{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:43:30Z","timestamp":1790700210551,"version":"4.1.0"},"reference-count":35,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"5465","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Science"],"published-print":{"date-parts":[[2000,4,21]]},"abstract":"<jats:p>\n            T cells from patients who had received chemotherapy for B-lineage acute lymphocytic leukemia were studied to determine whether genetic instability, a principal characteristic of cancer cells, can also occur in nonmalignant cells. Consistent with expectations for a genetic instability phenotype, multiple mutations were detected in the hypoxanthine-guanine phosphoribosyltransferase (\n            <jats:italic>HPRT<\/jats:italic>\n            ) reporter gene in independently isolated mutant T cells expressing identical rearranged T cell receptor \u03b2 (TCR\u03b2) gene hypervariable regions. These results indicate that cancer treatment can lead to genetic instability in nonmalignant cells in some individuals. They also suggest a mechanistic paradigm for the induction of second malignancies and drug resistance.\n          <\/jats:p>","DOI":"10.1126\/science.288.5465.514","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T09:50:55Z","timestamp":1027763455000},"page":"514-517","source":"Crossref","is-referenced-by-count":40,"title":["Emergence of Genetic Instability in Children Treated for Leukemia"],"prefix":"10.1126","volume":"288","author":[{"given":"B. A.","family":"Finette","sequence":"first","affiliation":[{"name":"Department of Pediatrics,"},{"name":"Department of Microbiology and Molecular Genetics,"},{"name":"Vermont Cancer Center, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. C.","family":"Homans","sequence":"additional","affiliation":[{"name":"Department of Pediatrics,"},{"name":"Vermont Cancer Center, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. J.","family":"Albertini","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics,"},{"name":"Vermont Cancer Center, and"},{"name":"Department of Medicine, University of Vermont, Medical Alumni Building, Burlington, VT 05405, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_1_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/25292"},{"key":"e_1_3_1_3_2","unstructured":"L. A. Loeb in Advances in Cancer Research G. F. Van de Woode and G. Klein Eds. (Academic Press San Diego 1998) vol. 72 pp. 26\u201356."},{"key":"e_1_3_1_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/4687"},{"key":"e_1_3_1_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/45836"},{"key":"e_1_3_1_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/386761a0"},{"key":"e_1_3_1_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/32520"},{"key":"e_1_3_1_8_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V93.11.3587"},{"key":"e_1_3_1_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81832-2"},{"key":"e_1_3_1_10_2","unstructured":"Peripheral blood samples were obtained from patients at the time of diagnosis with ALL and from patients previously treated for ALL at the Pediatric Oncology Clinic at the University of Vermont. Patients at the time of bone marrow relapse were also recruited from other Pediatric Oncology Group (POG) institutions before treatment began. Informed consent was obtained and procedures approved by the Committee on Human Research at the University of Vermont and other POG institutions were followed."},{"key":"e_1_3_1_11_2","unstructured":"Peripheral blood was separated and the mononuclear cell fraction was obtained for the T cell cloning assay within 12 to 24 hours of its collection. The T cell cloning assay and analysis have been described [see"},{"key":"e_1_3_1_11_3","doi-asserted-by":"publisher","DOI":"10.1016\/0027-5107(94)90157-0"},{"key":"e_1_3_1_12_2","doi-asserted-by":"crossref","unstructured":"B. A. Finette et al. Mutat. Res. 308 223 (1994).","DOI":"10.1016\/0027-5107(94)90157-0"},{"key":"e_1_3_1_13_2","unstructured":"Mutant frequencies in subjects at diagnoses remission and relapse were compared with normal controls by the nonparametric Kruskal\u2013Wallis test. Pairwise differences between groups were assessed by Mann\u2013Whitney tests with a Bonferroni adjustment for multiple comparisons. Linear regression analysis was used to examine the relationship between the logarithm of Mf (lnMf) and months since diagnosis."},{"key":"e_1_3_1_14_2","unstructured":"H. Hirota et al. Mutat. Res. 315 95 (1994)."},{"key":"e_1_3_1_15_2","doi-asserted-by":"crossref","unstructured":"S. Koishi et al. Mutat. Res. 422 213 (1998).","DOI":"10.1016\/S0027-5107(98)00199-7"},{"key":"e_1_3_1_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/0888-7543(90)90545-6"},{"key":"e_1_3_1_17_2","unstructured":"J. C. Fuscoe et al. Cancer Res. 51 6001 (1991)."},{"key":"e_1_3_1_18_2","unstructured":"B. A. Finette J. P. O'Neill"},{"key":"e_1_3_1_18_3","doi-asserted-by":"publisher","DOI":"10.1038\/2640"},{"key":"e_1_3_1_19_2","doi-asserted-by":"crossref","unstructured":"N. F. Cariello et al. Nucleic Acids Res. 26 198 (1998).","DOI":"10.1093\/nar\/26.1.198"},{"key":"e_1_3_1_20_2","unstructured":"Because the HPRT gene is located on the X chromosome molecular analysis at the DNA\/RNA level was performed in a different way for mutant isolates from males and females [B. A. Finette J. P. O'Neill"},{"key":"e_1_3_1_20_3","doi-asserted-by":"publisher","DOI":"10.1038\/2640"},{"key":"e_1_3_1_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/302575a0"},{"key":"e_1_3_1_22_2","doi-asserted-by":"crossref","unstructured":"R. J. Albertini J. A. Nicklas T. R. Skopeck L. Recio J. P. O'Neill Mutat. Res. 400 381 (1998).","DOI":"10.1016\/S0027-5107(98)00063-3"},{"key":"e_1_3_1_23_2","unstructured":"To determine the clonality of peripheral HPRT mutant T cell clones we performed a two-step polymerase chain reaction (PCR) with about 10 4 cells from each isolate to perform a reverse transcriptase\u2013PCR amplification followed by a TCR\u03b2 gene hot start PCR with a V \u03b2 and C \u03b2 consensus primer mix. The resulting PCR product was purified and the highly polymorphic CDR3\/variable regions of TCR\u03b2 were sequenced."},{"key":"e_1_3_1_24_2","unstructured":"Supplementary material is available at www.sciencemag.org\/feature\/data\/1047822.shl"},{"key":"e_1_3_1_25_2","unstructured":"Single-letter abbreviations for amino acid residues are as follows: A Ala; C Cys; D Asp; E Glu; F Phe; G Gly; H His; I Ile; K Lys; L Leu; M Met; N Asn; P Pro; Q Gln; R Arg; S Ser; T Thr; V Val; W Trp; and Y Tyr."},{"key":"e_1_3_1_26_2","unstructured":"R. F. Branda J. P. O'Neil"},{"key":"e_1_3_1_26_3","first-page":"6603","volume":"51","author":"Sullivan L. M.","year":"1991","unstructured":"Sullivan L. M., Albertini R. J., Cancer Res. 51, 6603 (1991).","journal-title":"Cancer Res."},{"key":"e_1_3_1_27_2","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/18.8.1445"},{"key":"e_1_3_1_28_2","doi-asserted-by":"publisher","DOI":"10.1006\/scbi.1998.0092"},{"key":"e_1_3_1_29_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.micro.50.1.625"},{"key":"e_1_3_1_30_2","doi-asserted-by":"publisher","DOI":"10.1128\/jb.179.2.417-422.1997"},{"key":"e_1_3_1_31_2","unstructured":"C. R. Hunt et al. Cancer Res. 58 3986 (1998)."},{"key":"e_1_3_1_32_2","unstructured":"Supported by National Institute of Child Health & Human Development grant 1R29HD35309 National Cancer Institute (NCI) grant 1K01CA77737 grant 6103-98 from the Leukemia Society of America the Lake Champlain Cancer Research Organization the Vermont Chapter of the American Cancer Society the Art Ehrmann Cancer Fund and NCI grant P30CA22435 to the University of Vermont Cancer Center DNA Analysis Facility. We thank C-C. Duriex-Lu H. Kendall and J. Rivers for technical assistance; S. Billado for assistance with blood samples; and P. Vacek for statistical analyses."}],"container-title":["Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/science.288.5465.514","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,13]],"date-time":"2024-01-13T10:01:40Z","timestamp":1705140100000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/science.288.5465.514"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2000,4,21]]},"references-count":35,"journal-issue":{"issue":"5465","published-print":{"date-parts":[[2000,4,21]]}},"alternative-id":["10.1126\/science.288.5465.514"],"URL":"https:\/\/doi.org\/10.1126\/science.288.5465.514","relation":{},"ISSN":["0036-8075","1095-9203"],"issn-type":[{"value":"0036-8075","type":"print"},{"value":"1095-9203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2000,4,21]]}}}