Prevalence and Prognosis of Lynch Syndrome and Sporadic Mismatch Repair Deficiency in Endometrial Cancer
Cathalijne C B Post, Ellen Stelloo, Vincent T H B M Smit, Dina Ruano, Carli M Tops, Lisa Vermij, Tessa A Rutten, Ina M Jürgenliemk-Schulz, Ludy C H W Lutgens, Jan J Jobsen, Remi A Nout, Emma J Crosbie, Melanie E Powell, Linda Mileshkin, Alexandra Leary, Paul Bessette, Hein Putter, Stephanie M de Boer, Nanda Horeweg, Maartje Nielsen, Tom van Wezel, Tjalling Bosse, Carien L Creutzberg, Cathalijne C B Post, Ellen Stelloo, Vincent T H B M Smit, Dina Ruano, Carli M Tops, Lisa Vermij, Tessa A Rutten, Ina M Jürgenliemk-Schulz, Ludy C H W Lutgens, Jan J Jobsen, Remi A Nout, Emma J Crosbie, Melanie E Powell, Linda Mileshkin, Alexandra Leary, Paul Bessette, Hein Putter, Stephanie M de Boer, Nanda Horeweg, Maartje Nielsen, Tom van Wezel, Tjalling Bosse, Carien L Creutzberg
Abstract
Background: Standard screening of endometrial cancer (EC) for Lynch syndrome (LS) is gaining traction; however, the prognostic impact of an underlying hereditary etiology is unknown. We established the prevalence, prognosis, and subsequent primary cancer incidence of patients with LS-associated EC in relation to sporadic mismatch repair deficient (MMRd)-EC in the large combined Post Operative Radiation Therapy in Endometrial Carcinoma-1, -2, and -3 trial cohort.
Methods: After MMR-immunohistochemistry, MLH1-promoter methylation testing, and next-generation sequencing, tumors were classified into 3 groups according to the molecular cause of their MMRd-EC. Kaplan-Meier method, log-rank test, and Cox model were used for survival analysis. Competing risk analysis was used to estimate the subsequent cancer probability. All statistical tests were 2-sided.
Results: Among the 1336 ECs, 410 (30.7%) were MMRd. A total of 380 (92.7%) were fully triaged: 275 (72.4%) were MLH1-hypermethylated MMRd-ECs; 36 (9.5%) LS MMRd-ECs, and 69 (18.2%) MMRd-ECs due to other causes. Limiting screening of EC patients to 60 years or younger or to 70 years or younger would have resulted in missing 18 (50.0%) and 6 (16.7%) LS diagnoses, respectively. Five-year recurrence-free survival was 91.7% (95% confidence interval [CI] = 83.1% to 100%; hazard ratio = 0.45, 95% CI = 0.16 to 1.24, P = .12) for LS, 95.5% (95% CI = 90.7% to 100%; hazard ratio = 0.17, 95% CI = 0.05 to 0.55, P = .003) for "other" vs 78.6% (95% CI = 73.8% to 83.7%) for MLH1-hypermethylated MMRd-EC. The probability of subsequent LS-associated cancer at 10 years was 11.6% (95% CI = 0.0% to 24.7%), 1.5% (95% CI = 0.0% to 4.3%), and 7.0% (95% CI = 3.0% to 10.9%) within the LS, "other," and MLH1-hypermethylated MMRd-EC groups, respectively.
Conclusions: The LS prevalence in the Post Operative Radiation Therapy in Endometrial Carcinoma trial population was 2.8% and among MMRd-ECs was 9.5%. Patients with LS-associated ECs showed a trend towards better recurrence-free survival and higher risk for second cancers compared with patients with MLH1-hypermethylated MMRd-EC.
© The Author(s) 2021. Published by Oxford University Press.
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References
- Dominguez-Valentin M, Sampson JR, Seppala TT, et al.Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database. Genet Med. 2020;22(1):15–25.
- Ten Broeke SW, van der Klift HM, Tops CMJ, et al.Cancer risks for PMS2-associated Lynch syndrome. J Clin Oncol. 2018;36(29):2961–2968.
- Lu KH, Dinh M, Kohlmann W, et al.Gynecologic cancer as a “sentinel cancer” for women with hereditary nonpolyposis colorectal cancer syndrome. Obstet Gynecol. 2005;105(3):569–574.
- Win AK, Lindor NM, Winship I, et al.Risks of colorectal and other cancers after endometrial cancer for women with Lynch syndrome. J Natl Cancer Inst. 2013;105(4):274–279.
- Stelloo E, Jansen AML, Osse EM, et al.Practical guidance for mismatch repair-deficiency testing in endometrial cancer. Ann Oncol. 2016;28(1):96–102.
- Goodfellow PJ, Billingsley CC, Lankes HA, 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. J Clin Oncol. 2015;33(36):4301–4308.
- Geurts-Giele WR, Leenen CH, Dubbink HJ, et al.Somatic aberrations of mismatch repair genes as a cause of microsatellite-unstable cancers. J Pathol. 2014;234(4):548–559.
- Mensenkamp AR, Vogelaar IP, van Zelst-Stams WA, et al.Somatic mutations in MLH1 and MSH2 are a frequent cause of mismatch-repair deficiency in Lynch syndrome-like tumors. Gastroenterology. 2014;146(3):643–646. e8.
- Haraldsdottir S, Hampel H, Tomsic J, et al.Colon and endometrial cancers with mismatch repair deficiency can arise from somatic, rather than germline, mutations. Gastroenterology. 2014;147(6):1308–1316.e1.
- Cancer Genome Atlas Research Network. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67–73.
- Stelloo E, Nout RA, Osse EM, et al.Improved risk assessment by integrating molecular and clinicopathological factors in early-stage endometrial cancer-combined analysis of the PORTEC cohorts. Clin Cancer Res. 2016;22(16):4215–4224.
- Leon-Castillo A, de Boer SM, Powell ME, et al.; on behalf of the TransPORTEC consortium. Molecular classification of the PORTEC-3 trial for high-risk endometrial cancer: impact on prognosis and benefit from adjuvant therapy. J Clin Oncol. 2020;38(29):3388–3397.
- Ott PA, Bang YJ, Piha-Paul SA, et al.T-cell-inflamed gene-expression profile, programmed death ligand 1 expression, and tumor mutational burden predict efficacy in patients treated with pembrolizumab across 20 cancers: KEYNOTE-028. J Clin Oncol. 2019;37(4):318–327.
- Ramchander NC, Ryan NAJ, Walker TDJ, et al.Distinct immunological landscapes characterize inherited and sporadic mismatch repair deficient endometrial cancer. Front Immunol. 2019;10:3023.
- Ryan NAJ, McMahon R, Tobi S, et al.The proportion of endometrial tumours associated with Lynch syndrome (PETALS): a prospective cross-sectional study. PLoS Med. 2020;17(9):e1003263.
- Ryan NAJ, Glaire MA, Blake D, et al.The proportion of endometrial cancers associated with Lynch syndrome: a systematic review of the literature and meta-analysis. Genet Med. 2019;21(10):2167–2180.
- Hampel H, Pearlman R, de la Chapelle A, et al.Double somatic mismatch repair gene pathogenic variants as common as Lynch syndrome among endometrial cancer patients. Gynecol Oncol. 2021;160(1):161–168.
- Hampel H, Frankel WL, Martin E, et al.Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med. 2005;352(18):1851–1860.
- Nout RA, Poll-Franse LVvd, Lybeert MLM, et al.Long-term outcome and quality of life of patients with endometrial carcinoma treated with or without pelvic radiotherapy in the Post Operative Radiation Therapy in Endometrial Carcinoma 1 (PORTEC-1) trial. J Clin Oncol. 2011;29(13):1692–1700.
- Wortman BG, Creutzberg CL, Putter H, et al.Ten-year results of the PORTEC-2 trial for high-intermediate risk endometrial carcinoma: improving patient selection for adjuvant therapy. Br J Cancer. 2018;119(9):1067–1074.
- de Boer SM, Powell ME, Mileshkin L, et al.Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial. Lancet Oncol. 2019;20(9):1273–1285.
- Leon-Castillo A, Gilvazquez E, Nout R, et al.Clinicopathological and molecular characterisation of ‘multiple-classifier’ endometrial carcinomas. J Pathol. 2020;250(3):312–322.
- Deng G, Chen A, Hong J, et al.Methylation of CpG in a small region of the hMLH1 promoter invariably correlates with the absence of gene expression. Cancer Res. 1999;59(9):2029–2033.
- Jansen AML, Tops CMJ, Ruano D, et al.The complexity of screening PMS2 in DNA isolated from formalin-fixed paraffin-embedded material. Eur J Hum Genet. 2020;28(3):333–338.
- Cohen D, Hondelink LM, Solleveld-Westerink N, et al.Optimizing mutation and fusion detection in NSCLC by Sequential DNA and RNA sequencing. J Thorac Oncol. 2020;15(6):1000–1014.
- Daniel WW.Biostatistics: A Foundation for Analysis in the Health Sciences. 7th ed. New York: John Wiley & Sons; 1999.
- Pakish JB, Zhang Q, Chen Z, et al.Immune microenvironment in microsatellite-instable endometrial cancers: hereditary or sporadic origin matters. Clin Cancer Res. 2017;23(15):4473–4481.
- Liu GC, Liu RY, Yan JP, et al.The heterogeneity between lynch-associated and sporadic MMR deficiency in colorectal cancers. J Natl Cancer Inst. 2018;110(9):975–984.
- Haraldsdottir S, Hampel H, Wu C, et al.Patients with colorectal cancer associated with Lynch syndrome and MLH1 promoter hypermethylation have similar prognoses. Genet Med. 2016;18(9):863–868.
- Moller P, Seppala T, Bernstein I, et al.; Mallorca Group (). Incidence of and survival after subsequent cancers in carriers of pathogenic MMR variants with previous cancer: a report from the prospective Lynch syndrome database. Gut. 2017;66(9):1657–1664.
- Woolderink JM, De Bock GH, de Hullu JA, et al.Characteristics of Lynch syndrome associated ovarian cancer. Gynecol Oncol. 2018;150(2):324–330.
- Sjursen W, Haukanes BI, Grindedal EM, et al.Current clinical criteria for Lynch syndrome are not sensitive enough to identify MSH6 mutation carriers. J Med Genet. 2010;47(9):579–585.
- LaDuca H, Polley EC, Yussuf A, et al.A clinical guide to hereditary cancer panel testing: evaluation of gene-specific cancer associations and sensitivity of genetic testing criteria in a cohort of 165,000 high-risk patients. Genet Med. 2020;22(2):407–415.
- Ryan NAJ, Morris J, Green K, et al.Association of mismatch repair mutation with age at cancer onset in lynch syndrome: implications for stratified surveillance strategies. JAMA Oncol. 2017;3(12):1702–1706.
- Bonadona V, Bonaiti B, Olschwang S, et al.; French Cancer Genetics Network. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. Jama. 2011;305(22):2304–2310.
- 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):1664.
- Burn J, Sheth H, Elliott F, et al.Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study: a double-blind, randomised, placebo-controlled trial. Lancet. 2020;395(10240):1855–1863.
- Moller P, Seppala T, Bernstein I, et al.; Mallorca Group (). Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database. Gut. 2017;66(3):464–472.
- Horeweg N, de Bruyn M, Nout RA, et al.Prognostic integrated image-based immune and molecular profiling in early-stage endometrial cancer. Cancer Immunol Res. 2020;8(12):1508–1519.
- Buchanan DD, Clendenning M, Jayasekara H, et al.Double somatic mutations as a cause of tumor mismatch repair-deficiency in population-based colorectal and endometrial cancer with Lynch-like syndrome. Cancer Res. 2017;77(13 Suppl):Abstract nr 4266.
Source: PubMed