Assessment of the Relationship Between ERBB4 rs13393577 Polymorphism and Breast Cancer Susceptibility in Iranian Population

Background: Studies have shown that the polymorphism of genes involved in breast cancer in combination with environmental factors has an important role in the progression of breast cancer. Objectives: In this study, the association between polymorphism of the ERBB4 gene with breast cancer was investigated. Methods: In the present study, 110 patients with breast cancer and 110 healthy individuals were selected as controls. DNA extraction was performed on patients’ samples. The tetra-ARMS-PCR method was used to study rs13393577 polymorphism. Finally, statistical analysis was performed using SPSS software using t-test. Results: The results of the study in the patients' group showed that the frequencies of TT, CT, and CC genotypes were 73, 15, and 1.8%, and allelic frequency in this group for T and C alleles were 95 and 5%, respectively. In addition, the results of the study in the control group showed that the frequencies of TT, CT, and CC genotypes were 86, 11, and 0.9%, respectively. The allelic frequencies in the control group for the T and C alleles were 97 and 3%, respectively. In addition, the risk ratio and allelic reliability were obtained for T allele was OR: 3.06: and CI = 0.31 – 29.94 and for C allele was OR: 0.32: and CI: 0.03 - 3.19, respectively. Finally, statistical analysis showed that no significant difference was observed between the two groups (P > 0.05). Conclusions: The results of the present study showed that rs13393577 polymorphism in the EGFR gene (ERBB4) is not a genetic predisposing factor for breast cancer.

The Utility of ERBB4 and RB1 Immunohistochemistry in Distinguishing Chromophobe Renal Cell Carcinoma From Renal Oncocytoma

Objectives. Differentiating renal oncocytoma (RO) from chromophobe renal cell carcinoma (ChRCC) can occasionally be challenging. We evaluated the expression of RB1 and ERBB4 in RO and ChRCC, and compared the immunohistochemistry (IHC) results to RB1 and ERBB4 gene abnormalities detected by fluorescence in situ hybridization (FISH). Materials and Methods. Fifty-three kidney resections (ChRCC, n=28; RO, n=25) were stained for RB1 and ERBB4 IHC and FISH was performed to evaluate gene copy number analysis. Results. A loss of RB1 staining was identified in 64% (18/28) of ChRCCs, which was not found in any ROs (0/25; P <.001). FISH analysis revealed 36% (10/28) of ChRCCs contained a RB1 hemizygous deletion with a concordance of 56% (10/18) between the IHC and FISH findings. No RB1 gene copy number variations were detected in any of the ROs (0/25; P <.001) and retained expression of RB1 by IHC. ERBB4 showed cytoplasmic/membranous staining in all ROs and ChRCCs. However, 75% (21/28) of ChRCCs also contained nuclear positivity for ERBB4, which was uncommonly seen in ROs (3/25, 12%; P < .001). A hemizygous ERBB4 gene deletion was detected in 46% of ChRCCs (13/28), but none of the ROs (0/25; 0%). Loss of labeling by RB1 or nuclear staining for ERBB4 IHC identified 25 of 28 (89%) of ChRCCs. Conclusion. In summary, the loss of RB1 expression is a highly specific diagnostic biomarker in distinguishing ChRCC from RO. Nuclear ERBB4 expression also appears to be a sensitive diagnostic biomarker for ChRCC, albeit the mechanism is unknown.

Analysis of Copy Number Loss of the ErbB4 Receptor Tyrosine Kinase in Glioblastoma

ABSTRACTCurrent treatments for glioblastoma multiforme (GBM)—an aggressive form of brain cancer—are minimally effective and yield a median survival of 14.6 months and a two-year survival rate of 30%. Given the severity of GBM and the limitations of its treatment, there is a need for the discovery of novel drug targets for GBM and more personalized treatment approaches based on the characteristics of an individual’s tumor. Most receptor tyrosine kinases—such as EGFR—act as oncogenes, but publicly available data from the Cancer Cell Line Encyclopedia (CCLE) indicates copy number loss in the ERBB4 RTK gene across dozens of GBM cell lines, suggesting a potential tumor suppressor role. This loss is mutually exclusive with loss of its cognate ligand NRG1 in CCLE as well, more strongly suggesting a functional role. The availability of higher resolution copy number data from clinical GBM patients in The Cancer Genome Atlas (TCGA) revealed that a region in Intron 1 of the ERBB4 gene was deleted in 69.1% of tumor samples harboring ERBB4 copy number loss; however, it was also found to be deleted in the matched normal tissue samples from these GBM patients (n = 81). Using the DECIPHER Genome Browser, we also discovered that this mutation occurs at approximately the same frequency in the general population as it does in the disease population. We conclude from these results that this loss in Intron 1 of the ERBB4 gene is neither a de novo driver mutation nor a predisposing factor to GBM, despite the indications from CCLE. A biological role of this significantly occurring genetic alteration is still unknown. While this is a negative result, the broader conclusion is that while copy number data from large cell line-based data repositories may yield compelling hypotheses, careful follow up with higher resolution copy number assays, patient data, and general population analyses are essential to codify initial hypotheses.