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Steven J. Wang - One of the best experts on this subject based on the ideXlab platform.
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Downregulation of Fanconi anemia genes in sporadic head and neck squamous cell carcinoma.
ORL, 2007Co-Authors: Volkert B. Wreesmann, Cherry L. Estilo, David W. Eisele, Bhuvanesh Singh, Steven J. WangAbstract:Background/Aims: Much of our understanding of human cancer has come from studies of the hereditary cancer predisposition syndromes. Fanconi anemia (FA) is an autosomal recessive disorder characterized by cellular hypersensitivity to DNA crosslinking agents, progressive bone marrow failure, and cancer predisposition to solid malignancies, especially head and neck squamous cell carcinoma (HNSCC). Since FA pathway-deficient cells are hypersensitive to DNA crosslinking chemotherapy agents, the presence of somatic FA gene inactivation in sporadic cancers may be of clinical interest. This study sought to determine the frequency of FA gene downregulation in sporadic HNSCC. Methods: The expression of the FA genes FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCJ, FANCL and FANCM in 11 HNSCC cell lines and 49 tongue carcinoma samples was studied with quantitative real-time polymerase chain reaction. Results: Downregulation of at least one FA gene was observed in 3 of 11 HNSCC cell lines and 66% of tongue carcinoma samples. FANCB, FANCF, FANCJ and FANCM were most commonly affected by downregulation, whereas downregulation of FANCA, FANCE and FANCD2 was rare. Conclusion: Our data suggest that downregulation of FA genes is common in sporadic HNSCC. The clinical implications of this finding merit further study.
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Dysregulation of the Fanconi anemia pathway in sporadic head and neck squamous cell carcinoma
Cancer Research, 2006Co-Authors: Volkert B. Wreesmann, Cherry L. Estilo, David W. Eisele, Bhuvanesh Singh, Steven J. WangAbstract:Proc Amer Assoc Cancer Res, Volume 47, 2006 4475 BACKGROUND: Much of our understanding of human cancer has come from studies of the hereditary cancer predisposition syndromes. Fanconi anemia (FA) is an autosomal recessive disorder characterized by cellular hypersensitivity to DNA cross-linking agents (mitomycin, cisplatin), progressive bone marrow failure, and cancer predisposition. Accumulating evidence suggests that patients with FA are predisposed to development of squamous cell carcinomas, particularly those involving the upper aerodigestive tract. extrapolation of this link to cancers in the general population may be of clinical interest. The purpose of this study was to determine whether dysregulation of FA genes occurs in sporadic head and neck squamous cell carcinoma (HNSCC). MAIN OUTCOME MEASURES: We used the immunoblot-based FANCD2 monoubiquitination assay to assess for aberrations in the FA pathway in 13 sporadic HNSCC cell lines. Using quantitative real-time PCR, we assessed the expression of the FA genes FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCJ, FANCL and FANCM in 13 HNSCC cell lines and 49 samples of oral tongue cancer. RESULTS: Defective FANCD2 monoubiquitination was identified in 2 cell lines. Compared to normal human keratinocytes, downregulation of FA genes was observed in 5 cell lines. Downregulation of FA genes was also seen in 50% of tongue carcinoma samples compared to matched normal oral mucosa. Analysis of clinicopathological data demonstrated that downregulation of the FA pathway was associated with a young age and aggressive clinical phenotype. CONCLUSION: Our data suggest that the FA pathway is dysregulated in HNSCC from patients without FA. The implications of this association merit further study.
Volkert B. Wreesmann - One of the best experts on this subject based on the ideXlab platform.
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Downregulation of Fanconi anemia genes in sporadic head and neck squamous cell carcinoma.
ORL, 2007Co-Authors: Volkert B. Wreesmann, Cherry L. Estilo, David W. Eisele, Bhuvanesh Singh, Steven J. WangAbstract:Background/Aims: Much of our understanding of human cancer has come from studies of the hereditary cancer predisposition syndromes. Fanconi anemia (FA) is an autosomal recessive disorder characterized by cellular hypersensitivity to DNA crosslinking agents, progressive bone marrow failure, and cancer predisposition to solid malignancies, especially head and neck squamous cell carcinoma (HNSCC). Since FA pathway-deficient cells are hypersensitive to DNA crosslinking chemotherapy agents, the presence of somatic FA gene inactivation in sporadic cancers may be of clinical interest. This study sought to determine the frequency of FA gene downregulation in sporadic HNSCC. Methods: The expression of the FA genes FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCJ, FANCL and FANCM in 11 HNSCC cell lines and 49 tongue carcinoma samples was studied with quantitative real-time polymerase chain reaction. Results: Downregulation of at least one FA gene was observed in 3 of 11 HNSCC cell lines and 66% of tongue carcinoma samples. FANCB, FANCF, FANCJ and FANCM were most commonly affected by downregulation, whereas downregulation of FANCA, FANCE and FANCD2 was rare. Conclusion: Our data suggest that downregulation of FA genes is common in sporadic HNSCC. The clinical implications of this finding merit further study.
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Dysregulation of the Fanconi anemia pathway in sporadic head and neck squamous cell carcinoma
Cancer Research, 2006Co-Authors: Volkert B. Wreesmann, Cherry L. Estilo, David W. Eisele, Bhuvanesh Singh, Steven J. WangAbstract:Proc Amer Assoc Cancer Res, Volume 47, 2006 4475 BACKGROUND: Much of our understanding of human cancer has come from studies of the hereditary cancer predisposition syndromes. Fanconi anemia (FA) is an autosomal recessive disorder characterized by cellular hypersensitivity to DNA cross-linking agents (mitomycin, cisplatin), progressive bone marrow failure, and cancer predisposition. Accumulating evidence suggests that patients with FA are predisposed to development of squamous cell carcinomas, particularly those involving the upper aerodigestive tract. extrapolation of this link to cancers in the general population may be of clinical interest. The purpose of this study was to determine whether dysregulation of FA genes occurs in sporadic head and neck squamous cell carcinoma (HNSCC). MAIN OUTCOME MEASURES: We used the immunoblot-based FANCD2 monoubiquitination assay to assess for aberrations in the FA pathway in 13 sporadic HNSCC cell lines. Using quantitative real-time PCR, we assessed the expression of the FA genes FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCJ, FANCL and FANCM in 13 HNSCC cell lines and 49 samples of oral tongue cancer. RESULTS: Defective FANCD2 monoubiquitination was identified in 2 cell lines. Compared to normal human keratinocytes, downregulation of FA genes was observed in 5 cell lines. Downregulation of FA genes was also seen in 50% of tongue carcinoma samples compared to matched normal oral mucosa. Analysis of clinicopathological data demonstrated that downregulation of the FA pathway was associated with a young age and aggressive clinical phenotype. CONCLUSION: Our data suggest that the FA pathway is dysregulated in HNSCC from patients without FA. The implications of this association merit further study.
Alan D. D'andrea - One of the best experts on this subject based on the ideXlab platform.
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FANCC The Fanconi anemia protein, FANCE, promotes the nuclear accumulation of
2013Co-Authors: Toshiyasu Taniguchi, Alan D. D'andreaAbstract:ABSTRACT Fanconi Anemia is an autosomal recessive disorder characterized by aplastic anemia, cancer susceptibility, and cellular sensitivity to mitomycin C. The six known Fanconi Anemia gene products (FANCA, FANCC, FANCD2, FANCE, FANCF and FANCGproteins) interact in a common pathway. The monoubiquitination and nuclear foci formation of FANCD2 are essential for the function of this pathway. FANCA, FANCC, FANCG and FANCF proteins form a multisubunit nuclear complex (FA complex)required for FANCD2 monoubiquitination. Since FANCE and FANCC interact in vitroand FANCE is required for the FANCD2 monoubiquitination, we reasoned that FANCE is a component of the FA complex in vivo. Here we demonstrate that retroviral transduction of FA-E cells with the FANCE cDNA restores the nuclear accumulation of FANCC protein, FANCA-FANCC complex formation, the monoubiquitination and nuclear foci formation of FANCD2, and mitomycin C resistance. HA-tagged FANCE protein localizes diffusely in the nucleus. In normal cells, HA-tagged FANCE protein co-immunoprecipitates with FANCA, FANCC, and FANCG but not with FANCD2. Our data indicate that FANCE is a component of the nuclear FA complex in vivo and is required for the monoubiquitination of FANCD2 and the downstream events in the FA pathway.From bloodjournal.hematologylibrary.org by guest on June 4, 2013. For personal use only.
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Screening of small molecule inhibitors of the Fanconi Anemia-BRCA pathway
Cancer Research, 2005Co-Authors: Toshiyasu Taniguchi, Maria Vasserman, Deborah Chirnomas, Alan D. D'andreaAbstract:4995 Fanconi anemia (FA) is a cancer-susceptibility syndrome characterized by hypersensitivity to DNA crosslinking agents, such as cisplatin and mitomycin C. All 9 known FA proteins cooperate with breast/ovarian cancer susceptibility gene products (BRCA1 and BRCA2) in a common DNA damage-activated signaling pathway called the Fanconi anemia(FA)-BRCA pathway. Seven FA proteins (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG and FANCL) are components of a multi-subunit ubiquitin ligase complex (FA complex) required for monoubiquitination of FANCD2. After DNA damage, FANCD2 is monoubiquitinated and targeted to BRCA1/BRCA2-containing nuclear foci in an ATR kinase-dependent fashion. Importantly, the pathway is inactivated in a wide variety of human cancers by methylation of the FANCF gene. This inactivation causes cisplatin sensitivity in some ovarian cancer cell lines, suggesting an important role of the pathway in cisplatin sensitivity of human tumors. We hypothesized that inhibitors of the FA-BRCA pathway will sensitize cancer cells to cisplatin and, therefore, may be useful for the treatment of cisplatin-resistant cancer. We developed a high-throughput small molecule screen using cells harboring a Green Fluorescent Protein tagged FANCD2 (GFP-FANCD2) and assaying for GFP-FANCD2 nuclear foci formation as a readout, because FANCD2 foci formation is a surrogate marker of the integrity of the pathway. We plated cells with GFP-FANCD2 onto 384-well plates, added small molecules, gamma-irradiated the cells and scored the GFP-FANCD2 nuclear foci. Wells lacking GFP-FANCD2 nuclear foci were scored as positive. We have screened more than 5000 chemicals so far, and found 30 positive chemicals, including kinase inhibitors (wortmannin, H-9, alsterpaullone), geldanamycin, and curcumin. We also found that wortmannin, H-9, and alsterpaullone inhibit ATR-dependent phosphorylation of Chk1. These results together with our previous finding that ATR is required for the activation of the pathway suggest that these drugs inhibit the pathway through inhibition of ATR. Furthermore, we confirmed that alsterpaullone sensitized an ovarian cancer cell line in an FA-BRCA pathway-dependent manner. These findings support the rationale for further screening for FA-BRCA pathway inhibitors.
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Monoubiquitinated FANCD2 Is Both Necessary and Sufficient for Mitomycin C Resistance in the Absence of a Functional Fanconi Anemia Core Complex.
Blood, 2004Co-Authors: Akiko Shimamura, Rebecca J. Leary, Maria Stotsky, Lisa A. Moreau, Alan D. D'andreaAbstract:Monoubiquitination of the Fanconi anemia (FA) protein, FANCD2, is necessary for resistance to MMC/DEB-induced chromosomal breakage, which is the diagnostic feature of Fanconi anemia. The upstream Fanconi proteins FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, and FANCL are necessary for FANCD2 monoubiquitination and Fanconi pathway function. We posed the question whether FANCD2 monoubiquitination is sufficient to restore the Fanconi pathway function in the absence of the upstream FA proteins. We constructed a chimeric monoubiquitinated FANCD2 protein by fusing the FANCD2 cDNA sequence contiguously (in-frame) with a ubiquitin coding sequence. This FANCD2-ubiquition fusion protein (D2-ubi) was stably expressed in FANCD2 − / −, FANCA − / −, FANCC − / −, and FANCG − / − human patient-derived cell lines. D2-ubi expression corrected the MMC hypersensitivity of these FA cell lines in the absence of a functional upstream FA core complex. By western blot analysis, the D2-ubi protein migrated at a slower rate than the endogenous monoubiquitinated FANCD2 protein, consistent with its higher molecular mass. An even slower migrating D2-ubi form (D2-ubi-L) was detectable in cells harboring an intact Fanconi core protein complex (i.e., FA-D2 cells) but was absent in cells lacking functional Fanconi proteins FANCA, FANCC, or FANCG. These results indicate the D2-ubi can be further monoubiquitinated on lysine 561, but only in the presence of an intact FA complex. Furthermore, D2-ubi-L was upregulated in response to DNA damage in transfected FA-D2 and wild type cells. Like endogenous FANCD2, D2-ubi formed nuclear foci in the presence of the upstream Fanconi core complex. In the absence of the FA core complex, D2-ubi was localized diffusely throughout the nucleus, but unlike endogenous FANCD2, D2-ubi was retained within the nucleus following detergent permeabilization of FA-A, FA-C, and FA-G cells. These results further support the epistatic relationship of the FA genes in a linear pathway. In summary, these data indicate that a constitutively monoubiquitinated FANCD2 polypeptide is able to bypass defects in the upstream FA core complex to restore Fanconi pathway function. These studies identify FANCD2 ubiquitination as a potential therapeutic target for patients lacking the upstream FA core complex.
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Disruption of the Fanconi anemia-BRCA pathway in cisplatin-sensitive ovarian tumors.
Nature medicine, 2003Co-Authors: Toshiyasu Taniguchi, Marc Tischkowitz, Shirley V. Hodgson, Hans Joenje, Najim Ameziane, Christopher Mathew, Samuel C. Mok, Alan D. D'andreaAbstract:Ovarian tumor cells are often genomically unstable and hypersensitive to cisplatin. To understand the molecular basis for this phenotype, we examined the integrity of the Fanconi anemia-BRCA (FANC-BRCA) pathway in those cells. This pathway regulates cisplatin sensitivity and is governed by the coordinate activity of six genes associated with Fanconi anemia (FANCA, FANCC, FANCD2, FANCE, FANCF and FANCG) as well as BRCA1 and BRCA2 (FANCD1). Here we show that the FANC-BRCA pathway is disrupted in a subset of ovarian tumor lines. Mono-ubiquitination of FANCD2, a measure of the function of this pathway, and cisplatin resistance were restored by functional complementation with FANCF, a gene that is upstream in this pathway. FANCF inactivation in ovarian tumors resulted from methylation of its CpG island, and acquired cisplatin resistance correlated with demethylation of FANCF. We propose a model for ovarian tumor progression in which the initial methylation of FANCF is followed by FANCF demethylation and ultimately results in cisplatin resistance.
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The Fanconi anemia protein, FANCE, promotes the nuclear accumulation of FANCC.
Blood, 2002Co-Authors: Toshiyasu Taniguchi, Alan D. D'andreaAbstract:Fanconi anemia is an autosomal recessive disorder characterized by aplastic anemia, cancer susceptibility, and cellular sensitivity to mitomycin C. The 6 known Fanconi anemia gene products (FANCA, FANCC, FANCD2, FANCE, FANCF, and FANCG proteins) interact in a common pathway. The monoubiquitination and nuclear foci formation of FANCD2 are essential for the function of this pathway. FANCA, FANCC, FANCG, and FANCF proteins form a multisubunit nuclear complex (FA complex) required for FANCD2 monoubiquitination. Because FANCE and FANCC interact in vitro and FANCE is required for FANCD2 monoubiquitination, we reasoned that FANCE is a component of the FA complex in vivo. Here we demonstrate that retroviral transduction of Fanconi anemia subtype E (FA-E) cells with the FANCE cDNA restores the nuclear accumulation of FANCC protein, FANCA–FANCC complex formation, monoubiquitination and nuclear foci formation of FANCD2, and mitomycin C resistance. Hemagglutinin (HA)-tagged FANCE protein localizes diffusely in the nucleus. In normal cells, HA-tagged FANCE protein coimmunoprecipitates with FANCA, FANCC, and FANCG but not with FANCD2. Our data indicate that FANCE is a component of the nuclear FA complex in vivo and is required for the monoubiquitination of FANCD2 and the downstream events in the FA pathway.
Cherry L. Estilo - One of the best experts on this subject based on the ideXlab platform.
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Downregulation of Fanconi anemia genes in sporadic head and neck squamous cell carcinoma.
ORL, 2007Co-Authors: Volkert B. Wreesmann, Cherry L. Estilo, David W. Eisele, Bhuvanesh Singh, Steven J. WangAbstract:Background/Aims: Much of our understanding of human cancer has come from studies of the hereditary cancer predisposition syndromes. Fanconi anemia (FA) is an autosomal recessive disorder characterized by cellular hypersensitivity to DNA crosslinking agents, progressive bone marrow failure, and cancer predisposition to solid malignancies, especially head and neck squamous cell carcinoma (HNSCC). Since FA pathway-deficient cells are hypersensitive to DNA crosslinking chemotherapy agents, the presence of somatic FA gene inactivation in sporadic cancers may be of clinical interest. This study sought to determine the frequency of FA gene downregulation in sporadic HNSCC. Methods: The expression of the FA genes FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCJ, FANCL and FANCM in 11 HNSCC cell lines and 49 tongue carcinoma samples was studied with quantitative real-time polymerase chain reaction. Results: Downregulation of at least one FA gene was observed in 3 of 11 HNSCC cell lines and 66% of tongue carcinoma samples. FANCB, FANCF, FANCJ and FANCM were most commonly affected by downregulation, whereas downregulation of FANCA, FANCE and FANCD2 was rare. Conclusion: Our data suggest that downregulation of FA genes is common in sporadic HNSCC. The clinical implications of this finding merit further study.
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Dysregulation of the Fanconi anemia pathway in sporadic head and neck squamous cell carcinoma
Cancer Research, 2006Co-Authors: Volkert B. Wreesmann, Cherry L. Estilo, David W. Eisele, Bhuvanesh Singh, Steven J. WangAbstract:Proc Amer Assoc Cancer Res, Volume 47, 2006 4475 BACKGROUND: Much of our understanding of human cancer has come from studies of the hereditary cancer predisposition syndromes. Fanconi anemia (FA) is an autosomal recessive disorder characterized by cellular hypersensitivity to DNA cross-linking agents (mitomycin, cisplatin), progressive bone marrow failure, and cancer predisposition. Accumulating evidence suggests that patients with FA are predisposed to development of squamous cell carcinomas, particularly those involving the upper aerodigestive tract. extrapolation of this link to cancers in the general population may be of clinical interest. The purpose of this study was to determine whether dysregulation of FA genes occurs in sporadic head and neck squamous cell carcinoma (HNSCC). MAIN OUTCOME MEASURES: We used the immunoblot-based FANCD2 monoubiquitination assay to assess for aberrations in the FA pathway in 13 sporadic HNSCC cell lines. Using quantitative real-time PCR, we assessed the expression of the FA genes FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCJ, FANCL and FANCM in 13 HNSCC cell lines and 49 samples of oral tongue cancer. RESULTS: Defective FANCD2 monoubiquitination was identified in 2 cell lines. Compared to normal human keratinocytes, downregulation of FA genes was observed in 5 cell lines. Downregulation of FA genes was also seen in 50% of tongue carcinoma samples compared to matched normal oral mucosa. Analysis of clinicopathological data demonstrated that downregulation of the FA pathway was associated with a young age and aggressive clinical phenotype. CONCLUSION: Our data suggest that the FA pathway is dysregulated in HNSCC from patients without FA. The implications of this association merit further study.
David W. Eisele - One of the best experts on this subject based on the ideXlab platform.
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Downregulation of Fanconi anemia genes in sporadic head and neck squamous cell carcinoma.
ORL, 2007Co-Authors: Volkert B. Wreesmann, Cherry L. Estilo, David W. Eisele, Bhuvanesh Singh, Steven J. WangAbstract:Background/Aims: Much of our understanding of human cancer has come from studies of the hereditary cancer predisposition syndromes. Fanconi anemia (FA) is an autosomal recessive disorder characterized by cellular hypersensitivity to DNA crosslinking agents, progressive bone marrow failure, and cancer predisposition to solid malignancies, especially head and neck squamous cell carcinoma (HNSCC). Since FA pathway-deficient cells are hypersensitive to DNA crosslinking chemotherapy agents, the presence of somatic FA gene inactivation in sporadic cancers may be of clinical interest. This study sought to determine the frequency of FA gene downregulation in sporadic HNSCC. Methods: The expression of the FA genes FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCJ, FANCL and FANCM in 11 HNSCC cell lines and 49 tongue carcinoma samples was studied with quantitative real-time polymerase chain reaction. Results: Downregulation of at least one FA gene was observed in 3 of 11 HNSCC cell lines and 66% of tongue carcinoma samples. FANCB, FANCF, FANCJ and FANCM were most commonly affected by downregulation, whereas downregulation of FANCA, FANCE and FANCD2 was rare. Conclusion: Our data suggest that downregulation of FA genes is common in sporadic HNSCC. The clinical implications of this finding merit further study.
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Dysregulation of the Fanconi anemia pathway in sporadic head and neck squamous cell carcinoma
Cancer Research, 2006Co-Authors: Volkert B. Wreesmann, Cherry L. Estilo, David W. Eisele, Bhuvanesh Singh, Steven J. WangAbstract:Proc Amer Assoc Cancer Res, Volume 47, 2006 4475 BACKGROUND: Much of our understanding of human cancer has come from studies of the hereditary cancer predisposition syndromes. Fanconi anemia (FA) is an autosomal recessive disorder characterized by cellular hypersensitivity to DNA cross-linking agents (mitomycin, cisplatin), progressive bone marrow failure, and cancer predisposition. Accumulating evidence suggests that patients with FA are predisposed to development of squamous cell carcinomas, particularly those involving the upper aerodigestive tract. extrapolation of this link to cancers in the general population may be of clinical interest. The purpose of this study was to determine whether dysregulation of FA genes occurs in sporadic head and neck squamous cell carcinoma (HNSCC). MAIN OUTCOME MEASURES: We used the immunoblot-based FANCD2 monoubiquitination assay to assess for aberrations in the FA pathway in 13 sporadic HNSCC cell lines. Using quantitative real-time PCR, we assessed the expression of the FA genes FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCJ, FANCL and FANCM in 13 HNSCC cell lines and 49 samples of oral tongue cancer. RESULTS: Defective FANCD2 monoubiquitination was identified in 2 cell lines. Compared to normal human keratinocytes, downregulation of FA genes was observed in 5 cell lines. Downregulation of FA genes was also seen in 50% of tongue carcinoma samples compared to matched normal oral mucosa. Analysis of clinicopathological data demonstrated that downregulation of the FA pathway was associated with a young age and aggressive clinical phenotype. CONCLUSION: Our data suggest that the FA pathway is dysregulated in HNSCC from patients without FA. The implications of this association merit further study.
