human
The task is to decide the Hallmarks of Cancer (HOC) taxonomy of the article based on its abstract. The input is an abstract text. There are 10 topics you will need to decide whether the article is related to. Topics: sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, genomic instability and mutation, tumor promoting inflammation, cellular energetics, avoiding immune destruction. The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics.
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    INPUT: Genomic instability drives tumorigenesis , but how it is initiated in sporadic neoplasias is unknown . In early preneoplasias , alterations at chromosome fragile sites arise due to DNA replication stress . A frequent , perhaps earliest , genetic alteration in preneoplasias is deletion within the fragile FRA3B/FHIT locus , leading to loss of Fhit protein expression . Because common chromosome fragile sites are exquisitely sensitive to replication stress , it has been proposed that their clonal alterations in cancer cells are due to stress sensitivity rather than to a selective advantage imparted by loss of expression of fragile gene products . Here , we show in normal , transformed , and cancer-derived cell lines that Fhit-depletion causes replication stress-induced DNA double-strand breaks . Using DNA combing , we observed a defect in replication fork progression in Fhit-deficient cells that stemmed primarily from fork stalling and collapse . The likely mechanism for the role of Fhit in replication fork progression is through regulation of Thymidine kinase 1 expression and thymidine triphosphate pool levels ; notably , restoration of nucleotide balance rescued DNA replication defects and suppressed DNA breakage in Fhit-deficient cells . Depletion of Fhit did not activate the DNA damage response nor cause cell cycle arrest , allowing continued cell proliferation and ongoing chromosomal instability . This finding was in accord with in vivo studies , as Fhit knockout mouse tissue showed no evidence of cell cycle arrest or senescence yet exhibited numerous somatic DNA copy number aberrations at replication stress-sensitive loci . Furthermore , cells established from Fhit knockout tissue showed rapid immortalization and selection of DNA deletions and amplifications , including amplification of the Mdm2 gene , suggesting that Fhit loss-induced genome instability facilitates transformation . We propose that loss of Fhit expression in precancerous lesions is the first step in the initiation of genomic instability , linking alterations at common fragile sites to the origin of genome instability .
    OUTPUT:

agent
genomic instability and mutation;sustaining proliferative signaling;enabling replicative immortality
The task is to decide the Hallmarks of Cancer (HOC) taxonomy of the article based on its abstract. The input is an abstract text. There are 10 topics you will need to decide whether the article is related to. Topics: sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, genomic instability and mutation, tumor promoting inflammation, cellular energetics, avoiding immune destruction. The output should be topics from the above 10 topics, that are related to the input article. Please note one article can be related to multiple topics. Output format: provide a semicolon-separated list of relevant topics.
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    INPUT: Genomic instability drives tumorigenesis , but how it is initiated in sporadic neoplasias is unknown . In early preneoplasias , alterations at chromosome fragile sites arise due to DNA replication stress . A frequent , perhaps earliest , genetic alteration in preneoplasias is deletion within the fragile FRA3B/FHIT locus , leading to loss of Fhit protein expression . Because common chromosome fragile sites are exquisitely sensitive to replication stress , it has been proposed that their clonal alterations in cancer cells are due to stress sensitivity rather than to a selective advantage imparted by loss of expression of fragile gene products . Here , we show in normal , transformed , and cancer-derived cell lines that Fhit-depletion causes replication stress-induced DNA double-strand breaks . Using DNA combing , we observed a defect in replication fork progression in Fhit-deficient cells that stemmed primarily from fork stalling and collapse . The likely mechanism for the role of Fhit in replication fork progression is through regulation of Thymidine kinase 1 expression and thymidine triphosphate pool levels ; notably , restoration of nucleotide balance rescued DNA replication defects and suppressed DNA breakage in Fhit-deficient cells . Depletion of Fhit did not activate the DNA damage response nor cause cell cycle arrest , allowing continued cell proliferation and ongoing chromosomal instability . This finding was in accord with in vivo studies , as Fhit knockout mouse tissue showed no evidence of cell cycle arrest or senescence yet exhibited numerous somatic DNA copy number aberrations at replication stress-sensitive loci . Furthermore , cells established from Fhit knockout tissue showed rapid immortalization and selection of DNA deletions and amplifications , including amplification of the Mdm2 gene , suggesting that Fhit loss-induced genome instability facilitates transformation . We propose that loss of Fhit expression in precancerous lesions is the first step in the initiation of genomic instability , linking alterations at common fragile sites to the origin of genome instability .
    OUTPUT:
