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


CONCLUSIONS
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.
Masonic Cancer Center, BCLC Group-Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, Barcelona, Spain. kengx001@umn.edu
Vincent W
VW
Keng
Daniela
D
Sia
Aaron L
AL
Sarver
Barbara R
BR
Tschida
Danhua
D
Fan
Clara
C
Alsinet
Manel
M
Solé
Wai L
WL
Lee
Timothy P
TP
Kuka
Branden S
BS
Moriarity
Augusto
A
Villanueva
Adam J
AJ
Dupuy
Jesse D
JD
Riordan
Jason B
JB
Bell
Kevin A T
KA
Silverstein
Josep M
JM
Llovet
David A
DA
Largaespada
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic; D002897:Chromosomes, Human, Pair 7; D004251:DNA Transposable Elements; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D022781:Hepatocytes / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016254:Mutagenesis, Insertional; D012737:Sex Factors; D051176:beta Catenin / Q000378:metabolism
C495270:CTNNB1 protein, human; D004251:DNA Transposable Elements; D051176:beta Catenin; C512478:EGFR protein, human; D066246:ErbB Receptors