Sex bias occurrence of hepatocellular carcinoma in Poly7 molecular subclass is associated with EGFR

Vincent W. Keng, Daniela Sia, Aaron L. Sarver, Barbara R. Tschida, Danhua Fan, Clara Alsinet, Manel Solé, Wai L. Lee, Timothy P. Kuka, Branden S. Moriarity, Augusto Villanueva, Adam J. Dupuy, Jesse D. Riordan, Jason B. Bell, Kevin A. Kevin, Josep M. Llovet, David A. Largaespada

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Abstract

Hepatocellular carcinoma (HCC) is one of the deadliest solid cancers and is the third leading cause of cancer-related death. There is a universal estimated male/female ratio of 2.5, but the reason for this is not well understood. The Sleeping Beauty (SB) transposon system was used to elucidate candidate oncogenic drivers of HCC in a forward genetics screening approach. Sex bias occurrence was conserved in our model, with male experimental mice developing liver tumors at reduced latency and higher tumor penetrance. In parallel, we explored sex differences regarding genomic aberrations in 235 HCC patients. Liver cancer candidate genes were identified from both sexes and genotypes. Interestingly, transposon insertions in the epidermal growth factor receptor (Egfr) gene were common in SB-induced liver tumors from male mice (10/10, 100%) but infrequent in female mice (2/9, 22%). Human single-nucleotide polymorphism data confirmed that polysomy of chromosome 7, locus of EGFR, was more frequent in males (26/62, 41%) than females (2/27, 7%) (P = 0.001). Gene expression-based Poly7 subclass patients were predominantly male (9/9) compared with 67% males (55/82) in other HCC subclasses (P = 0.02), and this subclass was accompanied by EGFR overexpression (P <0.001). Conclusion: Sex bias occurrence of HCC associated with EGFR was confirmed in experimental animals using the SB transposon system in a reverse genetic approach. This study provides evidence for the role of EGFR in sex bias occurrences of liver cancer and as the driver mutational gene in the Poly7 molecular subclass of human HCC. (HEPATOLOGY 2013)

Original languageEnglish
Pages (from-to)120-130
Number of pages11
JournalHepatology
Volume57
Issue number1
DOIs
Publication statusPublished - Jan 2013

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Sexism
Hepatocellular Carcinoma
Beauty
Neoplasms
Liver Neoplasms
erbB-1 Genes
Reverse Genetics
Chromosomes, Human, Pair 7
Penetrance
Neoplasm Genes
Liver
Genetic Testing
Sex Characteristics
Single Nucleotide Polymorphism
Genotype
Gene Expression
Genes

ASJC Scopus subject areas

  • Hepatology

Cite this

Keng, V. W., Sia, D., Sarver, A. L., Tschida, B. R., Fan, D., Alsinet, C., ... Largaespada, D. A. (2013). Sex bias occurrence of hepatocellular carcinoma in Poly7 molecular subclass is associated with EGFR. Hepatology, 57(1), 120-130. https://doi.org/10.1002/hep.26004

Sex bias occurrence of hepatocellular carcinoma in Poly7 molecular subclass is associated with EGFR. / Keng, Vincent W.; Sia, Daniela; Sarver, Aaron L.; Tschida, Barbara R.; Fan, Danhua; Alsinet, Clara; Solé, Manel; Lee, Wai L.; Kuka, Timothy P.; Moriarity, Branden S.; Villanueva, Augusto; Dupuy, Adam J.; Riordan, Jesse D.; Bell, Jason B.; Kevin, Kevin A.; Llovet, Josep M.; Largaespada, David A.

In: Hepatology, Vol. 57, No. 1, 01.2013, p. 120-130.

Research output: Contribution to journalArticle

Keng, VW, Sia, D, Sarver, AL, Tschida, BR, Fan, D, Alsinet, C, Solé, M, Lee, WL, Kuka, TP, Moriarity, BS, Villanueva, A, Dupuy, AJ, Riordan, JD, Bell, JB, Kevin, KA, Llovet, JM & Largaespada, DA 2013, 'Sex bias occurrence of hepatocellular carcinoma in Poly7 molecular subclass is associated with EGFR', Hepatology, vol. 57, no. 1, pp. 120-130. https://doi.org/10.1002/hep.26004
Keng, Vincent W. ; Sia, Daniela ; Sarver, Aaron L. ; Tschida, Barbara R. ; Fan, Danhua ; Alsinet, Clara ; Solé, Manel ; Lee, Wai L. ; Kuka, Timothy P. ; Moriarity, Branden S. ; Villanueva, Augusto ; Dupuy, Adam J. ; Riordan, Jesse D. ; Bell, Jason B. ; Kevin, Kevin A. ; Llovet, Josep M. ; Largaespada, David A. / Sex bias occurrence of hepatocellular carcinoma in Poly7 molecular subclass is associated with EGFR. In: Hepatology. 2013 ; Vol. 57, No. 1. pp. 120-130.
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abstract = "Hepatocellular carcinoma (HCC) is one of the deadliest solid cancers and is the third leading cause of cancer-related death. There is a universal estimated male/female ratio of 2.5, but the reason for this is not well understood. The Sleeping Beauty (SB) transposon system was used to elucidate candidate oncogenic drivers of HCC in a forward genetics screening approach. Sex bias occurrence was conserved in our model, with male experimental mice developing liver tumors at reduced latency and higher tumor penetrance. In parallel, we explored sex differences regarding genomic aberrations in 235 HCC patients. Liver cancer candidate genes were identified from both sexes and genotypes. Interestingly, transposon insertions in the epidermal growth factor receptor (Egfr) gene were common in SB-induced liver tumors from male mice (10/10, 100{\%}) but infrequent in female mice (2/9, 22{\%}). Human single-nucleotide polymorphism data confirmed that polysomy of chromosome 7, locus of EGFR, was more frequent in males (26/62, 41{\%}) than females (2/27, 7{\%}) (P = 0.001). Gene expression-based Poly7 subclass patients were predominantly male (9/9) compared with 67{\%} males (55/82) in other HCC subclasses (P = 0.02), and this subclass was accompanied by EGFR overexpression (P <0.001). Conclusion: Sex bias occurrence of HCC associated with EGFR was confirmed in experimental animals using the SB transposon system in a reverse genetic approach. This study provides evidence for the role of EGFR in sex bias occurrences of liver cancer and as the driver mutational gene in the Poly7 molecular subclass of human HCC. (HEPATOLOGY 2013)",
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N2 - Hepatocellular carcinoma (HCC) is one of the deadliest solid cancers and is the third leading cause of cancer-related death. There is a universal estimated male/female ratio of 2.5, but the reason for this is not well understood. The Sleeping Beauty (SB) transposon system was used to elucidate candidate oncogenic drivers of HCC in a forward genetics screening approach. Sex bias occurrence was conserved in our model, with male experimental mice developing liver tumors at reduced latency and higher tumor penetrance. In parallel, we explored sex differences regarding genomic aberrations in 235 HCC patients. Liver cancer candidate genes were identified from both sexes and genotypes. Interestingly, transposon insertions in the epidermal growth factor receptor (Egfr) gene were common in SB-induced liver tumors from male mice (10/10, 100%) but infrequent in female mice (2/9, 22%). Human single-nucleotide polymorphism data confirmed that polysomy of chromosome 7, locus of EGFR, was more frequent in males (26/62, 41%) than females (2/27, 7%) (P = 0.001). Gene expression-based Poly7 subclass patients were predominantly male (9/9) compared with 67% males (55/82) in other HCC subclasses (P = 0.02), and this subclass was accompanied by EGFR overexpression (P <0.001). Conclusion: Sex bias occurrence of HCC associated with EGFR was confirmed in experimental animals using the SB transposon system in a reverse genetic approach. This study provides evidence for the role of EGFR in sex bias occurrences of liver cancer and as the driver mutational gene in the Poly7 molecular subclass of human HCC. (HEPATOLOGY 2013)

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