{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T23:39:29Z","timestamp":1787009969053,"version":"build-2736575974"},"reference-count":41,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2021,8,6]],"date-time":"2021-08-06T00:00:00Z","timestamp":1628208000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      Genetic alterations in\n                      <jats:italic toggle=\"yes\">CDKN2A<\/jats:italic>\n                      tumor suppressor gene on chromosome 9p21 confer a predisposition to childhood acute lymphoblastic leukemia (ALL). Genome-wide association studies have identified missense variants in\n                      <jats:italic toggle=\"yes\">CDKN2A<\/jats:italic>\n                      associated with the development of ALL. This study systematically evaluated the effects of\n                      <jats:italic toggle=\"yes\">CDKN2A<\/jats:italic>\n                      coding variants on ALL risk.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We genotyped the\n                      <jats:italic toggle=\"yes\">CDKN2A<\/jats:italic>\n                      coding region in 308 childhood ALL cases enrolled in CCCG-ALL-2015 clinical trials by Sanger Sequencing. Cell growth assay, cell cycle assay, MTT-based cell toxicity assay, and western blot were performed to assess the\n                      <jats:italic toggle=\"yes\">CDKN2A<\/jats:italic>\n                      coding variants on ALL predisposition.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified 10 novel exonic germline variants, including 6 missense mutations (p.A21V, p.G45A and p.V115L of p16\n                      <jats:sup>INK4A<\/jats:sup>\n                      ; p.T31R, p.R90G, and p.R129L of p14\n                      <jats:sup>ARF<\/jats:sup>\n                      ) and 1 nonsense mutation and 1 heterozygous termination codon mutation in exon 2 (p16\n                      <jats:sup>INK4A<\/jats:sup>\n                      p.S129X). Functional studies indicate that five novel variants resulted in reduced tumor suppressor activity of p16\n                      <jats:sup>INK4A<\/jats:sup>\n                      , and increased the susceptibility to the leukemic transformation of hematopoietic progenitor cells. Compared to other variants, p.H142R contributes higher sensitivity to CDK4\/6 inhibitors.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      These findings provide direct insight into the influence of inherited genetic variants at the\n                      <jats:italic toggle=\"yes\">CDKN2A<\/jats:italic>\n                      coding region on the development of ALL and the precise clinical application of CDK4\/6 inhibitors.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1097\/fpc.0000000000000451","type":"journal-article","created":{"date-parts":[[2021,8,9]],"date-time":"2021-08-09T18:37:50Z","timestamp":1628534270000},"page":"43-50","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":12,"title":["The functional role of inherited CDKN2A variants in childhood acute lymphoblastic leukemia"],"prefix":"10.1097","volume":"32","author":[{"given":"Chunjie","family":"Li","sequence":"first","affiliation":[{"name":"Department of Hematology\/Oncology"},{"name":"Institute of Pediatrics, Affiliated Guangzhou Women and Children\u2019s Medical Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinying","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Hematology\/Oncology"},{"name":"Institute of Pediatrics, Affiliated Guangzhou Women and Children\u2019s Medical Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingyi","family":"He","sequence":"additional","affiliation":[{"name":"Department of Hematology\/Oncology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziping","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Hematology\/Oncology"},{"name":"Institute of Pediatrics, Affiliated Guangzhou Women and Children\u2019s Medical Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiabi","family":"Qian","sequence":"additional","affiliation":[{"name":"Department of Hematology\/Oncology"},{"name":"Institute of Pediatrics, Affiliated Guangzhou Women and Children\u2019s Medical Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Hematology\/Oncology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Hematology\/Oncology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Qiu","sequence":"additional","affiliation":[{"name":"Bioinspired Engineering and Biomechanics Center, Xi\u2019an Jiaotong University, Xi\u2019an, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Lian","sequence":"additional","affiliation":[{"name":"Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maoxiang","family":"Qian","sequence":"additional","affiliation":[{"name":"Institute of Pediatrics and Department of Hematology and Oncology, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Hematology\/Oncology"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2021,8,6]]},"reference":[{"key":"R1-20250808","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.1056\/NEJMra1400972","article-title":"Acute lymphoblastic leukemia in children.","volume":"373","author":"Hunger","year":"2015","journal-title":"N Engl J Med"},{"key":"R2-20250808","doi-asserted-by":"crossref","first-page":"e577","DOI":"10.1038\/bcj.2017.53","article-title":"Acute lymphoblastic leukemia: a comprehensive review and 2017 update.","volume":"7","author":"Terwilliger","year":"2017","journal-title":"Blood Cancer J"},{"key":"R3-20250808","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1080\/17474086.2020.1685866","article-title":"Recent advances in genetic predisposition to 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