Single nucleotide polymorphisms in AREG and EREG are prognostic biomarkers in locally advanced gastric cancer patients after surgery with curative intent

Abstract

Objective Amphiregulin (AREG) and epiregulin (EREG) are important ligands to the epithelial growth factor receptor (EGFR) which is involved in the regulation of progression and stemness in gastric cancer (GC). This study investigated whether frequent single nucleotide polymorphisms (SNPs) in genes of AREG and EREG are associated with recurrence-free survival and overall survival in patients with locally advanced gastric cancer (GC). Methods SNPs with a minor allele frequency of ≥10% were analyzed using direct DNA sequencing in two independent study populations. Results The minor allele of AREG rs1615111 was associated with a significant higher 3-year recurrence rate and lower 3-year survival rate (HR= 2.21 and 2.35 respectively) when compared to patients homozygous for the dominant allele G. The value for overall survival could be validated with a HR of 2.54 (P= 0.018) in an independent cohort. Patients homozygous for the minor allele A of EREG rs12641042 had a significant higher 3-year survival rate than patients having allele C (HR 0.48; P=0.034), but significance was lost in multivariable analysis (P=0.066). Value of rs12641042 could not be validated (P=0.98). Exploratory multivariable subgroup analysis revealed the strongest prognostic value for rs1615111 in tumors with a diffuse histology (Pfor interaction = 0.004). Conclusions AREG rs1615111, located in the AREG genomic region is able to significantly define different prognostic cohorts in locally advanced GC. This value is most evident in GC patients with diffuse histology which might be relevant as none of the trials testing EGFR-inhibitors has been enriched for diffuse histology or a molecularly defined population.

TRIM21 is critical in regulating hepatocellular carcinoma growth and response to therapy by altering the MST1/YAP pathway

“…Numerous studies have shown that high YAP and TAZ expression possess higher proliferative capability through transcriptional regulation of genes associated with cell cycle and division 45–47 . Except for YAP/TAZ, upregulation of their target genes, including CTGF, Cyr61, and AREG, has also been shown to promote tumorigenesis in gastric cancer 48–50 . MST1 inhibits YAP activation and acts as a tumor suppressor 12 .…”

“… 45 , 46 , 47 Except for YAP/TAZ, upregulation of their target genes, including CTGF, Cyr61, and AREG, has also been shown to promote tumorigenesis in gastric cancer. 48 , 49 , 50 MST1 inhibits YAP activation and acts as a tumor suppressor. 12 Genetic knockout MST1 results in hyperactivation of YAP and tumorigenesis.…”

Polymorphism in the EREG gene confers susceptibility to tuberculosis

“…Several previous experiments have concentrated on the association between EREG SNPs and various diseases. Takeru Wakatsukiet al [24] identified SNPs within the genomic regions of EREG in gastric cancer for the first time and demonstrated an association of those SNPs with the 3-year RFS (recurrence free) and 3-year overall survival rates. In a study of Behçet’s disease (BD) with a case-control study of 976 Iranian patients and 839 healthy controls, a new SNP, rs6845297, located downstream of EREG , was associated with BD [25].…”

Recent Advances in Our Knowledge of mCRC Tumor Biology and Genetics: A Focus on Targeted Therapy Development

“…41 Interestingly, MTORC2 activity was not detected in primary human and mouse CRC samples, but was found to be expressed in macrophages where it contributed to antitumor activity. 42 A number of factors other than KRAS/NRAS and BRAF mutations influence the efficacy of anti-EGFR therapy, including plasma levels of EGFR ligands such as amphiregulin (AREG) and epiregulin (EREG), 43 and these may be monitored to provide an indication of resistance to anti-EGFR therapy. 24 EGFR gene copy number and acquired mutations in extracellular domains also may contribute anti-EGFR therapy resistance in mCRC.…”