OBJECTIVES: To determine the relationship between mismatch repair (MMR) classification and clinicopathologic features including tumor volume, and explore outcomes by MMR class in a contemporary cohort. METHODS: Single institution cohort evaluating MMR classification for endometrial cancers (EC). MMR immunohistochemistry (IHC)±microsatellite instability (MSI) testing and reflex MLH1 methylation testing was performed. Tumors with MMR abnormalities by IHC or MSI and MLH1 methylation were classified as epigenetic MMR deficiency while those without MLH1 methylation were classified as probable MMR mutations. Clinicopathologic characteristics were analyzed. RESULTS: 466 endometrial cancers were classified; 75% as MMR proficient, 20% epigenetic MMR defects, and 5% as probable MMR mutations. Epigenetic MMR defects were associated with advanced stage, higher grade, presence of lymphovascular space invasion, and older age. MMR class was significantly associated with tumor volume, an association not previously reported. The epigenetic MMR defect tumors median volume was 10,220mm3 compared to 3321mm3 and 2,846mm3, for MMR proficient and probable MMR mutations respectively (P<0.0001). Higher tumor volume was associated with lymph node involvement. Endometrioid EC cases with epigenetic MMR defects had significantly reduced recurrence-free survival (RFS). Among advanced stage (III/IV) endometrioid EC the epigenetic MMR defect group was more likely to recur compared to the MMR proficient group (47.7% vs 3.4%) despite receiving similar adjuvant therapy. In contrast, there was no difference in the number of early stage recurrences for the different MMR classes. CONCLUSIONS: MMR testing that includes MLH1 methylation analysis defines a subset of tumors that have worse prognostic features and reduced RFS.
OBJECTIVES: To determine the relationship between mismatch repair (MMR) classification and clinicopathologic features including tumor volume, and explore outcomes by MMR class in a contemporary cohort. METHODS: Single institution cohort evaluating MMR classification for endometrial cancers (EC). MMR immunohistochemistry (IHC)±microsatellite instability (MSI) testing and reflex MLH1 methylation testing was performed. Tumors with MMR abnormalities by IHC or MSI and MLH1 methylation were classified as epigenetic MMR deficiency while those without MLH1 methylation were classified as probable MMR mutations. Clinicopathologic characteristics were analyzed. RESULTS: 466 endometrial cancers were classified; 75% as MMR proficient, 20% epigenetic MMR defects, and 5% as probable MMR mutations. Epigenetic MMR defects were associated with advanced stage, higher grade, presence of lymphovascular space invasion, and older age. MMR class was significantly associated with tumor volume, an association not previously reported. The epigenetic MMR defect tumors median volume was 10,220mm3 compared to 3321mm3 and 2,846mm3, for MMR proficient and probable MMR mutations respectively (P<0.0001). Higher tumor volume was associated with lymph node involvement. Endometrioid EC cases with epigenetic MMR defects had significantly reduced recurrence-free survival (RFS). Among advanced stage (III/IV) endometrioid EC the epigenetic MMR defect group was more likely to recur compared to the MMR proficient group (47.7% vs 3.4%) despite receiving similar adjuvant therapy. In contrast, there was no difference in the number of early stage recurrences for the different MMR classes. CONCLUSIONS: MMR testing that includes MLH1 methylation analysis defines a subset of tumors that have worse prognostic features and reduced RFS.
Authors: M K McConechy; A Talhouk; H H Li-Chang; S Leung; D G Huntsman; C B Gilks; J N McAlpine Journal: Gynecol Oncol Date: 2015-01-28 Impact factor: 5.482
Authors: Heather Hampel; Julie A Stephens; Eero Pukkala; Risto Sankila; Lauri A Aaltonen; Jukka-Pekka Mecklin; Albert de la Chapelle Journal: Gastroenterology Date: 2005-08 Impact factor: 22.682
Authors: Heather Hampel; Wendy Frankel; Jenny Panescu; Janet Lockman; Kaisa Sotamaa; Daniel Fix; Ilene Comeras; Jennifer La Jeunesse; Hidewaki Nakagawa; Judith A Westman; Thomas W Prior; Mark Clendenning; Pamela Penzone; Janet Lombardi; Patti Dunn; David E Cohn; Larry Copeland; Lynne Eaton; Jeffrey Fowler; George Lewandowski; Luis Vaccarello; Jeffrey Bell; Gary Reid; Albert de la Chapelle Journal: Cancer Res Date: 2006-08-01 Impact factor: 12.701
Authors: Floor J Backes; Marino E Leon; Iouri Ivanov; Adrian Suarez; Wendy L Frankel; Heather Hampel; Jeffrey M Fowler; Larry J Copeland; David M O'Malley; David E Cohn Journal: Gynecol Oncol Date: 2009-06-10 Impact factor: 5.482
Authors: Destin Black; Robert A Soslow; Douglas A Levine; Carmen Tornos; Shirley C Chen; Amanda J Hummer; Faina Bogomolniy; Narciso Olvera; Richard R Barakat; Jeff Boyd Journal: J Clin Oncol Date: 2006-03-20 Impact factor: 44.544
Authors: Israel Zighelboim; Paul J Goodfellow; Feng Gao; Randall K Gibb; Matthew A Powell; Janet S Rader; David G Mutch Journal: J Clin Oncol Date: 2007-05-20 Impact factor: 44.544
Authors: Rachel Pearlman; Wendy L Frankel; Benjamin Swanson; Weiqiang Zhao; Ahmet Yilmaz; Kristin Miller; Jason Bacher; Christopher Bigley; Lori Nelsen; Paul J Goodfellow; Richard M Goldberg; Electra Paskett; Peter G Shields; Jo L Freudenheim; Peter P Stanich; Ilene Lattimer; Mark Arnold; Sandya Liyanarachchi; Matthew Kalady; Brandie Heald; Carla Greenwood; Ian Paquette; Marla Prues; David J Draper; Carolyn Lindeman; J Philip Kuebler; Kelly Reynolds; Joanna M Brell; Amy A Shaper; Sameer Mahesh; Nicole Buie; Kisa Weeman; Kristin Shine; Mitchell Haut; Joan Edwards; Shyamal Bastola; Karen Wickham; Karamjit S Khanduja; Rosemary Zacks; Colin C Pritchard; Brian H Shirts; Angela Jacobson; Brian Allen; Albert de la Chapelle; Heather Hampel Journal: JAMA Oncol Date: 2017-04-01 Impact factor: 31.777
Authors: Paul J Goodfellow; Caroline C Billingsley; Heather A Lankes; Shamshad Ali; David E Cohn; Russell J Broaddus; Nilsa Ramirez; Colin C Pritchard; Heather Hampel; Alexis S Chassen; Luke V Simmons; Amy P Schmidt; Feng Gao; Louise A Brinton; Floor Backes; Lisa M Landrum; Melissa A Geller; Paul A DiSilvestro; Michael L Pearl; Shashikant B Lele; Matthew A Powell; Richard J Zaino; David Mutch Journal: J Clin Oncol Date: 2015-11-09 Impact factor: 44.544
Authors: Merrin Man Long Leong; Arthur Kwok Leung Cheung; Wei Dai; Sai Wah Tsao; Chi Man Tsang; Christopher W Dawson; Josephine Mun Yee Ko; Maria Li Lung Journal: Proc Natl Acad Sci U S A Date: 2019-06-24 Impact factor: 11.205
Authors: Rutulkumar Patel; Luchang Zhang; Amar Desai; Mark J Hoenerhoff; Lucy H Kennedy; Tomas Radivoyevitch; Chiara La Tessa; Stanton L Gerson; Scott M Welford Journal: Int J Radiat Oncol Biol Phys Date: 2020-07-04 Impact factor: 7.038
Authors: Karen A Cadoo; Diana L Mandelker; Semanti Mukherjee; Carolyn Stewart; Deborah DeLair; Vignesh Ravichandran; Preethi Srinivasan; Daire Hurley; Yelena Kemel; Angela G Arnold; Margaret Sheehan; Nisha Pradhan; Vijai Joseph; Dennis S Chi; Ginger J Gardner; Elizabeth L Jewell; Mario M Leitao; Kara Long Roche; Jennifer J Mueller; Yukio Sonoda; Oliver Zivanovic; Michael Walsh; Maria I Carlo; Michael F Berger; David Hyman; Liying Zhang; Mark E Robson; Kenneth Offit; Carol Aghajanian; Nadeem R Abu Rustum; Zsofia Stadler Journal: JCO Precis Oncol Date: 2019-04-25
Authors: David A Wheeler; Naoko Takebe; Toshinori Hinoue; Katherine A Hoadley; Maria F Cardenas; Alina M Hamilton; Peter W Laird; Linghua Wang; Adrienne Johnson; Ninad Dewal; Vincent Miller; David Piñeyro; Manuel Castro de Moura; Manel Esteller; Hui Shen; Jean Claude Zenklusen; Roy Tarnuzzer; Lisa M McShane; James V Tricoli; Paul M Williams; Irina Lubensky; Geraldine O'Sullivan-Coyne; Elise C Kohn; Richard F Little; Jeffrey White; Shakun Malik; Lyndsay Harris; Carol Weil; Alice P Chen; Chris Karlovich; Brian Rodgers; Lalitha Shankar; Paula Jacobs; Tracy Nolan; Jianhong Hu; Donna M Muzny; Harshavardhan Doddapaneni; Viktoriya Korchina; Julie Gastier-Foster; Jay Bowen; Kristen Leraas; Elijah F Edmondson; James H Doroshow; Barbara A Conley; S Percy Ivy; Louis M Staudt Journal: Cancer Cell Date: 2020-11-19 Impact factor: 31.743