Proteogenomic insights suggest druggable pathways in endometrial carcinoma

Clinical Proteomic Tumor Analysis Consortium; Yongchao Dou; Lizabeth Katsnelson; Marina A. Gritsenko; Yingwei Hu; Boris Reva; Runyu Hong; Yi Ting Wang; Iga Kolodziejczak; Rita Jui Hsien Lu; Chia Feng Tsai; Wen Bu; Wenke Liu; Xiaofang Guo; Eunkyung An; Rebecca C. Arend; Jasmin Bavarva; Lijun Chen; Rosalie K. Chu; Andrzej Czekański; Teresa Davoli; Elizabeth G. Demicco; Deborah DeLair; Kelly Devereaux; Saravana M. Dhanasekaran; Peter Dottino; Bailee Dover; Thomas L. Fillmore; McKenzie Foxall; Catherine E. Hermann; Tara Hiltke; Galen Hostetter; Marcin Jędryka; Scott D. Jewell; Isabelle Johnson; Andrea G. Kahn; Amy T. Ku; Chandan Kumar-Sinha; Paweł Kurzawa; Alexander J. Lazar; Rossana Lazcano; Jonathan T. Lei; Yi Li; Yuxing Liao; Tung Shing M. Lih; Tai Tu Lin; John A. Martignetti; Ramya P. Masand; Rafał Matkowski; Wilson McKerrow; Mehdi Mesri; Matthew E. Monroe; Jamie Moon; Ronald J. Moore; Michael D. Nestor; Chelsea Newton; Tatiana Omelchenko; Gilbert S. Omenn; Samuel H. Payne; Vladislav A. Petyuk; Ana I. Robles; Henry Rodriguez; Kelly V. Ruggles; Dmitry Rykunov; Sara R. Savage; Athena A. Schepmoes; Tujin Shi; Zhiao Shi; Jimin Tan; Mason Taylor; Mathangi Thiagarajan; Joshua M. Wang; Karl K. Weitz; Bo Wen; C. M. Williams; Yige Wu; Matthew A. Wyczalkowski; Xinpei Yi; Xu Zhang; Rui Zhao; David Mutch; Arul M. Chinnaiyan; Richard D. Smith; Alexey I. Nesvizhskii; Pei Wang; Maciej Wiznerowicz; Li Ding; D. R. Mani; Hui Zhang; Matthew L. Anderson; Karin D. Rodland; Bing Zhang; Tao Liu; David Fenyö; Andrzej Antczak; Meenakshi Anurag; Thomas Bauer; Chet Birger; Michael J. Birrer; Melissa Borucki; Shuang Cai; Anna Calinawan; Steven A. Carr; Patricia Castro; Sandra Cerda; Daniel W. Chan; David Chesla; Marcin P. Cieslik; Sandra Cottingham; Rajiv Dhir; Marcin J. Domagalski; Brian J. Druker; Elizabeth Duffy; Nathan J. Edwards; Robert Edwards; Matthew J. Ellis; Jennifer Eschbacher; Mina Fam; Brenda Fevrier-Sullivan; Jesse Francis; John Freymann; Stacey Gabriel; Gad Getz; Michael A. Gillette; Andrew K. Godwin; Charles A. Goldthwaite; Pamela Grady; Jason Hafron; Pushpa Hariharan; Barbara Hindenach; Katherine A. Hoadley; Jasmine Huang; Michael M. Ittmann; Ashlie Johnson; Corbin D. Jones; Karen A. Ketchum; Justin Kirby; Toan Le; Avi Ma'ayan; Rashna Madan; Sailaja Mareedu; Peter B. McGarvey; Francesmary Modugno; Rebecca Montgomery; Kristen Nyce; Amanda G. Paulovich; Barbara L. Pruetz; Liqun Qi; Shannon Richey; Eric E. Schadt; Yvonne Shutack; Shilpi Singh; Michael Smith; Darlene Tansil; Ratna R. Thangudu; Matt Tobin; Ki Sung Um; Negin Vatanian; Alex Webster; George D. Wilson; Jason Wright; Kakhaber Zaalishvili; Zhen Zhang; Grace Zhao

doi:10.1016/j.ccell.2023.07.007

Proteogenomic insights suggest druggable pathways in endometrial carcinoma

Clinical Proteomic Tumor Analysis Consortium, Yongchao Dou, Lizabeth Katsnelson, Marina A. Gritsenko, Yingwei Hu, Boris Reva, Runyu Hong, Yi Ting Wang, Iga Kolodziejczak, Rita Jui Hsien Lu, Chia Feng Tsai, Wen Bu, Wenke Liu, Xiaofang Guo, Eunkyung An, Rebecca C. Arend, Jasmin Bavarva, Lijun Chen, Rosalie K. Chu, Andrzej CzekańskiTeresa Davoli, Elizabeth G. Demicco, Deborah DeLair, Kelly Devereaux, Saravana M. Dhanasekaran, Peter Dottino, Bailee Dover, Thomas L. Fillmore, McKenzie Foxall, Catherine E. Hermann, Tara Hiltke, Galen Hostetter, Marcin Jędryka, Scott D. Jewell, Isabelle Johnson, Andrea G. Kahn, Amy T. Ku, Chandan Kumar-Sinha, Paweł Kurzawa, Alexander J. Lazar, Rossana Lazcano, Jonathan T. Lei, Yi Li, Yuxing Liao, Tung Shing M. Lih, Tai Tu Lin, John A. Martignetti, Ramya P. Masand, Rafał Matkowski, Wilson McKerrow, Mehdi Mesri, Matthew E. Monroe, Jamie Moon, Ronald J. Moore, Michael D. Nestor, Chelsea Newton, Tatiana Omelchenko, Gilbert S. Omenn, Samuel H. Payne, Vladislav A. Petyuk, Ana I. Robles, Henry Rodriguez, Kelly V. Ruggles, Dmitry Rykunov, Sara R. Savage, Athena A. Schepmoes, Tujin Shi, Zhiao Shi, Jimin Tan, Mason Taylor, Mathangi Thiagarajan, Joshua M. Wang, Karl K. Weitz, Bo Wen, C. M. Williams, Yige Wu, Matthew A. Wyczalkowski, Xinpei Yi, Xu Zhang, Rui Zhao, David Mutch, Arul M. Chinnaiyan, Richard D. Smith, Alexey I. Nesvizhskii, Pei Wang, Maciej Wiznerowicz, Li Ding, D. R. Mani, Hui Zhang, Matthew L. Anderson, Karin D. Rodland, Bing Zhang, Tao Liu, David Fenyö, Andrzej Antczak, Meenakshi Anurag, Thomas Bauer, Chet Birger, Michael J. Birrer, Melissa Borucki, Shuang Cai, Anna Calinawan, Steven A. Carr, Patricia Castro, Sandra Cerda, Daniel W. Chan, David Chesla, Marcin P. Cieslik, Sandra Cottingham, Rajiv Dhir, Marcin J. Domagalski, Brian J. Druker, Elizabeth Duffy, Nathan J. Edwards, Robert Edwards, Matthew J. Ellis, Jennifer Eschbacher, Mina Fam, Brenda Fevrier-Sullivan, Jesse Francis, John Freymann, Stacey Gabriel, Gad Getz, Michael A. Gillette, Andrew K. Godwin, Charles A. Goldthwaite, Pamela Grady, Jason Hafron, Pushpa Hariharan, Barbara Hindenach, Katherine A. Hoadley, Jasmine Huang, Michael M. Ittmann, Ashlie Johnson, Corbin D. Jones, Karen A. Ketchum, Justin Kirby, Toan Le, Avi Ma'ayan, Rashna Madan, Sailaja Mareedu, Peter B. McGarvey, Francesmary Modugno, Rebecca Montgomery, Kristen Nyce, Amanda G. Paulovich, Barbara L. Pruetz, Liqun Qi, Shannon Richey, Eric E. Schadt, Yvonne Shutack, Shilpi Singh, Michael Smith, Darlene Tansil, Ratna R. Thangudu, Matt Tobin, Ki Sung Um, Negin Vatanian, Alex Webster, George D. Wilson, Jason Wright, Kakhaber Zaalishvili, Zhen Zhang, Grace Zhao

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

Abstract

We characterized a prospective endometrial carcinoma (EC) cohort containing 138 tumors and 20 enriched normal tissues using 10 different omics platforms. Targeted quantitation of two peptides can predict antigen processing and presentation machinery activity, and may inform patient selection for immunotherapy. Association analysis between MYC activity and metformin treatment in both patients and cell lines suggests a potential role for metformin treatment in non-diabetic patients with elevated MYC activity. PIK3R1 in-frame indels are associated with elevated AKT phosphorylation and increased sensitivity to AKT inhibitors. CTNNB1 hotspot mutations are concentrated near phosphorylation sites mediating pS45-induced degradation of β-catenin, which may render Wnt-FZD antagonists ineffective. Deep learning accurately predicts EC subtypes and mutations from histopathology images, which may be useful for rapid diagnosis. Overall, this study identified molecular and imaging markers that can be further investigated to guide patient stratification for more precise treatment of EC.

Original language	English
Pages (from-to)	1586-1605.e15
Journal	Cancer Cell
Volume	41
Issue number	9
DOIs	https://doi.org/10.1016/j.ccell.2023.07.007
State	Published - Sep 11 2023

Keywords

CPTAC
CTNNB1
PIK3R1
deep learning
endometrial cancer
metformin
proteogenomics
target assays

Access to Document

10.1016/j.ccell.2023.07.007

Cite this

Clinical Proteomic Tumor Analysis Consortium, Dou, Y., Katsnelson, L., Gritsenko, M. A., Hu, Y., Reva, B., Hong, R., Wang, Y. T., Kolodziejczak, I., Lu, R. J. H., Tsai, C. F., Bu, W., Liu, W., Guo, X., An, E., Arend, R. C., Bavarva, J., Chen, L., Chu, R. K., ... Zhao, G. (2023). Proteogenomic insights suggest druggable pathways in endometrial carcinoma. Cancer Cell, 41(9), 1586-1605.e15. https://doi.org/10.1016/j.ccell.2023.07.007

@article{be05201a2eb14ff0ad7b68a036864082,

title = "Proteogenomic insights suggest druggable pathways in endometrial carcinoma",

abstract = "We characterized a prospective endometrial carcinoma (EC) cohort containing 138 tumors and 20 enriched normal tissues using 10 different omics platforms. Targeted quantitation of two peptides can predict antigen processing and presentation machinery activity, and may inform patient selection for immunotherapy. Association analysis between MYC activity and metformin treatment in both patients and cell lines suggests a potential role for metformin treatment in non-diabetic patients with elevated MYC activity. PIK3R1 in-frame indels are associated with elevated AKT phosphorylation and increased sensitivity to AKT inhibitors. CTNNB1 hotspot mutations are concentrated near phosphorylation sites mediating pS45-induced degradation of β-catenin, which may render Wnt-FZD antagonists ineffective. Deep learning accurately predicts EC subtypes and mutations from histopathology images, which may be useful for rapid diagnosis. Overall, this study identified molecular and imaging markers that can be further investigated to guide patient stratification for more precise treatment of EC.",

keywords = "CPTAC, CTNNB1, PIK3R1, deep learning, endometrial cancer, metformin, proteogenomics, target assays",

author = "{Clinical Proteomic Tumor Analysis Consortium} and Yongchao Dou and Lizabeth Katsnelson and Gritsenko, {Marina A.} and Yingwei Hu and Boris Reva and Runyu Hong and Wang, {Yi Ting} and Iga Kolodziejczak and Lu, {Rita Jui Hsien} and Tsai, {Chia Feng} and Wen Bu and Wenke Liu and Xiaofang Guo and Eunkyung An and Arend, {Rebecca C.} and Jasmin Bavarva and Lijun Chen and Chu, {Rosalie K.} and Andrzej Czeka{\'n}ski and Teresa Davoli and Demicco, {Elizabeth G.} and Deborah DeLair and Kelly Devereaux and Dhanasekaran, {Saravana M.} and Peter Dottino and Bailee Dover and Fillmore, {Thomas L.} and McKenzie Foxall and Hermann, {Catherine E.} and Tara Hiltke and Galen Hostetter and Marcin J{\c e}dryka and Jewell, {Scott D.} and Isabelle Johnson and Kahn, {Andrea G.} and Ku, {Amy T.} and Chandan Kumar-Sinha and Pawe{\l} Kurzawa and Lazar, {Alexander J.} and Rossana Lazcano and Lei, {Jonathan T.} and Yi Li and Yuxing Liao and Lih, {Tung Shing M.} and Lin, {Tai Tu} and Martignetti, {John A.} and Masand, {Ramya P.} and Rafa{\l} Matkowski and Wilson McKerrow and Mehdi Mesri and Monroe, {Matthew E.} and Jamie Moon and Moore, {Ronald J.} and Nestor, {Michael D.} and Chelsea Newton and Tatiana Omelchenko and Omenn, {Gilbert S.} and Payne, {Samuel H.} and Petyuk, {Vladislav A.} and Robles, {Ana I.} and Henry Rodriguez and Ruggles, {Kelly V.} and Dmitry Rykunov and Savage, {Sara R.} and Schepmoes, {Athena A.} and Tujin Shi and Zhiao Shi and Jimin Tan and Mason Taylor and Mathangi Thiagarajan and Wang, {Joshua M.} and Weitz, {Karl K.} and Bo Wen and Williams, {C. M.} and Yige Wu and Wyczalkowski, {Matthew A.} and Xinpei Yi and Xu Zhang and Rui Zhao and David Mutch and Chinnaiyan, {Arul M.} and Smith, {Richard D.} and Nesvizhskii, {Alexey I.} and Pei Wang and Maciej Wiznerowicz and Li Ding and Mani, {D. R.} and Hui Zhang and Anderson, {Matthew L.} and Rodland, {Karin D.} and Bing Zhang and Tao Liu and David Feny{\"o} and Andrzej Antczak and Meenakshi Anurag and Thomas Bauer and Chet Birger and Birrer, {Michael J.} and Melissa Borucki and Shuang Cai and Anna Calinawan and Carr, {Steven A.} and Patricia Castro and Sandra Cerda and Chan, {Daniel W.} and David Chesla and Cieslik, {Marcin P.} and Sandra Cottingham and Rajiv Dhir and Domagalski, {Marcin J.} and Druker, {Brian J.} and Elizabeth Duffy and Edwards, {Nathan J.} and Robert Edwards and Ellis, {Matthew J.} and Jennifer Eschbacher and Mina Fam and Brenda Fevrier-Sullivan and Jesse Francis and John Freymann and Stacey Gabriel and Gad Getz and Gillette, {Michael A.} and Godwin, {Andrew K.} and Goldthwaite, {Charles A.} and Pamela Grady and Jason Hafron and Pushpa Hariharan and Barbara Hindenach and Hoadley, {Katherine A.} and Jasmine Huang and Ittmann, {Michael M.} and Ashlie Johnson and Jones, {Corbin D.} and Ketchum, {Karen A.} and Justin Kirby and Toan Le and Avi Ma'ayan and Rashna Madan and Sailaja Mareedu and McGarvey, {Peter B.} and Francesmary Modugno and Rebecca Montgomery and Kristen Nyce and Paulovich, {Amanda G.} and Pruetz, {Barbara L.} and Liqun Qi and Shannon Richey and Schadt, {Eric E.} and Yvonne Shutack and Shilpi Singh and Michael Smith and Darlene Tansil and Thangudu, {Ratna R.} and Matt Tobin and Um, {Ki Sung} and Negin Vatanian and Alex Webster and Wilson, {George D.} and Jason Wright and Kakhaber Zaalishvili and Zhen Zhang and Grace Zhao",

note = "Publisher Copyright: {\textcopyright} 2023",

year = "2023",

month = sep,

day = "11",

doi = "10.1016/j.ccell.2023.07.007",

language = "English",

volume = "41",

pages = "1586--1605.e15",

journal = "Cancer Cell",

issn = "1535-6108",

number = "9",

}

Clinical Proteomic Tumor Analysis Consortium, Dou, Y, Katsnelson, L, Gritsenko, MA, Hu, Y, Reva, B, Hong, R, Wang, YT, Kolodziejczak, I, Lu, RJH, Tsai, CF, Bu, W, Liu, W, Guo, X, An, E, Arend, RC, Bavarva, J, Chen, L, Chu, RK, Czekański, A, Davoli, T, Demicco, EG, DeLair, D, Devereaux, K, Dhanasekaran, SM, Dottino, P, Dover, B, Fillmore, TL, Foxall, M, Hermann, CE, Hiltke, T, Hostetter, G, Jędryka, M, Jewell, SD, Johnson, I, Kahn, AG, Ku, AT, Kumar-Sinha, C, Kurzawa, P, Lazar, AJ, Lazcano, R, Lei, JT, Li, Y, Liao, Y, Lih, TSM, Lin, TT, Martignetti, JA, Masand, RP, Matkowski, R, McKerrow, W, Mesri, M, Monroe, ME, Moon, J, Moore, RJ, Nestor, MD, Newton, C, Omelchenko, T, Omenn, GS, Payne, SH, Petyuk, VA, Robles, AI, Rodriguez, H, Ruggles, KV, Rykunov, D, Savage, SR, Schepmoes, AA, Shi, T, Shi, Z, Tan, J, Taylor, M, Thiagarajan, M, Wang, JM, Weitz, KK, Wen, B, Williams, CM, Wu, Y, Wyczalkowski, MA, Yi, X, Zhang, X, Zhao, R, Mutch, D, Chinnaiyan, AM, Smith, RD, Nesvizhskii, AI, Wang, P, Wiznerowicz, M, Ding, L, Mani, DR, Zhang, H, Anderson, ML, Rodland, KD, Zhang, B, Liu, T, Fenyö, D, Antczak, A, Anurag, M, Bauer, T, Birger, C, Birrer, MJ, Borucki, M, Cai, S, Calinawan, A, Carr, SA, Castro, P, Cerda, S, Chan, DW, Chesla, D, Cieslik, MP, Cottingham, S, Dhir, R, Domagalski, MJ, Druker, BJ, Duffy, E, Edwards, NJ, Edwards, R, Ellis, MJ, Eschbacher, J, Fam, M, Fevrier-Sullivan, B, Francis, J, Freymann, J, Gabriel, S, Getz, G, Gillette, MA, Godwin, AK, Goldthwaite, CA, Grady, P, Hafron, J, Hariharan, P, Hindenach, B, Hoadley, KA, Huang, J, Ittmann, MM, Johnson, A, Jones, CD, Ketchum, KA, Kirby, J, Le, T, Ma'ayan, A, Madan, R, Mareedu, S, McGarvey, PB, Modugno, F, Montgomery, R, Nyce, K, Paulovich, AG, Pruetz, BL, Qi, L, Richey, S, Schadt, EE, Shutack, Y, Singh, S, Smith, M, Tansil, D, Thangudu, RR, Tobin, M, Um, KS, Vatanian, N, Webster, A, Wilson, GD, Wright, J, Zaalishvili, K, Zhang, Z & Zhao, G 2023, 'Proteogenomic insights suggest druggable pathways in endometrial carcinoma', Cancer Cell, vol. 41, no. 9, pp. 1586-1605.e15. https://doi.org/10.1016/j.ccell.2023.07.007

TY - JOUR

T1 - Proteogenomic insights suggest druggable pathways in endometrial carcinoma

AU - Clinical Proteomic Tumor Analysis Consortium

AU - Dou, Yongchao

AU - Katsnelson, Lizabeth

AU - Gritsenko, Marina A.

AU - Hu, Yingwei

AU - Reva, Boris

AU - Hong, Runyu

AU - Wang, Yi Ting

AU - Kolodziejczak, Iga

AU - Lu, Rita Jui Hsien

AU - Tsai, Chia Feng

AU - Bu, Wen

AU - Liu, Wenke

AU - Guo, Xiaofang

AU - An, Eunkyung

AU - Arend, Rebecca C.

AU - Bavarva, Jasmin

AU - Chen, Lijun

AU - Chu, Rosalie K.

AU - Czekański, Andrzej

AU - Davoli, Teresa

AU - Demicco, Elizabeth G.

AU - DeLair, Deborah

AU - Devereaux, Kelly

AU - Dhanasekaran, Saravana M.

AU - Dottino, Peter

AU - Dover, Bailee

AU - Fillmore, Thomas L.

AU - Foxall, McKenzie

AU - Hermann, Catherine E.

AU - Hiltke, Tara

AU - Hostetter, Galen

AU - Jędryka, Marcin

AU - Jewell, Scott D.

AU - Johnson, Isabelle

AU - Kahn, Andrea G.

AU - Ku, Amy T.

AU - Kumar-Sinha, Chandan

AU - Kurzawa, Paweł

AU - Lazar, Alexander J.

AU - Lazcano, Rossana

AU - Lei, Jonathan T.

AU - Li, Yi

AU - Liao, Yuxing

AU - Lih, Tung Shing M.

AU - Lin, Tai Tu

AU - Martignetti, John A.

AU - Masand, Ramya P.

AU - Matkowski, Rafał

AU - McKerrow, Wilson

AU - Mesri, Mehdi

AU - Monroe, Matthew E.

AU - Moon, Jamie

AU - Moore, Ronald J.

AU - Nestor, Michael D.

AU - Newton, Chelsea

AU - Omelchenko, Tatiana

AU - Omenn, Gilbert S.

AU - Payne, Samuel H.

AU - Petyuk, Vladislav A.

AU - Robles, Ana I.

AU - Rodriguez, Henry

AU - Ruggles, Kelly V.

AU - Rykunov, Dmitry

AU - Savage, Sara R.

AU - Schepmoes, Athena A.

AU - Shi, Tujin

AU - Shi, Zhiao

AU - Tan, Jimin

AU - Taylor, Mason

AU - Thiagarajan, Mathangi

AU - Wang, Joshua M.

AU - Weitz, Karl K.

AU - Wen, Bo

AU - Williams, C. M.

AU - Wu, Yige

AU - Wyczalkowski, Matthew A.

AU - Yi, Xinpei

AU - Zhang, Xu

AU - Zhao, Rui

AU - Mutch, David

AU - Chinnaiyan, Arul M.

AU - Smith, Richard D.

AU - Nesvizhskii, Alexey I.

AU - Wang, Pei

AU - Wiznerowicz, Maciej

AU - Ding, Li

AU - Mani, D. R.

AU - Zhang, Hui

AU - Anderson, Matthew L.

AU - Rodland, Karin D.

AU - Zhang, Bing

AU - Liu, Tao

AU - Fenyö, David

AU - Antczak, Andrzej

AU - Anurag, Meenakshi

AU - Bauer, Thomas

AU - Birger, Chet

AU - Birrer, Michael J.

AU - Borucki, Melissa

AU - Cai, Shuang

AU - Calinawan, Anna

AU - Carr, Steven A.

AU - Castro, Patricia

AU - Cerda, Sandra

AU - Chan, Daniel W.

AU - Chesla, David

AU - Cieslik, Marcin P.

AU - Cottingham, Sandra

AU - Dhir, Rajiv

AU - Domagalski, Marcin J.

AU - Druker, Brian J.

AU - Duffy, Elizabeth

AU - Edwards, Nathan J.

AU - Edwards, Robert

AU - Ellis, Matthew J.

AU - Eschbacher, Jennifer

AU - Fam, Mina

AU - Fevrier-Sullivan, Brenda

AU - Francis, Jesse

AU - Freymann, John

AU - Gabriel, Stacey

AU - Getz, Gad

AU - Gillette, Michael A.

AU - Godwin, Andrew K.

AU - Goldthwaite, Charles A.

AU - Grady, Pamela

AU - Hafron, Jason

AU - Hariharan, Pushpa

AU - Hindenach, Barbara

AU - Hoadley, Katherine A.

AU - Huang, Jasmine

AU - Ittmann, Michael M.

AU - Johnson, Ashlie

AU - Jones, Corbin D.

AU - Ketchum, Karen A.

AU - Kirby, Justin

AU - Le, Toan

AU - Ma'ayan, Avi

AU - Madan, Rashna

AU - Mareedu, Sailaja

AU - McGarvey, Peter B.

AU - Modugno, Francesmary

AU - Montgomery, Rebecca

AU - Nyce, Kristen

AU - Paulovich, Amanda G.

AU - Pruetz, Barbara L.

AU - Qi, Liqun

AU - Richey, Shannon

AU - Schadt, Eric E.

AU - Shutack, Yvonne

AU - Singh, Shilpi

AU - Smith, Michael

AU - Tansil, Darlene

AU - Thangudu, Ratna R.

AU - Tobin, Matt

AU - Um, Ki Sung

AU - Vatanian, Negin

AU - Webster, Alex

AU - Wilson, George D.

AU - Wright, Jason

AU - Zaalishvili, Kakhaber

AU - Zhang, Zhen

AU - Zhao, Grace

PY - 2023/9/11

Y1 - 2023/9/11

N2 - We characterized a prospective endometrial carcinoma (EC) cohort containing 138 tumors and 20 enriched normal tissues using 10 different omics platforms. Targeted quantitation of two peptides can predict antigen processing and presentation machinery activity, and may inform patient selection for immunotherapy. Association analysis between MYC activity and metformin treatment in both patients and cell lines suggests a potential role for metformin treatment in non-diabetic patients with elevated MYC activity. PIK3R1 in-frame indels are associated with elevated AKT phosphorylation and increased sensitivity to AKT inhibitors. CTNNB1 hotspot mutations are concentrated near phosphorylation sites mediating pS45-induced degradation of β-catenin, which may render Wnt-FZD antagonists ineffective. Deep learning accurately predicts EC subtypes and mutations from histopathology images, which may be useful for rapid diagnosis. Overall, this study identified molecular and imaging markers that can be further investigated to guide patient stratification for more precise treatment of EC.

AB - We characterized a prospective endometrial carcinoma (EC) cohort containing 138 tumors and 20 enriched normal tissues using 10 different omics platforms. Targeted quantitation of two peptides can predict antigen processing and presentation machinery activity, and may inform patient selection for immunotherapy. Association analysis between MYC activity and metformin treatment in both patients and cell lines suggests a potential role for metformin treatment in non-diabetic patients with elevated MYC activity. PIK3R1 in-frame indels are associated with elevated AKT phosphorylation and increased sensitivity to AKT inhibitors. CTNNB1 hotspot mutations are concentrated near phosphorylation sites mediating pS45-induced degradation of β-catenin, which may render Wnt-FZD antagonists ineffective. Deep learning accurately predicts EC subtypes and mutations from histopathology images, which may be useful for rapid diagnosis. Overall, this study identified molecular and imaging markers that can be further investigated to guide patient stratification for more precise treatment of EC.

KW - CPTAC

KW - CTNNB1

KW - PIK3R1

KW - deep learning

KW - endometrial cancer

KW - metformin

KW - proteogenomics

KW - target assays

UR - http://www.scopus.com/inward/record.url?scp=85169826543&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2023.07.007

DO - 10.1016/j.ccell.2023.07.007

M3 - Article

C2 - 37567170

AN - SCOPUS:85169826543

SN - 1535-6108

VL - 41

SP - 1586-1605.e15

JO - Cancer Cell

JF - Cancer Cell

IS - 9

ER -

Proteogenomic insights suggest druggable pathways in endometrial carcinoma

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