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Inactivation of the Fragile Histidine Triad Gene: Comparison
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Please note this is a comparison between Version 1 by Guangwen Cao and Version 2 by Jessie Wu.

Tumor development follows an evolutionary pattern of "mutation-selection-adaptation", characterized by exogenous oncogenic induction and endogenous replicative stress. The fragile histidine triad (FHIT) is a tumor suppressor. Tumor suppressor genes with regular expression inhibit cell proliferation and tumorigenesis. Decreased FHIT expression leads to the malignant transformation of affected cells and promotes the evolutionary development of cancer. Aberrant transcripts or decreases in the transcription and translation of the FHIT are present in at least 50% of preneoplastic lesions and human cancers, especially in esophageal, lung, liver, stomach, pancreatic, kidney, skin, breast, and cervical cancers. Abnormal expression of the FHIT is also evident in hyperplastic lesions, suggesting that the inactivation of the FHIT plays a vital role in inhibiting the formation of early preneoplastic and premalignant lesions. There are three basic pathways leading to the aberrant expression of the FHIT: replication stress, loss of heterozygous (LOH), and CpG methylation at the promoter region.

  • fragile histidine triad
  • cancer Evo-Dev
  • genomic instability

1. Introduction

Over the past few decades, cancer has become the second leading cause of human death [1], leading to enormous economic and medical burden. Cancer development represents an evolutionary process. Many attempts have been made to identify possible causes and evolutionary factors for cancer [2]. Cancers of most histological types result from persistent stimulation of both exogenous and endogenous carcinogenic factors. The endogenous contributors of carcinogenesis mainly includes ageing, genetic predisposition, metabolic syndrome, and non-resolving inflammation [3], while the exogenous contributors includes tobacco smoking, air pollution, radiation, toxins such as aflatoxin, and chronic infection with viruses and bacteria. Usually, exogenous oncogenic factors induce carcinogenesis via activating endogenous factors such as apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) family members and/or inactivating another group of endogenous factors including the fragile histidine triad (FHIT). Interaction of exogenous contributors and endogenous contributors should be important in understanding the mechanisms of carcinogenesis. For instance, hepatitis B virus (HBV)-induced hepatocarcinogenesis is significantly associated with genetic predisposition-determined immune selection of some HBV mutations, HBV integration into human genome, and non-resolving inflammation caused by HBV replication [4][5]. A cancer evolutionary theory presented by Henry Heng states that due to either exogenous oncogenic factors such as viral/bacterial infections, exposures to carcinogens and other stressors, and/or endogenous factors such as tissue/organs constrains or chromosomal instability, genomic chaos appears in a cell, leading to genomic disorganization, aneuploidy, and polyploid giant cancer cells. This is called the macroscopic stage of cancer evolution, or macroevolution, a discontinuous and rapid process causing the entire cell karyotype to be reorganized. This process is followed by a slower phase of continuous microevolution, or stepwise Darwinian clonal evolution, and a process of adaptation and selection then passes on new karyotypes in a gradual, slow and continuous manner, eventually evolving into cancer [6][7]. During this microevolutionary stage, the positive selection of cancer gene mutations and epigenetic factors can contribute to mutated cell growth [8]. Continuous cycling between macroevolution and microevolution via the polyploid and diploid genomes creates a highly dynamic evolving system for malignant transformation in response to endogenous and exogenous stresses [9]. The process of tumorigenesis follows an evolutionary pattern of “mutation-selection-adaptation” in affected cells [5][10]. Typically, mutations in acute inflammation are quickly cleared or repaired and do not drive cancer development [11]. In persistent external stimuli or chronic unresolved inflammation, proinflammatory molecules such as interleukin-6 (IL-6) may trans-activate the expression levels and/or alter the expression patterns of corresponding mutation-promoting genes including activation-induced deaminase (AID)/APOBEC3 family members and epigenetic modifying genes such as histone deacetylases (HDAC) within normal cells, resulting in multiple somatic mutations and epigenetic changes in cell cycle- and metabolism-related genes that can accumulate in the affected cells [5]. Endogenous APOBEC3 cytosine deaminases generate prevalent mutational signatures in human cancer cells [12][13]. During HBV-induced hepatocarcinogenesis, a large number of HCC-risk HBV mutations, aneuploidy, and somatic mutations emerge, which facilitates the evolutionary development of hepatocellular carcinoma (HCC). The affected cells might transform surrounding fibroblasts into cancer-associated fibroblasts (CAFs) via secreting some proinflammatory cytokines. CAFs recruit some immune inhibiting cells including M2 macrophage, myeloid derived suppressor cell, neutrophil, regulatory T (Treg) cells, and endothelial to establish the tumor microenvironment (TME) [5][10]. During HBV-induced hepatocarcinogenesis, the HBV mutations in the HBx gene and the large S gene, which are generated by incompetent immunity during the chronic infection, in turn promote the generation of pro-inflammatory TME via secreting plasminogen activator inhibitor-1 and activating STAT3 signaling pathways, respectively [14][15]. Under selection pressures of TME and accompanying hypoxia, a small number of viral or somatic mutations conferring “stemness” and survival advantage to the mutated cells are selected out. High-grade tumor development is remarkably similar to pre-embryogenic development [9]. Retro-differentiation or reverse development, which is in contrast to embryogenic development, is common in cancer development. When positive selection outweighs negative selection, some driver mutations accumulate, leading to cancer development, recurrence, and metastasis [16][17]. Finally, these cells gain stemness and strong clonal capacity through reverse differentiation and/or epithelial–mesenchymal transition (EMT), adapting to the TME [5][10][18][19]. Based on evidence obtained in HBV-induced hepatocarcinogenesis and other research, rwesearchers proposed a novel theory of cancer development, namely Cancer Evo-Dev [5][10].
Throughout the process, the APOBEC3 signature mutation is a key to the signature mutation of most cancer types [12][13][20]. Aberrant expression of APOBEC3B can generate several C>U or C>T mutations in the genome that drive cancer development [21][22]. APOBEC3B mutations prefer to induce mutation in single-stranded DNA (ssDNA) [23]. Therefore, genes that promote the rise of ssDNA in the genome are critical in cancer evolution. Decreased FHIT expression, especially FHIT deletion, increases double-bond breaks in the genome and increases levels of ssDNA [24][25]. As ssDNA is an optimal substrate for the AID/APOBEC3 cytidine deaminases, the FHIT facilitates the mutagenic effect of AID/APOBEC3s. Thus, the FHIT might bridge macroevolution and microevolution, the two sequential forms of cancer evolution. As discussed late in this article, FHIT loss facilitates the development of the EMT. Thus, the role of the FHIT is indispensable in Cancer Evo-Dev.
The FHIT gene, located on chromosome 3p14.2, was identified in 1996 through exon capture [26]. The FHIT is a histidine triplet protein superfamily member, a diadenosine 59,5–P1, P3-triphosphate (Ap3A) hydrolase. The FHIT gene consists of ten exons, of which exons one to four and ten are involved only in transcription. Exons five to nine are protein codons that form an open reading frame (ORF), encoding a small protein of 147 amino acids [25]. The 5′ end contains a noncoding region, and the 3′ untranslated region has a poly-A consensus sequence and a poly-A tail. The FHIT functions as a tumor suppressor. The tumorigenicity of the FHIT-transfected cells is significantly reduced in vivo [25][27].

2. The Fragile Histidine TriadIT/FRA3B Is Sensitive to Replication Pressure

The FHIT gene spans a 2-Mb genome and contains one of the most common fragile sites (CFSs), FRA3B [28]. FRA3B deletions are frequently observed in cancer cells due to endogenous or exogenous damage. The corresponding deletion of the FHIT protein after FRA3B deletion may predict malignant tumor formation [29][30]. Studies show that the changes in the FHIT expression are associated with FRA3B deletion [31]. CFSs are preferentially unstable in pre-cancerous lesions or preneoplastic stages, leading to altered gene function during tumorigenesis or progression [32]. CFSs are genomic loci prone to the formation of breaks or gaps on metaphase chromosomes, which are characterized by AT-rich sequences, complex replication, and transcriptional repression due to late replication timing and large transcription units [33]. The completion of replication at CFS occurs very late in the cell cycle at mitosis through a process termed mitotic DNA synthesis (MiDAS) [34]. The transcriptional process of oversized genes often extends well beyond one cell cycle and even into the next, leading to simultaneous replication and transcription and creating "fragility" [35]. Typically, CFSs are stabilized by relaxing the DNA superhelix and restricting the formation of R-loops to resolve transcription–replication collision [32][36][37]. CFSs are hypersensitive to replication stress. When stimulated by exogenous or endogenous factors, they are highly susceptible to breakage [38]. Early pre-cancerous lesions create a continuous environment of replication stress. FRA3B is one of the most common CFSs, and exposure to constant stress predisposes it to more breakage due to replication–transcription conflicts.

3. Repeated Breakages and Repairs Cause Loss of Heterozygosity in the Fragile Histidine ITriad 

After DNA damage, DNA repair is performed by the flanking, long interspersed nuclear element 1. Aphidicolin blocks replication forks in replicating S-phase cells, resulting in DNA double-strand breaks (DSBs). The extent of DNA end excision is the primary factor determining whether repair proceeds via non-homologous end joining (NHEJ) or homologous recombination. NHEJ occurs at any time throughout the cell cycle, unlike homologous recombination, which occurs mainly in the S/G2 phase [33][39]. Prolonged and repeated breaks and repairs cause improper segregation of chromosomes during mitosis, resulting in LOH [40][41]. LOH is evident at the FHIT in more than 90% of lung tumors, and at least one allele of three markers (D3S1300, D3S1312, or D3S1313) is lost in the primary tumor and the corresponding bronchoalveolar lavage fluid [42]. There are 11 recurring breakpoint/repair regions, and deletions occur mainly between intron three (near exon four) and intron five (150 kb distal to exon five) [43]. In addition, splicing events also affect the FHIT expression, usually appearing as exon 4–6 deletions caused by aberrant splicing in exons 3–7 and exon 4–8 deletions caused by aberrant splicing in exons 3–9. 82% of colorectal adenocarcinomas have the FHIT deletions, fragment insertions, point mutations, or alternative splicing in exon ten [44]. Notably, partial deletion of the FRA3B sequence does not reduce the occurrence of breakages and instability within the remaining sequences at the FHIT gene, with the highest frequency of chromosomal breaks and gaps occurring in the 300-kb interval between exon four and D3S1300 [45]. Depletion of FHIT neither activate the DNA damage response nor cause cell cycle arrest, allowing continued cell proliferation and ongoing chromosomal instability. LOH can be fatal in inactivating the function of the FHIT, which prevents the FHIT from acting as a “gene caretaker”, leading to a significant increase in genomic instability.

4. CpG Methylation at the Fragile Histidine TriadIT Promoter Region

Methylation at the FHIT gene promoter is also an essential mechanism of the promoter inactivation. The methylation tends to suppress the expression of the FHIT, allowing the generation and accumulation of mutations in tumors that drive the evolutionary development of cancer [29]. In locally advanced lung cancer, FHIT mRNA expression is frequently absent via the CpG methylation [46]. For Asian populations, aberrant methylation of the FHIT can be used as a potential diagnostic biomarker for non-small cell lung cancer [46]. The FHITlow/pHER2high signature is associated with the higher size of tumors, lymph node involvement, and late TNM stages, serving as an independent predictor of poor prognosis in lung adenocarcinoma whilst also being predictive of a poor response to immune checkpoint inhibitors in advanced lung cancer [47]. Double allelic inactivation of the FHIT gene and its complete silencing of the FHIT gene by heterozygous deletion has also been found in breast cancer [48]. Exposure to ambient air pollution throughout life may be associated with DNA methylation of some tumor suppressor genes such as FHIT in breast tumor tissue [49]. In esophageal cancer, variations in the FHIT gene mainly arise from a loss of exon five or eight or hypermethylation of the FHIT promoter [50]. Nevertheless, it remains unknown how the CpG methylation is induced. Because inactivation is often observed at the early stages of pre-cancerous lesions, it is likely to be caused by chronic inflammation or activated oncogenes.

References

  1. Siegel, R.L.; Miller, K.D.; Jemal, A Cancer statistics. CA Cancer J. Clin 2020, 70, 7-30, https://doi.org/10.3322/caac.21590.
  2. Somarelli, J.A.; DeGregori, J.; Gerlinger, M.; Heng, H.H.; Marusyk, A.; Welch, D.R.; Laukien, F.H. Questions to guide cancer evolution as a framework for furthering progress in cancer research and sustainable patient outcomes. Medical oncology 2022, 39(9), 137, 10.1007/s12032-022-01721-z.
  3. Greten, F.R.; Grivennikov, S.I. Inflammation and Cancer: Triggers, Mechanisms, and Consequenc. Immunity 2019, 51(1), 27-41, 10.1016/j.immuni.2019.06.025.
  4. Zhang, Q., Ji, X. W., Hou, X. M., Lu, F. M., Du, Y., Yin, J. H., Sun, X. Y., Deng, Y., Zhao, J., Han, X., Yang, G. S., Zhang, H. W., Chen, X. M., Shen, H. B., Wang, H. Y., Cao, G. W. Effect of functional nuclear factor-kappaB genetic polymorphisms on hepatitis B virus persistence and their interactions with viral mutations on the risk of hepatocellular carcinoma. Annals of oncology : official journal of the European Society for Medical Oncology 2014, 25(12), 2413-2419, 10.1093/annonc/mdu451.
  5. Cao, G.-W. Cancer Evo-Dev, a novel hypothesis derived from studies on hepatitis B virus-induced carcinogenesis. Hepatoma Research 2017, 3, 241-59, 10.20517/2394-5079.2017.45.
  6. Paul, D Cancer as a form of life: Musings of the cancer and evolution symposium. Progress in biophysics and molecular biology 2021, 165, 120-139, 10.1016/j.pbiomolbio.2021.05.003.
  7. Heng, H.H.Q.; Stevens, J.B.; Liu, G.; Bremer, S.W.; Ye, K.J.; Reddy, P.-V.; Wu, G.S.; Wang, Y.A.; Tainsky, M.A.; Ye, C.J.; et al. Stochastic cancer progression driven by non-clonal chromosome aberrations. Journal of cellular physiology 2006, 208(2), 461-472.
  8. Heng, J.; Heng, H.H. Genome chaos: Creating new genomic information essential for cancer macroevolution. Seminars in cancer biology 2022, 81, 160-175, 10.1016/j.semcancer.2020.11.003..
  9. Li, X.; Zhong, Y.; Zhang, X.; Sood, A.K.; Liu, J. Spatiotemporal view of malignant histogenesis and macroevolution via formation of polyploid giant cancer cells. Oncogene 2023, Online ahead of print, Online ahead of print, 10.1038/s41388-022-02588-0.
  10. Liu, W.; Deng, Y.; Li, Z.; Chen, Y.; Zhu, X.; Tan, X.; Cao, G. Cancer Evo–Dev: A Theory of Inflammation-Induced Oncogenesis. Frontiers in immunology 2021, 12, 768098, 10.3389/fimmu.2021.768098.
  11. Martincorena, I.; Campbell, P.J. Somatic mutation in cancer and normal cells. Science 2015, 349, 6255, 10.1126/science.aab4082.
  12. Petljak, M., Dananberg, A., Chu, K., Bergstrom, E. N., Striepen, J., von Morgen, P., Chen, Y., Shah, H., Sale, J. E., Alexandrov, L. B., Stratton, M. R., Maciejowski, J. Mechanisms of APOBEC3 mutagenesis in human cancer cells. Nature 2022, 607(7920), 799-807, 10.1038/s41586-022-04972-y.
  13. Alexandrov, L.B.; Kim, J.; Haradhvala, N.J.; Huang, M.N.; Ng, A.W.T.; Wu, Y.; Boot, A.; Covington, K.R.; Gordenin, D.A.; Bergstrom, E.N.; et al.et al. The repertoire of mutational signatures in human cancer. Nature 2020, 578(7793), 94-101, 10.1038/s41586-020-1943-3.
  14. Pu, R., Liu, W., Zhou, X., Chen, X., Hou, X., Cai, S., Chen, L., Wu, J., Yang, F., Tan, X., Yin, J., Wang, X., Cao, G. The Effects and Underlying Mechanisms of Hepatitis B Virus X Gene Mutants on the Development of Hepatocellular Carcinoma. Frontiers in oncology 2022, 12, 836517, 10.3389/fonc.2022.836517.
  15. Liu, W., Cai, S., Pu, R., Li, Z., Liu, D., Zhou, X., Yin, J., Chen, X., Chen, L., Wu, J., Tan, X., Wang, X., & Cao, G. HBV preS Mutations Promote Hepatocarcinogenesis by Inducing Endoplasmic Reticulum Stress and Upregulating Inflammatory Signaling. Cancers 2022, 14(13), 3274, 10.3390/cancers14133274..
  16. Martincorena, I.; Raine, K.M.; Gerstung, M.; Dawson, K.J.; Haase, K.; Van Loo, P.; Davies, H.; Stratton, M.R.; Campbell, P.J. Universal Patterns of Selection in Cancer and Somatic Tissues. Cell 2017, 171(5), 1029-1041, 10.1016/j.cell.2017.09.042.
  17. Rheinbay, E.; Nielsen, M.M.; Abascal, F.; Wala, J.A.; Shapira, O.; Tiao, G.; Hornshøj, H.; Hess, J.M.; Juul, R.I.; Lin, Z.; et al.et al. Analyses of non-coding somatic drivers in 2658 cancer whole genomes. Nature 2020, 578, 102-111, 10.1038/s41586-020-1965-x.
  18. Suarez-Carmona, M.; Lesage, J.; Cataldo, D.; Gilles, C. EMT and inflammation: Inseparable actors of cancer progression. Molecular oncology 2017, 11(7), 805-823, 10.1002/1878-0261.12095.
  19. Babaei, G.; Aziz, S.G.-G.; Jaghi, N.Z.Z. EMT, cancer stem cells and autophagy; The three main axes of metastasis. Biomedicine & pharmacotherapy 2021, 133, 110909, 10.1016/j.biopha.2020.110909.
  20. Jarvis, M.; Ebrahimi, D.; Temiz, N.A.; Harris, R.S. Mutation Signatures Including APOBEC in Cancer Cell Lines. JNCI cancer spectrum 2018, 2(1), pky002, 10.1093/jncics/pky002.
  21. Venkatesan, S.; Angelova, M.; Puttick, C.; Zhai, H.; Caswell, D.R.; Lu, W.-T.; Dietzen, M.; Galanos, P.; Evangelou, K.; Bellelli, R.; et al.et al. Induction of APOBEC3 Exacerbates DNA Replication Stress and Chromosomal Instability in Early Breast and Lung Cancer Evolution. Cancer discovery 2021, 11(10), 2456-2473, 10.1158/2159-8290.CD-20-0725.
  22. Liu, W., Ji, H., Zhao, J., Song, J., Zheng, S., Chen, L., Li, P., Tan, X., Ding, Y., Pu, R., Yin, J., Han, X., & Cao, G. Transcriptional repression and apoptosis influence the effect of APOBEC3A / 3B functional polymorphisms on biliary tract cancer risk. International journal of cancer 2022, 150(11), 1825-1837, 10.1002/ijc.33930.
  23. Brown, A.L.; Collins, C.D.; Thompson, S.; Coxon, M.; Mertz, T.M.; Roberts, S.A. Single-stranded DNA binding proteins influence APOBEC3A substrate preference. Scientific reports 2021, 11(1), 21008, 10.1038/s41598-021-00435-y.
  24. Salter, J. D., & Smith, H. C. Modeling the Embrace of a Mutator: APOBEC Selection of Nucleic Acid Ligands. Trends in biochemical sciences 2018, 43(8）, 606-622, 10.1016/j.tibs.2018.04.013.
  25. Waters, C.E.; Saldivar, J.C.; Hosseini, S.A.; Huebner, K. The FHIT gene product: Tumor suppressor and genome “caretaker”. Cellular and molecular life sciences 2014, 71(23), 4577-4587, 10.1007/s00018-014-1722-0.
  26. Ohta, M.; Inoue, H.; Cotticelli, M.G.; Kastury, K.; Baffa, R.; Palazzo, J.; Siprashvili, Z.; Mori, M.; McCue, P.; Druck, T.; et al.et al The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers. Cell 1996, 84, 587-597.
  27. Palumbo, E.; Tosoni, E.; Matricardi, L.; Russo, A. Genetic instability of the tumor suppressor gene FHIT in normal human cells. Genes, chromosomes & cancer 2013, 52(9), 832-844, 10.1002/gcc.22079.
  28. Gao, G.; Smith, D.I. Very large common fragile site genes and their potential role in cancer development. Cellular and molecular life sciences 2014, 71(23), 4601-4615, 10.1007/s00018-014-1753-6.
  29. Wu, D.-W.; Hsu, N.-Y.; Wang, Y.-C.; Lee, M.-C.; Cheng, Y.-W.; Chen, C.-Y.; Lee, H. c-Myc suppresses microRNA-29b to promote tumor aggressiveness and poor outcomes in non-small cell lung cancer by targeting FHIT. Oncogene 2015, 34, 2072-2082, 10.1038/onc.2014.152.
  30. Da Silva, J.; Jouida, A.; Ancel, J.; Dalstein, V.; Routhier, J.; Delepine, G.; Cutrona, J.; Jonquet, A.; Dewolf, M.; Birembaut, P.; et al.et al. FHIT(low) /pHER2(high) signature in non-small cell lung cancer is predictive of anti-HER2 molecule efficacy. The Journal of pathology 2020, 251(2), 187-199, 10.1002/path.5439.
  31. Guadarrama-Ponce, R.; Aranda-Anzaldo, A. The epicenter of chromosomal fragility of Fra14A2, the mouse ortholog of human FRA3B common fragile site, is largely attached to the nuclear matrix in lymphocytes but not in other cell types that do not express such a fragility. Journal of cellular biochemistry 2020, 121(3), 2209-2224, 10.1002/jcb.29444.
  32. Sarni, D.; Sasaki, T.; Tur-Sinai, M.I.; Miron, K.; Rivera-Mulia, J.C.; Magnuson, B.; Ljungman, M.; Gilbert, D.M.; Kerem, B. 3D genome organization contributes to genome instability at fragile sites. Nature communications 2020, 11(1), 3613, 10.1038/s41467-020-17448-2.
  33. Ji, F.; Liao, H.; Pan, S.; Ouyang, L.; Fu, Z.; Zhang, F.; Geng, X.; Wang, X.; Li, T.; Liu, S.; et al.et al. Genome-wide high-resolution mapping of mitotic DNA synthesis sites and common fragile sites by direct sequencing. Cell research 2020, 30(11), 1009-1023, 10.1038/s41422-020-0357-y.
  34. Epum, E.A.; Haber, J.E. DNA replication: The recombination connection. Trends in cell biology 2022, 32(1), 45-57, 10.1016/j.tcb.2021.07.005.
  35. Park, S.H.; Bennett-Baker, P.; Ahmed, S.; Arlt, M.F.; Ljungman, M.; Glover, T.W.; Wilson, T.E. Locus-specific transcription silencing at the FHIT gene suppresses replication stress-induced copy number variant formation and associated replication delay. Nucleic acids research 2021, 49(13), 7507-7524, 10.1093/nar/gkab559.
  36. García-Muse, T.; Aguilera, A. R Loops: From Physiological to Pathological Roles. Cell 2019, 179, 604-618, 10.1016/j.cell.2019.08.055.
  37. Niehrs, C.; Luke, B. Regulatory R-loops as facilitators of gene expression and genome stability. Nature reviews. Molecular cell biology 2020, 21, 167-178, 10.1038/s41580-019-0206-3.
  38. Minocherhomji, S.; Ying, S.; Bjerregaard, V.A.; Bursomanno, S.; Aleliunaite, A.; Wu, W.; Mankouri, H.W.; Shen, H.; Liu, Y.; Hickson, I.D.; et al. Replication stress activates DNA repair synthesis in mitosis. Nature 2015, 528, 286-290, 10.1038/nature16139.
  39. Xu, Y.; Xu, D. Repair pathway choice for double-strand breaks. Essays in biochemistry 2020, 64, 765-777, 10.1042/EBC20200007.
  40. Rabelo, R.A.S.; Antunes, L.; Etchebehere, R.M.; Nomelini, R.S.; Nascentes, G.A.N.; Murta, E.F.C.; Pedrosa, A.L. Loss of heterozygosity in the fragile histidine triad (FHIT) locus and expression analysis of FHIT protein in patients with breast disorders. Clinical and experimental obstetrics & gynecology 2013, 40, 89-94.
  41. Yoshioka, K.-I.; Kusumoto-Matsuo, R.; Matsuno, Y.; Ishiai, M. Genomic Instability and Cancer Risk Associated with Erroneous DNA Repair. International journal of molecular sciences 2021, 22, 12254, 10.3390/ijms222212254.
  42. Wali, A.; Srinivasan, R.; Shabnam, M.S.; Majumdar, S.; Joshi, K.; Behera, D. Loss of Fragile Histidine Triad Gene Expression in Advanced Lung Cancer Is Consequent to Allelic Loss at 3p14 Locus and Promoter Methylation. Molecular cancer research 2006, 4, 93-99, 10.1158/1541-7786.MCR-05-0070.
  43. Saldivar, J.C.; Miuma, S.; Bene, J.; Hosseini, S.A.; Shibata, H.; Sun, J.; Wheeler, L.J.; Mathews, C.K.; Huebner, K. Initiation of Genome Instability and Preneoplastic Processes through Loss of Fhit Expression. PLoS genetics 2012, 8, e1003077, 10.1371/journal.pgen.1003077.
  44. Cao, J.; Li, W.; Xie, J.; Du, H.; Tang, W.; Wang, H.; Chen, X.; Xiao, W.; Li, Y. Down-regulation of FHIT inhibits apoptosis of colorectal cancer: Mechanism and clinical implication. Surgical oncology 2006, 15, 223-233, 10.1016/j.suronc.2007.01.006.
  45. Hassan, I.; Naiyer, A.; Ahmad, F. Fragile histidine triad protein: Structure, function, and its association with tumorogenesis. Journal of cancer research and clinical oncology 2010, 136, 333-350, 10.1007/s00432-009-0751-9.
  46. Czarnecka, K.H.; Migdalska-S ˛ek, M.; Doma ´nska, D.; Pastuszak-Lewandoska, D.; Dutkowska, A.; Kordiak, J.; Nawrot, E.; Kiszałkiewicz, J.; Antczak, A.; Brzezia ´nska-Lasota, E.; et al. FHIT promoter methylation status, low protein and high mRNA levels in patients with non-small cell lung cancer. International journal of oncology 2016, 49, 1175-1184, 10.3892/ijo.2016.3610.
  47. Brisebarre, A.; Ancel, J.; Ponchel, T.; Loeffler, E.; Germain, A.; Dalstein, V.; Dormoy, V.; Durlach, A.; Delepine, G.; Deslée, G.; et al.et al. Transcriptomic FHITlow/pHER2high signature as a predictive factor of outcome and immunotherapy response in non-small cell lung cancer. Frontiers in immunology 2022, 13, 1058531, 10.3389/fimmu.2022.1058531.
  48. Ismail, H.M.S.; Medhat, A.M.; Karim, A.M.; Zakhary, N.I. FHIT gene and flanking region on chromosome 3p are subjected to extensive allelic loss in Egyptian breast cancer patients. Molecular carcinogenesis 2011, 50, 625-634, 10.1002/mc.20797.
  49. Callahan, C.L.; Bonner, M.R.; Nie, J.; Han, D.; Wang, Y.; Tao, M.-H.; Shields, P.G.; Marian, C.; Eng, K.H.; Trevisan, M.; et al.et al. Lifetime exposure to ambient air pollution and methylation of tumor suppressor genes in breast tumors. Environmental research 2017, 161, 418-424, 10.1016/j.envres.2017.11.040.
  50. Ma, K.; Cao, B.; Guo, M. The detective, prognostic, and predictive value of DNA methylation in human esophageal squamous cell carcinoma. Clinical epigenetics 2016, 8, 43, 10.1186/s13148-016-0210-9.
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