PMID- 34234236 OWN - NLM STAT- MEDLINE DCOM- 20211124 LR - 20221207 IS - 2045-2322 (Electronic) IS - 2045-2322 (Linking) VI - 11 IP - 1 DP - 2021 Jul 7 TI - SPP1 overexpression is associated with poor outcomes in ALK fusion lung cancer patients without receiving targeted therapy. PG - 14031 LID - 10.1038/s41598-021-93484-2 [doi] LID - 14031 AB - The screening of non-small cell lung cancer (NSCLC) tumors for anaplastic lymphoma receptor tyrosine kinase (ALK) gene rearrangements is important because of the dramatically favorable therapy response to ALK inhibitor. However, the exact mechanism of poor survival in ALK fusion lung cancer patients without receiving targeted therapy is unclear. In this study, total of 521 tumor specimens from Chinese patients with lung cancer were screened for ALK fusion by immunohistochemistry (IHC) and confirmed by fluorescence in situ hybridization (FISH). As results, there were no cases of coexisting EGFR and ALK mutations identified. Fourteen cases (2.7%) harbored ALK fusion, including eight solid adenocarcinomas with signet ring cell features, four acinar adenocarcinomas with cribriform pattern containing mucin, one adenosquamous carcinoma and one micropapillary adenocarcinoma with mucin. Six (42.9%) of fourteen patients with ALK-positive lung cancer had stage IV disease, and five ALK-positive patients treated with platinum-based chemotherapy had poor outcome (all patients were dead and the mean survival time was 12 months), compared to 72 months for patients with ALK inhibitor therapy. Furthermore, Five ALK-positive cases were analyzed by whole exome sequencing (WES) and via direct transcript counting using a digital probe-base (NanoString) to explore the driver genes. Deregulation of PI3K/AKT signaling pathway in ALK-positive lung cancer was demonstrated by WES analysis, and significantly increased mRNA of ALK, ROS1, MET, SPP1 and PI3K signaling pathway was identified by NanoString assay. The concordance between NanoString, IHC and FISH methodologies for detecting ALK fusion was 100%. Significant overexpression of SPP1 protein in ALK-positive lung cancer was confirmed by IHC compared to paired adjacent normal tissues and ALK-negative cancers. Thus we concluded that SPP1 overexpression is associated with poor outcomes for patients with ALK fusion lung cancer without receiving targeted therapy and PI3K/AKT/SPP1 pathway may become the promising targets in patients with aggressive lung cancer. FAU - Ji, Xiaolin AU - Ji X AD - Department of Pathology, Peking University Third Hospital, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xue Yuan Road, Haidian District, Beijing, 100191, People's Republic of China. FAU - Liu, Yan AU - Liu Y AD - Department of Pathology, Peking University Third Hospital, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xue Yuan Road, Haidian District, Beijing, 100191, People's Republic of China. FAU - Mei, Fang AU - Mei F AD - Department of Pathology, Peking University Third Hospital, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xue Yuan Road, Haidian District, Beijing, 100191, People's Republic of China. FAU - Li, Xinyang AU - Li X AD - Department of Pathology, Peking University Third Hospital, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xue Yuan Road, Haidian District, Beijing, 100191, People's Republic of China. FAU - Zhang, Mengxue AU - Zhang M AD - Department of Pathology, Peking University Third Hospital, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xue Yuan Road, Haidian District, Beijing, 100191, People's Republic of China. FAU - Yao, Buwen AU - Yao B AD - Department of Pathology, Peking University Third Hospital, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xue Yuan Road, Haidian District, Beijing, 100191, People's Republic of China. FAU - Wu, Rui AU - Wu R AD - Department of Pathology, Peking University Third Hospital, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xue Yuan Road, Haidian District, Beijing, 100191, People's Republic of China. FAU - You, Jiangfeng AU - You J AD - Department of Pathology, Peking University Third Hospital, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xue Yuan Road, Haidian District, Beijing, 100191, People's Republic of China. FAU - Pei, Fei AU - Pei F AD - Department of Pathology, Peking University Third Hospital, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xue Yuan Road, Haidian District, Beijing, 100191, People's Republic of China. peifei@bjmu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210707 PL - England TA - Sci Rep JT - Scientific reports JID - 101563288 RN - 0 (Biomarkers, Tumor) RN - 0 (Oncogene Proteins, Fusion) RN - 0 (SPP1 protein, human) RN - 106441-73-0 (Osteopontin) RN - EC 2.7.10.1 (ALK protein, human) RN - EC 2.7.10.1 (Anaplastic Lymphoma Kinase) RN - EC 2.7.10.1 (EGFR protein, human) RN - EC 2.7.10.1 (ErbB Receptors) SB - IM MH - Adolescent MH - Adult MH - Aged MH - Aged, 80 and over MH - Anaplastic Lymphoma Kinase/*genetics MH - Antineoplastic Combined Chemotherapy Protocols/adverse effects/therapeutic use MH - Biomarkers, Tumor MH - Carcinoma, Non-Small-Cell Lung/diagnosis/genetics/mortality/therapy MH - Disease Management MH - ErbB Receptors/genetics MH - Female MH - *Gene Expression MH - Gene Rearrangement MH - Humans MH - Immunohistochemistry MH - In Situ Hybridization, Fluorescence MH - Lung Neoplasms/diagnosis/*genetics/*mortality/therapy MH - Male MH - Middle Aged MH - Mutation MH - Oncogene Proteins, Fusion/*genetics MH - Osteopontin/*genetics MH - Prognosis MH - Exome Sequencing MH - Young Adult PMC - PMC8263595 COIS- The authors declare no competing interests. EDAT- 2021/07/09 06:00 MHDA- 2021/11/25 06:00 PMCR- 2021/07/07 CRDT- 2021/07/08 06:20 PHST- 2021/03/13 00:00 [received] PHST- 2021/06/17 00:00 [accepted] PHST- 2021/07/08 06:20 [entrez] PHST- 2021/07/09 06:00 [pubmed] PHST- 2021/11/25 06:00 [medline] PHST- 2021/07/07 00:00 [pmc-release] AID - 10.1038/s41598-021-93484-2 [pii] AID - 93484 [pii] AID - 10.1038/s41598-021-93484-2 [doi] PST - epublish SO - Sci Rep. 2021 Jul 7;11(1):14031. doi: 10.1038/s41598-021-93484-2.