydatidiform mole (HM) and demonstrate the results for 4 p57 Abs in various cell types. Five cases of complete HM, diploid with 2 paternal genome sets (CHM;PP), 5 cases of partial HM, triploid with 2 paternal and 1 maternal genome sets (PHM;PPM), and 5 cases of non-HM, with diploid biparental genomes (non-HM;PM) were stained with p57 Abs: 57P06, EP183, KP10, and KP39. Assessment of the fraction of nuclei stained, and the intensity of staining of the nuclei and cytoplasm was performed. For evaluation of the Abs, the observations in cytotrophoblasts, villous stromal cells, maternal decidual cells, and intermediate trophoblasts were scored. The fraction of stained nuclei in cytotrophoblasts and villous stromal cells and the staining of cytoplasm showed to be important parameters in the evaluation of the Abs. 57P06 was evaluated as optimal. KP10 showed moderate cytoplasmatic staining in maternal decidual cells and intermediate trophoblasts, and was evaluated as good. EP183 was evaluated as poor, primarily due to nuclear staining in ≥10% of the villous stromal cells in CHM;PP. KP39 was evaluated as poor, primarily due to strong cytoplasmatic staining in some cytotrophoblasts and villous stromal cells. A structured testing of p57 for diagnosing HM is recommended. No nuclear staining was observed in syncytiotrophoblasts of CHM;PP, indicating that in syncytiotrophoblasts also, CDKN1C is paternally imprinted.

Nucleotide-binding oligomerization domain (NOD)-like receptors with a pyrin domain (PYD), NLRPs, are pattern recognition receptors, well recognized for their important roles in innate immunity and apoptosis. However, several NLRPs have received attention for their new, specialized roles as maternally contributed genes important in reproduction and embryo development. Several NLRPs have been shown to be specifically expressed in oocytes and preimplantation embryos. Interestingly, and in line with divergent functions, NLRP genes reveal a complex evolutionary divergence. The most pronounced difference is the human-specific NLRP7 gene, not identified in rodents. However, mouse models have been extensively used to study maternally contributed NLRPs. The NLRP2 and NLRP5 proteins are components of the subcortical maternal complex (SCMC), which was recently identified as essential for mouse preimplantation development. The SCMC integrates multiple proteins, including KHDC3L, NLRP5, TLE6, OOEP, NLRP2, and PADI6. The NLRP5 (also known as MATER) has been extensively studied. In humans, inactivating variants in specific NLRP genes in the mother are associated with distinct phenotypes in the offspring, such as biparental hydatidiform moles (BiHMs) and preterm birth. Maternal-effect recessive mutations in KHDC3L and NLRP5 (and NLRP7) are associated with reduced reproductive outcomes, BiHM, and broad multilocus imprinting perturbations. The precise mechanisms of NLRPs are unknown, but research strongly indicates their pivotal roles in the establishment of genomic imprints and post-zygotic methylation maintenance, among other processes. Challenges for the future include translations of findings from the mouse model into human contexts and implementation in therapies and clinical fertility management.

Background In gestational trophoblastic disease, the prognosis is related to the genetic constitution. In some cases, taking a biopsy is contraindicated. Methods In a pregnant woman, ultrasound scanning suggested hydatidiform mole. To explore if the genetic constitution can be established without taking a biopsy (or terminating the pregnancy), cell‐free DNA and circulating gestational trophoblasts were isolated from maternal blood before evacuation of the uterus. The evacuated tissue showed the morphology of a complete hydatidiform mole. Without prior whole‐genome amplification, short tandem repeat analysis of 24 DNA markers was performed on the samples, and on DNA isolated from evacuated tissue, and from the blood of the patient and her partner. Results Identical genetic results were obtained in each of three circulating gestational trophoblasts and the evacuated tissue, showing that this conceptus had a diploid androgenetic nuclear genome. In contrast, analysis of cell‐free DNA was less informative and less specific due to the inherent presence of cell‐free DNA from the patient. Conclusion Our results show that it is possible to isolate and analyze circulating gestational trophoblasts originating in a pregnancy without maternal nuclear genome. For diagnosing gestational trophoblastic diseases, genotyping circulating gestational trophoblasts appears to be superior to analysis of cell‐free DNA., The prognosis in gestational trophoblastic diseases is related to the genetic constitution. Performing biopsy may not be feasible due to the risk of miscarriage or bleeding. Analyzing circulating gestational trophoblasts is a feasible and an attractive alternative

Incidences of hydatidiform mole (HM) registered in European countries varies from 0.98/1000 to 2.17/1000 deliveries, while higher incidences have been reported in other parts of the world. We calculated the incidence by selecting data on HMs classified as ”first”, “second” and “third” from 01.01.1999 to 31.12.2014 registered in the Danish Pathology Registry, which we previously showed to be the most complete data source on the number of HMs in Denmark. In the study period, 1976 first HMs were registered; 1080 (55%) were classified as PHMs (partial HMs) and 896 (45%) as NPHMs (HMs not registered as PHMs). The average incidence of HM was 1.98/1000 deliveries. The incidence of PHM was 1.08/1000 deliveries and the incidence of NPHM was 0.90/1000 deliveries. Forty HMs were registered as second HMs; 85% (34/40) were of the same histopathological type as the first HM. The registered incidence of HM decreased from 2.55/1000 deliveries in 1999 to 1.61/1000 deliveries in 2014 (p

Lynch syndrome (LS) results from pathogenic variants in the mismatch repair (MMR) genes and is the most common hereditary cancer syndrome, affecting an estimated 1 in 300 individuals. Pathogenic variants in each of the MMR genes path_MLH1, path_MSH2, path_MSH6, and path_PMS2 result in different risks for cancers in organs including the colorectum, endometrium, ovaries, stomach, small bowel, bile duct, pancreas, and upper urinary tract. Accurate estimates of these risks are essential for planning appropriate approaches to the prevention or early diagnosis of cancers but the robustness of previous studies has been limited by factors including retrospective design,1,2 lack of validation in independent cohorts,3-5 and inconsistent classification of genetic variants. Unexpected findings from previous studies have included path_MLH1 and path_MSH2 carriers appearing to have a lifetime risk of colorectal cancer (CRC) of approximately 50%, despite surveillance colonoscopy,6-8 and that shorter intervals between colonoscopies do not seem to reduce the incidence of CRC in LS.9,10 These findings challenge the assumptions that CRC in LS usually develops from a noninfiltrative adenoma precursor and that CRC can be prevented by colonoscopic detection and removal of adenomas in the colon and rectum. Additionally, previous studies in the Prospective Lynch Syndrome Database (PLSD) have shown no increase in cancer risk in path_PMS2 carriers before 40 years of age and, although observation years were limited in older path_PMS2 carriers, LS-associated cancers other than endometrial and prostate were not observed.6-8 In this study we collected prospective data from a new large cohort of path_MMR carriers to validate previous findings from PLSD. We also updated information on the original cohort to ensure consistent classification of pathogenicity of MMR gene variants. We then combined both data sets, providing larger numbers that allowed us to derive more precise risk estimates for cancers in LS categorized by gene and gender.

Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3′ region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25–2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63–5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71–4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12–11.54; P = 0.0002). No genotype–phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder with highly varying disease manifestations, many of which cause extensive morbidity. There are international consensus criteria for the diagnosis, monitoring and treatment of TSC, and approved medical treatment for some of the most serious disease manifestations. However, organisation of a rational and coordinated care of TSC patients involves many different medical specialities and is only sparsely described. This review describes the interdisciplinary care of TSC patients at Aarhus University Hospital, Denmark.

Purpose: Biallelic pathogenic variants in the mismatch repair (MMR) genes cause a recessive childhood cancer predisposition syndrome known as constitutional mismatch repair deficiency (CMMRD). Family members with a heterozygous MMR variant have Lynch syndrome. We aimed at estimating cancer risk in these heterozygous carriers as a novel approach to avoid complicated statistical methods to correct for ascertainment bias.Methods: Cumulative colorectal cancer incidence was estimated in a cohort of PMS2- and MSH6-associated families, ascertained by the CMMRD phenotype of the index, by using mutation probabilities based on kinship coefficients as analytical weights in a proportional hazard regression on the cause-specific hazards. Confidence intervals (CIs) were obtained by bootstrapping at the family level.Results: The estimated cumulative colorectal cancer risk at age 70 years for heterozygous PMS2 variant carriers was 8.7% (95% CI 4.3-12.7%) for both sexes combined, and 9.9% (95% CI 4.9-15.3%) for men and 5.9% (95% CI 1.6-11.1%) for women separately. For heterozygous MSH6 variant carriers these estimates are 11.8% (95% CI 4.5-22.7%) for both sexes combined, 10.0% (95% CI 1.83-24.5%) for men and 11.7% (95% CI 2.10-26.5%) for women.Conclusion: Our findings are consistent with previous reports that used more complex statistical methods to correct for ascertainment bias. These results underline the need for MMR gene-specific surveillance protocols for Lynch syndrome.

Background We previously reported that in pathogenic mismatch repair (path_MMR) 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 path_MMR variants scored by the InSiGHT variant database as class 4 or 5 (clinically actionable) were included in the analysis. Results Ninety-nine path_MMR 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 path_MLH1, 17 path_MSH2, and 2 path_MSH6 carriers. The number of cancers detected within 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 (p 3.5 years before diagnosis, was 89, 90, 90 and 92%, respectively (p = 0.91). Conclusions In path_MLH1 and path_MSH2 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 path_MMR variant carriers with colonoscopy intervals of less than 3 years provides significant benefit.

The Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) calculates the probability that a woman carries a pathogenic variant in BRCA1 or BRCA2 based on her pedigree and the population frequencies of pathogenic alleles of BRCA1 (0.0006394) and BRCA2 (0.00102) in the United Kingdom (UK). BOADICEA allows the clinician to define the population frequencies of pathogenic alleles of BRCA1 and BRCA2 for other populations but only includes preset values for the Ashkenazy Jewish and Icelandic populations. Among 173 early-onset breast cancer pedigrees in Denmark, BOADICEA discriminated well between carriers and non-carriers of pathogenic variants (area under the receiver operating characteristics curve: 0.81; 95% CI 0.74-0.86) but underestimated the frequency of carriers of pathogenic variants in BRCA1 or BRCA2 as measured by the observed-to-expected ratio (O/E 1.83; 95% CI 1.18-2.84). This reflects findings from older studies of BOADICEA in UK, German, Italian, and Chinese populations, all accounting for the different calibration for different carrier probabilities. To improve the performance of BOADICEA for non-UK populations, we developed a method to derive population frequencies of pathogenic alleles of BRCA1 and BRCA2. Compared to the UK population frequencies, we estimated the Danish population frequencies of pathogenic alleles to be higher for BRCA1 (0.0015; 95% CI 0.00064-0.0034) and lower for BRCA2 (0.00052; 95% CI 0.00018-0.0017) after adjusting for the different calibration of BOADICEA for different carrier probabilities. Incorporating additional population frequencies into BOADICEA could improve its performance for non-UK populations.

Choroid plexus hyperplasia leading to communicating hydrocephalus is a rare disorder with only 24 patients reported so far in the literature. Furthermore, genetic information is only available for six of these cases: In one patient the condition was associated with trisomy 9p, in one patient with trisomy 9 mosaicism and in three patients with tetrasomy 9p. Here, we describe four additional patients with choroid plexus hyperplasia leading to various levels of hydrocephalus, and gain of the entire chromosome 9p region: Three with trisomy 9p and one with tetrasomy 9p. The three patients with trisomy 9p were siblings. Normal karyotypes were identified in the lymphocytes of the parents. Likely one of the parents is a mosaic for a cell line with trisomy 9p in the gonads. We demonstrate the importance of correctly diagnosing choroid plexus hyperplasia as the cause of hydrocephalus in patients with chromosome 9p gain since ventriculoperitoneal shunting is likely to fail due to intolerable formation of ascites.

Background Autosomal dominant polycystic kidney disease (ADPKD) is the most common heritable kidney disease. ADPKD leads to cysts, kidney enlargement and end-stage renal disease. ADPKD is mainly caused by variants in PKD1 and PKD2, with truncating PKD1 variants causing the most severe phenotype. This study aimed to characterize variants in Danish patients referred for screening of genes related to cystic kidney disease. Methods 147 families were analysed for variants in PKD1, PKD2 and GANAB using next generation sequencing and multiplex ligation-dependent probe amplification. If a variant was identified, relatives were analysed for the specific variant using Sanger sequencing. Results A pathogenic or possibly pathogenic variant was identified in 87% (103/118) of patients suspected to suffer from ADPKD, according to the requisition form. In total, 112 pathogenic or possibly pathogenic variants were observed, of which 94 were unique; 74 (79%) in PKD1 and 20 (21%) in PKD2, while 41 variants were novel. No variants in GANAB were observed. Ten recurrent variants were observed in 26 (26%) families. These were either PKD2 variants (N = 6) or non-truncating PKD1 variants (N = 4). Five of these were likely founder variants. Conclusions The distribution of pathogenic or possibly pathogenic variants in the Danish ADPKD population is similar to that in other populations, except that recurrent truncating PKD1 variants appear to be rare, i.e. founder variants tend to be variant types associated with a mild phenotype. Patients with a mild phenotype may remain undiagnosed, consequently the frequency of founder variants and prevalence of ADPKD may be underestimated.

AIM: This study estimated the urinary tract infection (UTI) risk in a nationwide cohort of infants prenatally diagnosed with parenchymal kidney anomalies compared with a comparison cohort.METHODS: A Danish population-based nationwide cohort of foetuses diagnosed with parenchymal kidney anomalies between 2007 and 2012 had previously been identified. These were compared with foetuses without kidney anomalies who were prenatally scanned the same year. Live born infants were followed from birth until the diagnosis of UTI, emigration, death or two years of age. Cumulative incidences of UTIs were computed. Mortality was estimated using the Kaplan-Meier method.RESULTS: We identified 412 foetuses with parenchymal kidney anomalies out of 362 069 who underwent ultrasound scans and 277 were born alive. The overall risk of a UTI before the age of two years was 19%, and it was 14% among infants without prenatally diagnosed co-occurring urinary tract malformations. The corresponding risk in the 4074 controls was 1%. After two years, mortality was 2.2% in infants with prenatally diagnosed parenchymal kidney anomalies and 0.2% in the controls.CONCLUSION: Infants prenatally diagnosed with parenchymal kidney anomalies had a substantially increased risk of UTI. Awareness of this increased risk may facilitate earlier diagnosis of UTIs in this population.

The majority of bladder cancers (> 90%) are urothelial carcinomas arising in the urothelium of the bladder. Especially invasive and high-grade tumors are able to differentiate into various morpholo...

This review summarises the knowledge of recurrent diploid biparental hydatidiform mole, which is a rare genetic condition. Pathogenic variants in both alleles of NLRP7 or KHDC3L are associated with maternal imprinting defects and can cause the condition. Women with biallelic inactivation of NLRP7 can achieve a normal pregnancy by oocyte donation, and it is highly likely, that this applies to women with biallelic inactivation of KHDCL3 as well. Identifying the cause of the recurrent moles can prevent that couples waist time and possibly reduce medical expenses related to fertility treatment.