Pharmacogenomic analysis of patient-derived tumor cells in gynecologic cancers

Jason K. Sa, Jae Ryoung Hwang, Young Jae Cho, Ji Yoon Ryu, Jung Joo Choi, Soo Young Jeong, Jihye Kim, Myeong Seon Kim, E. Sun Paik, Yoo Young Lee, Chel Hun Choi, Tae Joong Kim, Byoung Gie Kim, Duk Soo Bae, Yeri Lee, Nam Gu Her, Yong Jae Shin, Hee Jin Cho, Ja Yeon Kim, Yun Jee SeoHarim Koo, Jeong Woo Oh, Taebum Lee, Hyun Soo Kim, Sang Yong Song, Joon Seol Bae, Woong Yang Park, Hee Dong Han, Hyung Jun Ahn, Anil K. Sood, Raul Rabadan, Jin Ku Lee, Do Hyun Nam, Jeong Won Lee

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

Background: Gynecologic malignancy is one of the leading causes of mortality in female adults worldwide. Comprehensive genomic analysis has revealed a list of molecular aberrations that are essential to tumorigenesis, progression, and metastasis of gynecologic tumors. However, targeting such alterations has frequently led to treatment failures due to underlying genomic complexity and simultaneous activation of various tumor cell survival pathway molecules. A compilation of molecular characterization of tumors with pharmacological drug response is the next step toward clinical application of patient-tailored treatment regimens. Results: Toward this goal, we establish a library of 139 gynecologic tumors including epithelial ovarian cancers (EOCs), cervical, endometrial tumors, and uterine sarcomas that are genomically and/or pharmacologically annotated and explore dynamic pharmacogenomic associations against 37 molecularly targeted drugs. We discover lineage-specific drug sensitivities based on subcategorization of gynecologic tumors and identify TP53 mutation as a molecular determinant that elicits therapeutic response to poly (ADP-Ribose) polymerase (PARP) inhibitor. We further identify transcriptome expression of inhibitor of DNA biding 2 (ID2) as a potential predictive biomarker for treatment response to olaparib. Conclusions: Together, our results demonstrate the potential utility of rapid drug screening combined with genomic profiling for precision treatment of gynecologic cancers.

Original languageEnglish
Article number253
JournalGenome Biology
Volume20
Issue number1
DOIs
Publication statusPublished - 2019 Nov 26

Keywords

  • Gynecologic malignancy
  • ID2
  • PARP inhibitor
  • Pharmacogenomic analysis
  • TP53 mutations

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Genetics
  • Cell Biology

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