The proportion of endometrial tumours associated with Lynch syndrome (PETALS): A prospective cross-sectional study

Autoři: Neil A. J. Ryan aff001;  Raymond McMahon aff003;  Simon Tobi aff004;  Tristan Snowsill aff005;  Shona Esquibel aff003;  Andrew J. Wallace aff004;  Sancha Bunstone aff004;  Naomi Bowers aff004;  Ioana E. Mosneag aff001;  Sarah J. Kitson aff001;  Helena O’Flynn aff001;  Neal C. Ramchander aff001;  Vanitha N. Sivalingam aff001;  Ian M. Frayling aff006;  James Bolton aff003;  Rhona J. McVey aff003;  D. Gareth Evans aff002;  Emma J. Crosbie aff001
Působiště autorů: Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, St Mary's Hospital, Manchester, United Kingdom aff001;  Division of Evolution and Genomic Medicine, University of Manchester, St Mary's Hospital, Manchester, United Kingdom aff002;  Department of Pathology, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom aff003;  Manchester Centre for Genomic Medicine, North-West Genomics Laboratory Hub, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom aff004;  Health Economics Group, University of Exeter Medical School, University of Exeter, Exeter, Devon, United Kingdom aff005;  Inherited Tumour Syndromes Research Group, Institute of Cancer & Genetics, Cardiff University, Cardiff, United Kingdom aff006;  Department of Obstetrics and Gynaecology, St Mary’s Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom aff007
Vyšlo v časopise: The proportion of endometrial tumours associated with Lynch syndrome (PETALS): A prospective cross-sectional study. PLoS Med 17(9): e32767. doi:10.1371/journal.pmed.1003263
Kategorie: Research Article
doi: 10.1371/journal.pmed.1003263



Lynch syndrome (LS) predisposes to endometrial cancer (EC), colorectal cancer, and other cancers through inherited pathogenic variants affecting mismatch-repair (MMR) genes. Diagnosing LS in women with EC can reduce subsequent cancer mortality through colonoscopic surveillance and aspirin chemoprevention; it also enables cascade testing of relatives. A growing consensus supports LS screening in EC; however, the expected proportion of test positives, and optimal testing strategy is uncertain. Previous studies from insurance-based healthcare systems were limited by narrow selection criteria, failure to apply reference standard tests consistently, and poor conversion to definitive testing. The aim of this study was to establish the prevalence of LS and the diagnostic accuracy of LS testing strategies in an unselected EC population.

Methods and findings

This was a prospective cross-sectional study carried out at a large United Kingdom gynaecological cancer centre between October 2015 and January 2017. Women diagnosed with EC or atypical hyperplasia (AH) were offered LS testing. Tumours underwent MMR immunohistochemistry (IHC), microsatellite instability (MSI), and targeted MLH1-methylation testing. Women <50 years, with strong family histories and/or indicative tumour molecular features, underwent MMR germline sequencing. Somatic MMR sequencing was performed when indicative molecular features were unexplained by LS or MLH1-hypermethylation. The main outcome measures were the prevalence of LS in an unselected EC population and the diagnostic accuracy of clinical and tumour testing strategies for risk stratifying women with EC for MMR germline sequencing. In total, 500 women participated in the study; only 2 (<1%) declined. Germline sequencing was indicated and conducted for 136 and 135 women, respectively. A total of 16/500 women (3.2%, 95% CI 1.8% to 5.1%) had LS, and 11 more (2.2%) had MMR variants of uncertain significance. Restricting testing to age <50 years, indicative family history (revised Bethesda guidelines or Amsterdam II criteria) or endometrioid histology alone would have missed 9/16 (56%), 8/13 (62%) or 9/13 (69%), and 5/16 (31%) cases of LS, respectively. In total 132/500 tumours were MMR deficient by IHC of which 83/132 (63%) had MLH1-hypermethylation, and 16/49 (33%) of the remaining patients had LS (16/132 with MMR deficiency, 12%). MMR-IHC with targeted MLH1-methylation testing was more discriminatory for LS than MSI with targeted methylation testing, with 100% versus 56.3% (16/16 versus 9/16) sensitivity (p = 0.016) and equal 97.5% (468/484) specificity; 64% MSI-H and 73% MMR deficient tumours unexplained by LS or MLH1-hypermethylation had somatic MMR mutations. The main limitation of the study was failure to conduct MMR germline sequencing for the whole study population, which means that the sensitivity and specificity of tumour triage strategies for LS detection may be overestimated, although the risk of LS in women with no clinical or tumour predictors is expected to be extremely low.


In this study, we observed that age, family history, and histology are imprecise clinical correlates of LS-EC. IHC outperformed MSI for tumour triage and reliably identified both germline and somatic MMR mutations. The 3.2% proportion of LS-EC is similar to colorectal cancer, supporting unselected screening of EC for LS.

Klíčová slova:

Cancer detection and diagnosis – Cancers and neoplasms – Colorectal cancer – Immunohistochemistry techniques – Triage – Uterine cancer – Weight loss – Gynecologic cancers


1. Crosbie E, Morrison J. The emerging epidemic of endometrial cancer: Time to take action. Tovey D, editor. The Cochrane database of systematic reviews. 2014;12: ED000095. doi: 10.1002/14651858 ed000095

2. Win AK, Jenkins MA, Dowty JG, et al. Prevalence and Penetrance of Major Genes and Polygenes for Colorectal Cancer. Cancer Epidemiol Biomarkers Prev. 2017;26(3):404–412. doi: 10.1158/1055-9965.EPI-16-0693

3. Møller P, Seppälä T, Bernstein I, Holinski-Feder E, Sala P, Evans DG, et al. Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database. Gut. 2017;66: 464–472. doi: 10.1136/gutjnl-2015-309675

4. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA: A Cancer Journal for Clinicians. 2017;67: 7–30. doi: 10.3322/caac.21387

5. Lu KH, Dinh M, Kohlmann W, Watson P, Green J, Syngal S, et al. Gynecologic Cancer as a “Sentinel Cancer” for Women With Hereditary Nonpolyposis Colorectal Cancer Syndrome. Obstetrics and gynecology. 2005;105: 569–574. doi: 10.1097/

6. Boks DES, Trujillo AP, Voogd AC, Morreau H, Kenter GG, Vasen HFA. Survival analysis of endometrial carcinoma associated with hereditary nonpolyposis colorectal cancer. International journal of cancer. 2002;102: 198–200. doi: 10.1002/ijc.10667

7. Win AK, Lindor NM, Winship I, Tucker KM, Buchanan DD, Young JP, et al. Risks of colorectal and other cancers after endometrial cancer for women with Lynch syndrome. Journal of the National Cancer Institute. 2013;105: 274–279. doi: 10.1093/jnci/djs525

8. Hampel H, Frankel WL, Martin E, Arnold M, Khanduja K, Kuebler P, et al. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). The New England journal of medicine. 2005;352: 1851–1860. doi: 10.1056/nejmoa043146

9. Burn J, Gerdes A-M, Macrae F, Mecklin J-P, Moeslein G, Olschwang S, et al. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. The Lancet. 2011;378: 2081–2087. doi: 10.1016/s0140-6736(11)61049-0

10. Schmeler KM, Lynch HT, Chen L-M, Munsell MF, Soliman PT, Clark MB, et al. Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome. The New England journal of medicine. 2006;354: 261–269. doi: 10.1056/nejmoa052627

11. Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357: 409–413. doi: 10.1126/science.aan6733

12. Rabban JT, Calkins SM, Karnezis AN, Grenert JP, Blanco A, Crawford B, et al. Association of tumor morphology with mismatch-repair protein status in older endometrial cancer patients: implications for universal versus selective screening strategies for Lynch syndrome. The American Journal of Surgical Pathology. 2014;38: 793–800. doi: 10.1097/pas.0000000000000177

13. Ryan NAJ, Glaire MA, Blake D, Cabrera-Dandy M, Evans DG, Crosbie EJ. The proportion of endometrial cancers associated with Lynch syndrome: a systematic review of the literature and meta-analysis. Genet Med. 2019;21: 2167–2180. doi: 10.1038/s41436-019-0536-8

14. Molecular testing strategies for Lynch syndrome in people with colorectal cancer. National Institute for Health and Care Excellence, Guideline DG27 London, UK 2017; 1–37.

15. Crosbie EJ, Ryan NAJ, Bosse T, Frayling IM, Hampel H, Kitchener HC, et al. The Manchester International Consensus Group recommendations for the management of gynecological cancers in Lynch syndrome. Genetics in Medicine. 2019;21(10):2390–2400. doi: 10.1038/s41436-019-0489-y

16. Wu Y, Berends MJ, Mensink RG, Kempinga C, Sijmons RH, Zee AG van D, et al. Association of hereditary nonpolyposis colorectal cancer-related tumors displaying low microsatellite instability with MSH6 germline mutations. The American Journal of Human Genetics. 1999;65: 1291–1298. doi: 10.1086/302612

17. Prince AER. Prevention for those who can pay: insurance reimbursement of genetic-based preventive interventions in the liminal state between health and disease. Journal of law and the biosciences. 2015;2: 365–395. doi: 10.1093/jlb/lsv008

18. Kausmeyer DT, Lengerich EJ, Kluhsman BC, Morrone D, Harper GR, Baker MJ. A survey of patients’ experiences with the cancer genetic counseling process: recommendations for cancer genetics programs. Journal of genetic counseling. 2006;15: 409–431. doi: 10.1007/s10897-006-9039-2

19. Umar A, Boland CR, Terdiman JP, Syngal S, Chapelle A de la, Rüschoff J, et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. 2004. pp. 261–268. doi: 10.1093/jnci/djh034

20. Vasen HF, Watson P, Mecklin J-P, Lynch HT. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. 1999. pp. 1453–1456.

21. Kastrinos F, Uno H, Ukaegbu C, Alvero C, McFarland A, Yurgelun MB, et al. Development and Validation of the PREMM5 Model for Comprehensive Risk Assessment of Lynch Syndrome. Journal of clinical oncology. 2017; JCO2016696120. doi: 10.1200/jco.2016.69.6120

22. Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Annals of oncology. 2014;26: 259–271. doi: 10.1093/annonc/mdu450

23. Ryan N, Wall J, Crosbie EJ, Arends M, Bosse T, Arif S, et al. Lynch Syndrome Screening in Gynecological Cancers: Results of an International Survey with Recommendations for Uniform Reporting Terminology for Mismatch Repair Immunohistochemistry Results. Histopathology. 2019;28: his.13925. doi: 10.1111/his.13925

24. Newton K, Jorgensen NM, Wallace AJ, Buchanan DD, Lalloo F, McMahon RFT, et al. Tumour MLH1 promoter region methylation testing is an effective prescreen for Lynch Syndrome (HNPCC). Journal of medical genetics. 2014;51: jmedgenet-2014–102552-796. doi: 10.1136/jmedgenet-2014-102552

25. Arya R, Antonisamy B, Kumar S. Sample Size Estimation in Prevalence Studies. Indian J Pediatrics. 2012;79: 1482–1488. doi: 10.1007/s12098-012-0763-3

26. D’Agostino R, Belanger A. A Suggestion for Using Powerful and Informative Tests of Normality. Am Statistician. 1990;44: 316. doi: 10.2307/2684359

27. Batte BAL, Bruegl AS, Daniels MS, Ring KL, Dempsey KM, Djordjevic B, et al. Consequences of universal MSI/IHC in screening ENDOMETRIAL cancer patients for Lynch syndrome. Gynecologic oncology. 2014;134: 319–325. doi: 10.1016/j.ygyno.2014.06.009

28. Buchanan DD, Tan YY, Walsh MD, Clendenning M, Metcalf AM, Ferguson K, et al. Tumor Mismatch Repair Immunohistochemistry and DNA MLH1 Methylation Testing of Patients With Endometrial Cancer Diagnosed at Age Younger Than 60 Years Optimizes Triage for Population-Level Germline Mismatch Repair Gene Mutation Testing. Journal of Clinical Oncology. 2014;32: 90–+. doi: 10.1200/jco.2013.51.2129

29. Goodfellow PJ, Billingsley CC, Lankes HA, Ali S, Cohn DE, Broaddus RJ, et al. Combined Microsatellite Instability, MLH1 Methylation Analysis, and Immunohistochemistry for Lynch Syndrome Screening in Endometrial Cancers From GOG210: An NRG Oncology and Gynecologic Oncology Group Study. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2015;33: 4301–4308. doi: 10.1200/jco.2015.63.9518

30. Hampel H, Frankel WL, Martin E, Arnold M, Khanduja K, Kuebler P, et al. Screening for the Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer). The New England journal of medicine. 2005;352: 1851–1860.

31. Joehlin-Price AS, Perrino CM, Stephens J, Backes FJ, Goodfellow PJ, Cohn DE, et al. Mismatch repair protein expression in 1049 endometrial carcinomas, associations with body mass index, and other clinicopathologic variables. Gynecologic oncology. 2014;133: 43–47. doi: 10.1016/j.ygyno.2014.01.017

32. Mills AM, Liou S, Ford JM, Berek JS, Pai RK, Longacre TA. Lynch syndrome screening should be considered for all patients with newly diagnosed endometrial cancer. The American Journal of Surgical Pathology. 2014;38: 1501–1509. doi: 10.1097/pas.0000000000000321

33. Buecher B, Pauw A, Bazire L, Houdayer C, Fievet A, Moncoutier V, et al. Sporadic endometrial adenocarcinoma with MMR deficiency due to biallelic MSH2 somatic mutations. Fam Cancer. 2017;17: 281–285. doi: 10.1007/s10689-017-0032-8

34. Buchanan D, Clendenning M, Jayasekara H, Joo J, Wong E, Southey M, et al. Abstract 4266: Double somatic mutations as a cause of tumor mismatch repair-deficiency in population-based colorectal and endometrial cancer with Lynch-like syndrome. 2017; 4266–4266. doi: 10.1158/1538-7445.am2017-4266

35. Crosbie EJ, Evans DG. Response to Benusiglio et al. Genetics in Medicine 2020; doi: 10.1038/s41436-020-0820-7

36. Huang M, Djordjevic B, Yates MS, Urbauer D, Sun C, Burzawa J, et al. Molecular pathogenesis of endometrial cancers in patients with Lynch syndrome. Cancer. 2013;119: 3027–3033. doi: 10.1002/cncr.28152

37. Ryan NAJ, Davison NJ, Payne K, Cole A, Evans DG, Crosbie EJ. A Micro-Costing Study of Screening for Lynch Syndrome-Associated Pathogenic Variants in an Unselected Endometrial Cancer Population: Cheap as NGS Chips? Frontiers in Oncology. 2019;9: 1. doi: 10.3389/fonc.2019.00061

38. Snowsill TM, Ryan NAJ, Crosbie EJ, Frayling IM, Evans DG, Hyde CJ. Cost-effectiveness analysis of reflex testing for Lynch syndrome in women with endometrial cancer in the UK setting. PloS one. 2019;14: e0221419. doi: 10.1371/journal.pone.0221419

39. Snowsill TM, Ryan NAJ, Crosbie EJ. Cost-Effectiveness of the Manchester Approach to Identifying Lynch Syndrome in Women with Endometrial Cancer. J Clin Med. 2020;9(6):E1664. doi: 10.3390/jcm9061664

40. Stelloo E, Bosse T, Nout RA, MacKay HJ, Church DN, Nijman HW, et al. Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; a TransPORTEC initiative. Modern Pathology. 2015; doi: 10.1038/modpathol.2015.43

41. Cosgrove CM, Cohn DE, Hampel H, Frankel WL, Jones D, McElroy JP, et al. Epigenetic silencing of MLH1 in endometrial cancers is associated with larger tumor volume, increased rate of lymph node positivity and reduced recurrence-free survival. Gynecologic Oncology. 2017;146: 588–595. doi: 10.1016/j.ygyno.2017.07.003

42. Ryan NA, Donnelly L, Stocking K, Evans DG, Crosbie EJ. Feasibility of Gynaecologist Led Lynch Syndrome Testing in Women with Endometrial Cancer. J Clin Med. 2020;9(6):E1842. doi: 10.3390/jcm9061842

Článek vyšel v časopise

PLOS Medicine

2020 Číslo 9

Nejčtenější v tomto čísle

Tomuto tématu se dále věnují…


Zvyšte si kvalifikaci online z pohodlí domova

Nová éra v léčbě migrény
nový kurz
Autoři: MUDr. Eva Medová, MUDr. Tomáš Nežádal, Ph.D.

Imunitní trombocytopenie (ITP) u dospělých pacientů
Autoři: prof. MUDr. Tomáš Kozák, Ph.D., MBA

Pěnová skleroterapie
Autoři: MUDr. Marek Šlais

White paper - jak vidíme optimální péči o zubní náhrady
Autoři: MUDr. Jindřich Charvát, CSc.

Hemofilie - série kurzů

Všechny kurzy
Kurzy Doporučená témata Časopisy
Zapomenuté heslo

Nemáte účet?  Registrujte se

Zapomenuté heslo

Zadejte e-mailovou adresu se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.


Nemáte účet?  Registrujte se

VIRTUÁLNÍ ČEKÁRNA ČR Jste praktický lékař nebo pediatr? Zapojte se! Jste praktik nebo pediatr? Zapojte se!