Family Support and Training Centers for Lynch Syndrome

Abstruse

Purpose

There are no internationally agreed upon clinical guidelines equally to which women with gynecological cancer would benefit from Lynch syndrome screening or how best to manage the risk of gynecological cancer in women with Lynch syndrome. The Manchester International Consensus Group was convened in April 2017 to address this unmet need. The aim of the Group was to develop clear and comprehensive clinical guidance regarding the management of the gynecological sequelae of Lynch syndrome based on existing evidence and practiced stance from medical professionals and patients.

Methods

Stakeholders from Europe and N America worked together over a two-day workshop to reach consensus on best practice.

Results

Guidance was developed in iv key areas: (1) whether women with gynecological cancer should be screened for Lynch syndrome and (ii) how this should be washed, (three) whether there was a role for gynecological surveillance in women at run a risk of Lynch syndrome, and (4) what preventive measures should exist recommended for women with Lynch syndrome to reduce their hazard of gynecological cancer.

Conclusion

This document provides comprehensive clinical guidance that tin can be referenced by both patients and clinicians so that women with Lynch syndrome tin can wait and receive advisable standards of care.

INTRODUCTION

Lynch syndrome is an autosomal dominantly inherited cancer syndrome including colorectal (CRC), endometrial (EC), and ovarian cancer (OC).¹ It is caused by pathogenic variants of the Dna mismatch repair (MMR) system genes MLH1, MSH2, MSH6, and PMS2, which prevent the correction of acquired errors during DNA synthesis. Gynecological cancers are often the sentinel Lynch syndrome event in women and have an excellent prognosis.² This provides an opportunity to diagnose women before farther oncological sequelae touch them or their family unit. Early diagnosis allows women to be enrolled in cancer surveillance programs and enables pour testing for at-risk relatives. There is well-documented survival reward for those with Lynch syndrome who are compliant with CRC surveillance.³ Farther, early identification of Lynch syndrome can enable the uptake of cancer prevention strategies, including aspirin and take chances-reducing surgery.^4,five A timely diagnosis may also have cancer prognosis and treatment implications. For example, MMR-deficient tumors are susceptible to allowed checkpoint inhibition through PD-i occludent.⁶ These considerations necessitate guidelines to direct the identification and care of individuals affected by Lynch syndrome. Although CRC clinical guidance is widely bachelor, the same is not true for gynecological cancers (eTable i). The lack of comprehensive guidance has led to a nonuniform arroyo to direction of women with Lynch syndrome globally. The aim of the Manchester International Consensus Meeting was to provide the first gynecological-specific guidance for the diagnosis, prevention, and surveillance of Lynch syndrome–associated gynecological malignancies.

The Manchester International Consensus Meeting 2017 for the direction of gynecological cancers in Lynch syndrome

The coming together was held on 24–25 Apr 2017. Fifty stakeholders attended from across Europe and N America, including patients (n = 2), patient back up grouping representatives (n = 2), gynecological oncology surgeons (n = 12), gynecology nurse specialists (due north = five), clinical geneticists (due north = x), genetic counselors (n = 2), medical oncologists (n = 1), colorectal surgeons (n = ii), gastroenterologists (n = ane), histopathologists (n = ten), genetic pathologists (northward = one), health economists (n = 1), and epidemiologists (due north = i).

Preparation for the meeting included a systematic review of the literature to identify key papers to inform discussion. A systematic review with meta-analysis was performed to provide a robust estimate of the prevalence of Lynch syndrome in women with endometrial cancer, using the methodology described in our published protocol.^seven The body of literature identified through this search also enabled informed discussion regarding the comparable utility of MMR immunohistochemistry (IHC), microsatellite instability (MSI), MLH1 methylation testing, and direct germline sequencing for pathological variants of the MMR genes by next-generation sequencing (NGS) for Lynch syndrome testing (eTable ii). An identical search was conducted in parallel, substituting the Medical Discipline Heading (MeSH) term "endometrial" with "ovarian." Further searches to identify bear witness for gamble-reducing interventions and the clinical effectiveness of gynecological surveillance in Lynch syndrome (eTable three) were conducted. Key studies were identified by abstract review and graded according to the category of bear witness they achieved (Table 1). Potential bias was assessed past two reviewers, and discrepancies settled by a third, every bit previously described;^vii those studies with a high likelihood of bias were excluded. Papers identified through these searches were grouped according to the 4 clinical questions detailed in this document, and sent to the practiced assigned equally question pb before the meeting.

Tabular array 1 Grading of evidence

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At the coming together, solar day i consisted of 11 lectures covering the prevalence of Lynch syndrome and its associated cancer risks, the patient's perspective, the process of developing clinical guidance, lessons learned from the colorectal community, current diagnostic technologies, and methods of gynecological surveillance. These lectures provided a critical review of the studies identified through the systematic searches described to a higher place and had the purpose of providing the consensus group with up-to-appointment evidence on which to base its recommendations. Participation was encouraged when assessing the quality of the bachelor evidence during the lectures.

The 2nd day rotated delegates through working groups focused on screening for Lynch syndrome in gynecological cancer, diagnostic methods for such screening, the function of run a risk-reducing surgery and gynecological surveillance. Each group benefited from multidisciplinary health-care professional and lay representation. Topics were debated until an agreed statement could be reached. The precise wording of these statements was decided through careful deliberation until unanimous agreement was confirmed past a prove of hands. One time all delegates had rotated through the 4 focus groups, a concluding forum enabled group chairpersons to feed dorsum where consensus had been reached. A farther show of easily was required for individual statements to achieve this consensus certificate. The document was written and edited by the skilful writing group and circulated through all authors until each recommendation was ratified. The levels of recommendation are shown in Table ii.

Table 2 Levels of recommendation

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Question 1: Should women with gynecological cancer be screened for Lynch syndrome? (Box 1)

One in 279 of the general population carry pathogenic variants in ane of the MMR genes, of which the vast majority are unaware.^eight Approximately i in 30 CRCs are Lynch syndrome associated.⁹ The proportion of ECs that are Lynch syndrome associated is around ane  in 30, but estimates are based on small studies hampered by methodological limitations. The largest of these (n > 300) are shown in eTable 2.

Current UK guidance from the National Institute for Health and Care Excellence (NICE) supports the universal screening of CRC for Lynch syndrome.¹⁰ Given similar rates of Lynch syndrome in EC and CRC, and the potential to reduce mortality through colorectal surveillance and cascade testing of relatives, the Consensus Group strongly recommends that women with EC should also exist screened for Lynch syndrome.

Restricting screening to those with a higher pretest probability of Lynch syndrome (e.g., younger patients) is likely to reduce the resource burden, although at the price of missing more Lynch syndrome cases. I study establish only 25% of IHC MMR-scarce tumors were in women <50 years.¹¹ Hampel et al. establish xx% of proven Lynch cases presented >60 years.¹² While older patients may accept a lower risk of Lynch syndrome, and less potential to benefit from risk-reducing measures, they may as well have younger relatives who could benefit from the identification of family pathogenic variants. Farther, targeted screening has its own challenges, particularly that screening is not conducted despite existence indicated.

Amsterdam-Ii and Bethesda criteria are family unit history–based prediction tools designed to target Lynch syndrome screening in CRC. Extrapolation of these tools to EC has shown specificity of 61% and 49% for Amsterdam-II and Bethesda criteria, respectively.^xiii Newer prediction tools, MMRpredict_one,26, MMRpro, and PREMM_v, have increased sensitivity and specificity.^{fourteen,15,16} Yet, they rely on accurate family cocky-reported history being recorded by the clinician. A quality-controlled family history is time consuming, outside the scope of many busy clinical settings, and does non encounter the specificity or sensitivity needed for a first-line test to identify MMR pathogenic variant carriers,¹⁷ however, in the absence of tumor textile, such prediction models can be useful to guide germline testing.

Restricting Lynch syndrome screening to tumors with certain pathological phenotypes, for example endometrioid or clear jail cell morphology, tumors of the lower uterine segment, and those with heavy infiltrates of tumor-associated T-lymphocytes, has not been tested prospectively as a means to directly Lynch syndrome screening.¹⁸ A depression torso mass index (BMI) increases the likelihood of Lynch syndrome being the underlying cause in EC.¹⁹ In CRC, restricting screening for Lynch syndrome to sure loftier-risk pathological features is not sufficiently sensitive.^twenty

With regard to Lynch syndrome–associated OC, there is minimal evidence to guide clinical intendance. A single-center study found 21% of nonserous epithelial OC to be MMR deficient by IHC.²¹ Lynch syndrome–associated OC is predominantly endometrioid, presenting at an before age and stage than sporadic OC, with improved survival rates.²² Lynch syndrome is plant in vii% of women with synchronous EC and OC.²³ Many professional organizations now recommend testing all epithelial OC patients for BRCA1/2 pathological variants.^24,25 Given the similar cumulative gamble of OC in Lynch syndrome, testing premenopausal women with epithelial OC for both BRCA1/ii and Lynch syndrome is appropriate. This is even more persuasive in an era of panel gene testing where there is no additional cost to add more genes.

At that place is no bear witness to support a link between Lynch syndrome and other gynecological cancers, neither myometrial, nor squamous cancers of the vulva, vagina, or cervix, in which the most important etiological driver is persistent infection with high-risk human papillomavirus (HPV). Thus screening for Lynch syndrome in women affected by cancers of the lower genital tract is not recommended, with the exception of (HPV-contained) endocervical adenocarcinomas, given the difficulty of distinguishing them from lower uterine segment endometrial cancers.²⁶

Question two: How should women with gynecological cancer be screened for Lynch syndrome? (Box ii)

Screening women with gynecological cancer for Lynch syndrome is a multidisciplinary responsibility. Wellness-care systems require robust procedures for quality-bodacious tumor testing and communication of results. Tissue analysis to triage women for Lynch syndrome testing highlights the potential of having Lynch syndrome rather than diagnosing it. Furthermore, identifying MMR-defective status provides important  prognostic information and can straight, for case, immunotherapy treatment strategies.²⁷ Thus, MMR IHC/MSI testing should form part of standard patient intendance and prior consent is not required. When germline testing is recommended, informed consent should be sought and patients are entitled to receive specialist counseling.

Four options were explored for the initial screening of tumor samples for Lynch syndrome: MSI, IHC with methylation testing, MSI with IHC and/or methylation testing, and germline NGS (Fig. 1). NGS is the golden standard for identifying somatic pathogenic variants in MMR genes; there remain challenges in working with formalin-fixed methane series-embedded tumor samples, simply performance of NGS on such samples is improving.²⁸ It should exist noted that exon panel NGS will non identify MLH1 silencing due to methylation.²⁹ Sequencing of PMS2 is problematic due to the presence of numerous pseudogenes.³⁰ NGS is expensive and many hospitals have limited access to it. Thus most studies and current clinical exercise apply a screening triage with the use of IHC and/or MSI before germline NGS and big rearrangement testing (eTable two).

Fig. ane

Proposed diagnostic schema of endometrial cancer screening for Lynch syndrome. Consent should exist sought from the patient before germline testing. ^#We recognize the possibility of using a two poly peptide screen using PMS2 and MSH6 initially, however the evidence base is not definitive. *If only microsatellite testing used without immunohistochemistry then all those found to be MSI-H should either be further triaged with methylation testing or undergo direct germline analysis. IHC immunohistochemistry, MSI-H microsatellite instability loftier, MSI-L microsatellite instability low, MMR mismatch repair, MSS microsatellite stable.

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In that location is good cyclopedia between MSI and IHC analysis.^31,32 Where there is discordance this may, for example, reflect MSI secondary to POLE pathogenic variants, heterogeneity of MMR loss within the tumor, or microsatellite stable (MSS) MSH6 or PMS2 loss.^32,33 The beginning is important considering POLE pathogenic variants accept prognostic implications; the last because MSI triage may miss Lynch syndrome cases due to MSH6 pathogenic variants.³⁴ For IHC, sensitivity and specificity range between 86–100% and 48–67%, respectively.^19,35,36 For MSI, sensitivity and specificity are similar at 77–100% and 38–81% (refs. ^19,35,36). Where there is a strong family history and where EC/OC presents under the age of fifty years with normal IHC and/or MSI, at that place is still an statement for definitive NGS.³⁷ Investigations should be performed in an agreed stepwise and protocol-driven fashion.^ten

IHC analysis has the reward of identifying the specific protein that has been lost, thus indicating the potentially mutated gene. Furthermore, some pathogenic variants in MSH6 have been shown to associate with tumor MSS.³⁸ The identification of MLH1 protein loss enables methylation analysis, which tin exclude women with somatic MLH1 loss from unnecessary NGS.³⁸ Methylation-specific polymerase concatenation reaction (PCR) is simple and cost-effective, still validation work has been near exclusively in the CRC population.^39,40 Methylation-specific PCR is not widely available, with only specialist laboratories offering this test. The molecular mechanism for the strong association of BRAF variant with CRC harboring somatic MLH1 hypermethylation is incompletely understood simply appears to be tissue/tumor-specific; unlike algorithms in use for CRC, BRAF immunohistochemistry or sequencing cannot be used every bit a proxy for somatic MLH1 hypermethylation in gynecological cancers, equally oncogenic BRAF variants occur and so rarely in these.⁴¹ Therefore, moving direct to germline NGS on the basis of IHC MLH1 loss is also an option, although an expensive 1.

The MMR proteins form heterodimers, with MLH1 pairing with PMS2 and MSH2 pairing with MSH6. These proteins are unstable in their unpaired state, and while MLH1 and MSH2 tin class stable heterodimers with other proteins, PMS2 and MSH6 tin can but dimerize with MLH1 and MSH2 respectively. Information technology has therefore been proposed that IHC analysis tin be performed past testing but ii of the 4 MMR proteins, PMS2 and MSH6, because loss of MLH1 and MSH2 leads to loss of their heterodimer partner (PMS2 and MSH6 respectively).⁴² However, the accuracy of this arrangement is unproven in gynecological cancers.⁴³ The estimation of stained slides requires an experienced senior clinician, and IHC more frequently needs to be repeated due to uninterpretable staining patterns in EC compared with CRC.⁴⁴ Furthermore, the upshot of neoadjuvant treatment on tissue analysis for MMR dysfunction has not been defined in EC.⁴⁵ A reporting proforma is shown in eFigure one. The standing use of tightly regulated and high quality IHC protocols should be assured by laboratory participation in a national or international external quality assurance scheme that covers both IHC methods and interpretation.

A testing strategy using IHC and MLH1 methylation is likely to exist more cost-effective than strategies using MSI testing (because MLH1 methylation must be conducted on all MSI tumors) and strategies non using MLH1 methylation (because methylation testing is cheaper than NGS and excludes a meaning proportion of sporadic cases). Documented IHC results tin besides assist translate NGS results.

Question 3: Is there a role for gynecological surveillance in women at risk of Lynch syndrome? (Box 3)

Many female MMR pathogenic variant carriers opt to undergo gynecological surveillance in lieu of, or whilst awaiting, risk-reducing surgery. The aim of surveillance is to detect premalignant illness or early on phase cancer, with the ultimate aim of improving morbidity and mortality from the malignant gynecological  sequelae of Lynch syndrome.

The data relating to gynecological surveillance in Lynch syndrome are generally of low quality, with single-center, retrospective studies predominating (eTable 3). Some studies show benefit and others show no benefit of gynecological surveillance in the early detection of endometrial cancer.⁴⁶ Survival data are limited and mortality data are defective. However, both preinvasive (atypical hyperplasia) and stage one affliction accept been diagnosed in asymptomatic women undergoing EC surveillance (eTable 3). 1 written report institute that women who were not under surveillance were more likely to die from their EC than those in surveillance, although this did not achieve statistical significance. In addition, three cancers were "missed" in the surveillance group.⁴⁷ Some other found a high proportion of interval ECs in women undergoing surveillance (6/13) (ref. ⁴⁸). It is of import to note that EC survival rates in women with Lynch syndrome are extremely good, with 10-year survival of 98% in those undergoing surveillance;³ comparative data for LS-EC in women not undergoing surveillance are not available.

The Consensus Group best-selling that ultrasonography, biopsy, and hysteroscopy could detect EC and premalignant pathological abnormalities. Even so, there is no testify that this leads to a stage shift or improved survival in women with Lynch syndrome–associated EC. Furthermore, many patients identified during gynecological surveillance are symptomatic of endometrial pathology (eTable three). Patient representatives in the Group were potent advocates of gynecological surveillance every bit a ways of regular review and reassurance. Therefore the Consensus Group supported a discussion with individual women as to whether they would wish an annual appointment to undergo detailed symptom inquiry, a rediscussion regarding the option for risk-reducing hysterectomy and bilateral salpingo-oophorectomy and the timing of this, as well as a holistic review of a woman'due south contraceptive and fertility needs, and communication regarding cancer run a risk-reducing behaviors. Women with crimson flag symptoms of gynecological cancer, including aberrant bleeding, weight loss, bloating, change in bowel addiction, recurrent urinary symptoms, and abdominal pain should undergo targeted investigations for gynecological pathology.^49,50 The Consensus Group was strongly supportive of the need for rapid admission facilities being bachelor for women with Lynch syndrome and that suspicious symptoms or signs of malignant gynecological disease should not await routine review in dispensary.

Regarding OC, at that place is currently insufficient prove that surveillance is of benefit.⁴⁶ Large randomized controlled trials (RCTs) of general population screening for OC through ultrasound scanning (USS) or multimodal screening (CA125 analyzed by an algorithm as a first-line examination, followed by reflex USS) have so far failed to demonstrate a statistically significant mortality benefit.^51,52 However, screening in high-risk BRCA1/two pathogenic variant carriers with 4-monthly CA125 analyzed by an algorithm and reflex USS does lead to a stage shift in the disease detected; whether this translates into mortality benefit has yet to be established.⁵³ Extrapolation of OC screening enquiry to the LS population is limited by the known biological differences between LS-associated and sporadic/BRCA1/ii-associated OC.⁵⁴

Whilst there is true equipoise in the literature, high quality research regarding the value of gynecological surveillance in Lynch syndrome could be performed. The options for written report design could include a cluster RCT or a centralized repository for routine data collection from local surveillance programs. Studies should be adequately powered to determine whether surveillance picks up before illness with benefits for patient outcomes, also as assessing its psychological impact and toll-effectiveness.

Question iv: What preventive measures should be recommended in Lynch syndrome to reduce gynecological cancer adventure? (Box four)

Chance-reducing total hysterectomy and bilateral salpingo-oophorectomy prevents gynecological cancer in women at risk of Lynch syndrome.⁵ Surgery is not without risk and potential long-term side effects, notwithstanding, and preoperative counseling is of import. The laparoscopic arroyo is associated with less postoperative pain, quicker recovery, and improved brusque-term quality of life, making it the preferred approach in simple cases, where resources permit.⁵⁵ Surgical menopause follows risk-reducing  oophorectomy in premenopausal women. This is associated with vasomotor symptoms, urogenital dryness and atrophy, reduced sexual office, emotional lability, and cerebral reject, as well every bit increased risks of osteoporosis, cardiovascular disease and CRC.⁵⁶ Thus prescription of estrogen-only hormone replacement therapy (HRT) until at least natural menopause age (~ 51 years) is strongly recommended to preclude these sequelae. At that place is some bear witness that prior hysterectomy may be associated with greater discomfort during intubation at colonoscopy, and lower cecal intubation rates.⁵⁷ Thus it has been suggested that women undergoing colonoscopic surveillance post-obit hysterectomy undergo specific preprocedure counseling and measures to reduce procedural discomfort.⁵⁸

In that location are skilful quality prospective data outlining the cancer risk associated with specific pathogenic variants and the historic period at which these occur.⁵⁹ A woman'southward personal risk should be used to provide individualized counseling regarding the need for risk-reducing surgery and the optimal timing of this. According to the Prospective Lynch Syndrome Database (PLSD; http://www.lscarisk.org), the lifetime risk of EC in women with MSH2, MLH1, and MSH6 pathogenic variants is 57%, 43%, and 46%, respectively. The cumulative risk of EC at 40 years of age is 2%, 3%, and 0%, respectively. Lifetime risk for OC in women with MSH2, MLH1, and MSH6 pathogenic variants is 17%, x%, and 13%, respectively. The cumulative chance of OC at xl years of age is 4%, 3%, and four%, respectively.⁵⁹ Thus MSH6 pathogenic variant carriers may consider undergoing risk-reducing surgery after the age of 40 years, while women with pathogenic variants in either MSH2 or MLH1 may consider risk-reducing surgery at effectually 35 years of historic period bold their childbearing is complete.⁶⁰ Take chances-reducing surgery at 40 years of age is a toll-effective strategy.⁶¹ The take a chance of gynecological cancer in PMS2 carriers is low; however, patient representatives with PMS2 pathogenic variants felt strongly that they should be offered risk-reducing surgery alongside other women with Lynch syndrome.⁵⁹

In that location is express evidence as to how reproductive and lifestyle factors impact on gynecological cancer gamble in Lynch syndrome. One study suggested that hormonal influences practice modulate cancer risk, however. In addition to combined oral contraceptives, progestin-merely methods (pills, injectable, implants, or intrauterine organization [IUS]) may protect, simply at that place is little supporting bear witness.⁶² The POET trial looked to explore the use of the IUS for the prevention of EC in women with Lynch syndrome. This trial closed due to poor recruitment without results. Some other study showed an antiproliferative upshot of exogenous progesterone on the endometrium of women with Lynch syndrome, suggesting that these agents could be useful for the chemoprevention of EC.⁶³ Exogenous hormones may also protect against CRC.⁶⁴

Aspirin reduces incidence of Lynch syndrome–associated EC and other cancers.⁶⁵ The main toxic effects of aspirin are gastrointestinal. Major gastrointestinal bleeds (those requiring transfusion) are increased in aspirin-takers with an odds ratio (OR) of 1.v–2 (ref. ⁶⁶). Even so, the absolute rates are small and mainly touch on older individuals. Considering gastrointestinal toxicity is dose dependent, the optimal dose for cancer risk reduction is being explored through the CaPP3 study of 100 mg, 300 mg, or 600 mg/24-hour interval (http://www.capp3.org/).

Smoking, booze employ, and increased BMI may increase the risk of CRC in individuals with Lynch syndrome; however, the impact of lifestyle factors on gynecological cancer adventure is unknown. Aspirin may "normalize" EC chance in obese women with Lynch syndrome.⁶⁷ Despite lack of robust evidence, women are brash to swallow a healthy diet, avoid obesity, take regular exercise, avert smoking, only drink alcohol in moderation, and avoid known carcinogens as office of maintaining healthy lifestyles.

Discussion

This is the first gynecology-focused internationally agreed-upon clinical guideline for the care of women with or at risk of Lynch syndrome.

Our key recommendations are as follows: (1) all stakeholders should be informed of the affect of Lynch syndrome on gynecological cancer take a chance; (two) systems should exist established to screen for Lynch syndrome in women with endometrial cancer; (iii) women at risk of Lynch syndrome should exist offered take a chance-reducing hysterectomy with bilateral salpingo-oophorectomy, at a time appropriate to them; and (4) further inquiry is required to establish the value of gynecological cancer surveillance in Lynch syndrome and to explore other key areas where there is currently scarce evidence to define advisable standards of care. Screening for Lynch syndrome is only recommended if effective management exists to benefit those who screen positive.

The strength of our guidance comes from the wide and expert medical specialty representation that forms our Consensus Group. All relevant stakeholders, including patients and patient advocates, were given equal voice during discussion. Despite different perspectives and expertise, we were able to achieve a consensus view on topics of international importance. Past focusing solely on the gynecological aspects of Lynch syndrome, we were able to provide the most comprehensive guidelines yet for the empowerment of both clinicians and patients. This was all achieved without corporate sponsorship.

The major limitation of our work is the lack of robust bear witness on which to base our discussions and recommendations. It is hoped that these guidelines will provide the much-needed impetus to inspire researchers and funders to undertake and commission loftier quality enquiry to fill these gaps in our understanding.

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Acknowledgements

We would similar to acknowledge Laura Gordon, Christine Dark-brown, and Angela Cooke from the University of Manchester, UK for the administrative support they provided for the Consensus coming together. E.J.C. was supported through a National Constitute for Health Enquiry (NIHR) Clinician Scientist Award (NIHR-CS-012–009), N.A.J.R. was supported through a Medical Research Council (MRC) Doctoral Research Fellowship (MR/M018431/ane), and D.Yard.E is an NIHR Senior Investigator (NF-SI- 0513–10076). E.J.C. and D.G.E are supported by the NIHR Manchester Biomedical Research Centre (IS-BRC-1215–20007). Researchers at University Higher London are supported by the NIHR Biomedical Research Heart at Academy College London Hospitals NHS Foundation Trust and Academy College London. This article presents independent enquiry funded by the NIHR and MRC. The views expressed are those of the authors and non necessarily those of the MRC, NHS, NIHR, or the Department of Wellness.

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Affiliations

1. Division of Cancer Sciences, Faculty of Biological science, Medicine and Wellness, University of Manchester, St Mary's Infirmary, Manchester, United kingdom

   Emma J. Crosbie PhD, Neil A. J. Ryan MBChB, Henry C. Kitchener Medico, Sarah J. Kitson PhD & Mourad W. Seif Doctor

2. Directorate of Gynaecology, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Scientific discipline Centre, Manchester, Britain

   Emma J. Crosbie PhD & Mourad W. Seif MD

3. Prevention Early Detection Theme, NIHR Biomedical Research Centre, The Christie NHS Foundation Trust, Manchester, UK

   Emma J. Crosbie PhD & D. Gareth Evans MD

4. Division of Evolution and Genomic Medicine, University of Manchester, St Mary'due south Hospital, Manchester, United kingdom

   Neil A. J. Ryan MBChB & D. Gareth Evans Medico

5. Sectionalisation of Pathology & Centre for Comparative Pathology, Cancer Enquiry UK Edinburgh Centre, Establish of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, United kingdom of great britain and northern ireland

   Mark J. Arends PhD

6. Pathology Section, Leiden University Medical Heart, Leiden, holland

   Tjalling Bosse PhD

7. Establish of Genetic Medicine, Newcastle University, Newcastle upon Tyne, Uk

   John Burn MD

8. Patient Representative, Cambridge, U.k.

   Joanna Yard. Cornes BSc, Joanna M. Cornes & Paula Gollop

9. Department of Gynaecological Oncology, Addenbrookes Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, U.k.

   Robin Crawford Doc

10. Faculty of Medicine, University of Southampton, University Hospital Southampton, Southampton, United kingdom

    Diana Eccles Doctor

11. Institute of Cancer and Genetics, Cardiff University, Cardiff, United kingdom

    Ian M. Frayling PhD

12. Department of Surgery and Cancer, Imperial College, London, UK

    Sadaf Ghaem-Maghami PhD

13. Division of Homo Genetics, Department of Internal Medicine, The Ohio Country Academy Comprehensive Cancer Heart, Columbus, OH, USA

    Heather Hampel MS

14. Knuckles Cancer Found, Duke University Medical Center, Durham, NC, The states

    Noah D. Kauff MD

15. Barts Cancer Institute, Queen Mary University of London, London, UK

    Ranjit Manchanda PhD, Ranjit Manchanda & Naveena Singh

16. Department of Histopathology, Manchester University NHS Foundation Trust, Manchester, UK

    Raymond F. T. McMahon Doctor

17. Chelsea & Westminster Hospital NHS Trust, London, UK

    Kevin J. Monahan PhD & Kevin J. Monahan

18. MRC Clinical Trials Unit of measurement at UCL, Institute of Clinical Trials and Methodology, London, UK

    Usha Menon Doctor

19. Department of Tumor Biological science, Institute of Cancer Research, The Norwegian Radium Hospital, part of Oslo Academy Infirmary, Oslo, Norway

    Pål Møller PhD

20. Enquiry Group Inherited Cancer, Department of Medical Genetics, Oslo Academy Hospital, Oslo, Kingdom of norway

    Pål Møller PhD

21. Center for Hereditary Tumors, Helios University Infirmary Wuppertal, University of Witten-, Herdecke, Germany

    Pål Møller PhD & Gabriela Möslein MD

22. Department of Women'due south Cancer, UCL EGA Institute for Women'southward Health, Academy College London, London, UK

    Adam Rosenthal PhD

23. School of Cancer and Pharmaceutical Sciences, Kings College London, London, UK

    Peter Sasieni PhD

24. Department of Cellular Pathology, Barts Health NHS Trust, London, UK

    Naveena Singh Doctor

25. Lynch Syndrome Uk, Linden House, 9/11 Chief Street, Ingleton, Carnforth, UK

    Pauline Skarrott MBChB

26. Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, U.k.

    Tristan M. Snowsill PhD

27. Health Economic science Group, University of Exeter, Exeter, Great britain

    Tristan Chiliad. Snowsill PhD

28. Sectionalisation of Cancer, Medical Inquiry Institute, Ninewells Hospital and Medical School, Dundee, UK

    Robert Steele MD

29. Bookish Laboratory of Medical Genetics, University of Cambridge, Cambridge, Uk

    Marc Tischkowitz MD

30. National Institute for Health Research Cambridge Biomedical Research Eye, Cambridge, UK

    Marc Tischkowitz Medico

31. Manchester Centre for Genomic Medicine, Manchester Academy NHS Foundation Trust, Manchester Academic Health Scientific discipline Eye, Manchester, Britain

    D. Gareth Evans MD

32. Hospital of Navarra, Navarra, Espana

    Affections Alonso Sanchez

33. University of Edinburgh, Edinburgh, UK

    Marker J. Arends

34. Manchester University NHS Foundation Trust, Manchester, U.k.

    James Bolton, Karen Donnelly, Fiona Lalloo, Anne Lowry, Raymond F. T. McMahon, Rhona J. McVey, Mourad West. Seif, Andrew Wallace, Luciya Whyte, Godfrey Wilson & Jo Wilson

35. Leiden Academy Medical Center, Leiden, The Netherlands

    Tjalling Bosse

36. Newcastle Academy, Newcastle upon Tyne, UK

    John Burn

37. Academy of Manchester, Manchester, UK

    Emma J. Crosbie, Richard J. Edmondson, D. Gareth Evans, Henry C. Kitchener, Sarah J. Kitson & Neil A. J. Ryan

38. University of Oxford, Oxford, UK

    David Church building

39. Cambridge University Hospitals NHS Foundation Trust, Cambridge, United kingdom

    Robin Crawford

40. Academy of Southampton, Southampton, UK

    Diana Eccles

41. Cardiff Academy, Cardiff, Uk

    Ian M. Frayling

42. Majestic College London, London, U.k.

    Sadaf Ghaem-Maghami

43. Academy of Plymouth, Plymouth, UK

    Selina Goodman

44. The Ohio Land University, Columbus, USA

    Heather Hampel

45. St Georges, University of London, London, Uk

    Shirley Hodgson

46. Duke University, Durham, USA

    Noah D. Kauff

47. University College London Hospital, London, UK

    Usha Menon, Adam Rosenthal & Nafisa Wilkinson

48. Eve Entreatment, London, United kingdom

    Tracie Miles

49. University of Witten-Herdecke, Witten, Frg

    Gabriela Moeslein

50. Oslo Academy Hospital, Oslo, Kingdom of norway

    Pal Moller & Astrid Stormoken

51. Kings College London, London, UK

    Peter Sasieni

52. Lynch Syndrome UK, Carnforth, UK

    Pauline Skarrott

53. Academy of Exeter, Exeter, UK

    Tristan Yard. Snowsill

54. Dundee University, Dundee, UK

    Robert Steele

55. Lancashire Teaching Hospitals NHS Foundation Trust, Lancashire, UK

    Helen Stringfellow & Nick Wood

56. University of Cambridge, Cambridge, UK

    Marc Tischkowitz

Consortia

Manchester International Consensus Grouping

• Affections Alonso Sanchez
• , Mark J. Arends
• , James Bolton
• , Tjalling Bosse
• , John Burn
• , Emma J. Crosbie
• , David Church building
• , Joanna Yard. Cornes
• , Robin Crawford
• , Karen Donnelly
• , Diana Eccles
• , Richard J. Edmondson
• , D. Gareth Evans
• , Ian Yard. Frayling
• , Sadaf Ghaem-Maghami
• , Paula Gollop
• , Selina Goodman
• , Heather Hampel
• , Shirley Hodgson
• , Noah D. Kauff
• , Henry C. Kitchener
• , Sarah J. Kitson
• , Fiona Lalloo
• , Anne Lowry
• , Ranjit Manchanda
• , Raymond F. T. McMahon
• , Rhona J. McVey
• , Usha Menon
• , Tracie Miles
• , Gabriela Moeslein
• , Pal Moller
• , Kevin J. Monahan
• , Adam Rosenthal
• , Neil A. J. Ryan
• , Peter Sasieni
• , Mourad W. Seif
• , Pauline Skarrott
• , Naveena Singh
• , Tristan Thou. Snowsill
• , Robert Steele
• , Astrid Stormoken
• , Helen Stringfellow
• , Marc Tischkowitz
• , Andrew Wallace
• , Luciya Whyte
• , Nafisa Wilkinson
• , Godfrey Wilson
• , Jo Wilson
•  & Nick Wood

Corresponding author

Correspondence to Emma J. Crosbie PhD.

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The authors declare no conflicts of interest.

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The members of the Manchester International Consensus Grouping are listed in the Acknowledgements

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Crosbie, Due east.J., Ryan, Northward.A.J., Arends, M.J. et al. The Manchester International Consensus Group recommendations for the direction of gynecological cancers in Lynch syndrome. Genet Med 21, 2390–2400 (2019). https://doi.org/x.1038/s41436-019-0489-y

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• Received: 22 November 2018

• Accustomed: 06 March 2019

• Published: 28 March 2019

• Issue Date: Oct 2019

• DOI : https://doi.org/10.1038/s41436-019-0489-y

Keywords

• Lynch syndrome
• endometrial cancer
• screening
• surveillance
• guidance

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Source: https://www.nature.com/articles/s41436-019-0489-y

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