title: Genomic alterations in BCL2L1 and DLC1 contribute to drug sensitivity in gastric cancer.
abstract: Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide. Recent high-throughput analyses of genomic alterations revealed several driver genes and altered pathways in GC. However, therapeutic applications from genomic data are limited, largely as a result of the lack of druggable molecular targets and preclinical models for drug selection. To identify new therapeutic targets for GC, we performed array comparative genomic hybridization (aCGH) of DNA from 103 patients with GC for copy number alteration (CNA) analysis, and whole-exome sequencing from 55 GCs from the same patients for mutation profiling. Pathway analysis showed recurrent alterations in the Wnt signaling [APC, CTNNB1, and DLC1 (deleted in liver cancer 1)], ErbB signaling (ERBB2, PIK3CA, and KRAS), and p53 signaling/apoptosis [TP53 and BCL2L1 (BCL2-like 1)] pathways. In 18.4% of GC cases (19/103), amplification of the antiapoptotic gene BCL2L1 was observed, and subsequently a BCL2L1 inhibitor was shown to markedly decrease cell viability in BCL2L1-amplified cell lines and in similarly altered patient-derived GC xenografts, especially when combined with other chemotherapeutic agents. In 10.9% of cases (6/55), mutations in DLC1 were found and were also shown to confer a growth advantage for these cells via activation of Rho-ROCK signaling, rendering these cells more susceptible to a ROCK inhibitor. Taken together, our study implicates BCL2L1 and DLC1 as potential druggable targets for specific subsets of GC cases.
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032;
authors.forename: Hansoo
authors.initials: H
authors.lastname: Park
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Korea;
authors.forename: Sung-Yup
authors.initials: SY
authors.lastname: Cho
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032;
authors.forename: Hyerim
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Korea;
authors.forename: Deukchae
authors.initials: D
authors.lastname: Na
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Korea;
authors.forename: Jee Yun
authors.initials: JY
authors.lastname: Han
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Korea;
authors.forename: Jeesoo
authors.initials: J
authors.lastname: Chae
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Korea;
authors.forename: Changho
authors.initials: C
authors.lastname: Park
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Korea;
authors.forename: Ok-Kyoung
authors.initials: OK
authors.lastname: Park
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Korea;
authors.forename: Seoyeon
authors.initials: S
authors.lastname: Min
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Korea;
authors.forename: Jinjoo
authors.initials: J
authors.lastname: Kang
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Korea;
authors.forename: Boram
authors.initials: B
authors.lastname: Choi
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Korea;
authors.forename: Jimin
authors.initials: J
authors.lastname: Min
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032;
authors.forename: Jee Young
authors.initials: JY
authors.lastname: Kwon
authors.affiliation: Department of Surgery, Seoul National University College of Medicine, Seoul 110-799, Korea;
authors.forename: Yun-Suhk
authors.initials: YS
authors.lastname: Suh
authors.affiliation: Department of Surgery, Seoul National University College of Medicine, Seoul 110-799, Korea;
authors.forename: Seong-Ho
authors.initials: SH
authors.lastname: Kong
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Korea; Department of Surgery, Seoul National University College of Medicine, Seoul 110-799, Korea;
authors.forename: Hyuk-Joon
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032;
authors.forename: Edison T
authors.initials: ET
authors.lastname: Liu
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Korea;
authors.forename: Jong-Il
authors.initials: JI
authors.lastname: Kim
authors.affiliation: Medicinal Bioconvergence Research Center, Seoul National University, Seoul 151-742, Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Sunghoon
authors.initials: S
authors.lastname: Kim
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Korea; Department of Surgery, Seoul National University College of Medicine, Seoul 110-799, Korea; Charles.Lee@jax.org hkyang@snu.ac.kr.
authors.forename: Han-Kwang
authors.initials: HK
authors.lastname: Yang
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Korea; Charles.Lee@jax.org hkyang@snu.ac.kr.
authors.forename: Charles
authors.initials: C
authors.lastname: Lee
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D059472:Exome / Q000235:genetics; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics* / Q000378:metabolism; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D008297:Male; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008875:Middle Aged; D009154:Mutation; D034622:RNA Interference; D017422:Sequence Analysis, DNA / Q000379:methods; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: C494811:BCL2L1 protein, human; C112352:DLC1 protein, human; D020690:GTPase-Activating Proteins; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D025521:Tumor Suppressor Proteins; D051020:bcl-X Protein
keywords: copy number alteration; druggable target; gastric cancer; patient-derived xenograft; whole-exome sequencing