Association of HER2 codon 655 polymorphism with ovarian cancer

Abstract

The role of the human epidermal growth factor receptor 2 (HER2) codon 655 (Ile655Val) polymorphism in ovarian cancer is not fully understood. Two studies indicated a possible association between the Val allele and elevated risk or reduced prognosis of ovarian cancer. We investigated the HER2 codon 655 (rs1136201) polymorphism in 242 Austrian women-142 ovarian cancer patients and 100 healthy controls-by polymerase chain reaction and pyrosequencing. Associations between Ile655Val polymorphism and clinicopathological variables (e.g., age, FIGO stage, grading, serous vs. non-serous histology) were evaluated. The genotype distributions in ovarian cancer patients and controls were: AA; 66.2 %, AG; 25.35 %, GG; 8.45 %, and AA; 63 %, AG; 34 %, GG; 3.7 %, respectively (OR 1.15, CI 95 % 0.67-1.96). We observed a non-significant trend toward elevated cancer risk in Val/Val genotype (OR 2.98, CI 95 % 0.82-10.87, p = 0.10). Of note, 11 out of 12 Val/Val homozygotes were postmenopausal. The link between the Val/Val homozygosity and age over 50 years at diagnosis (OR 0.15, CI 95 % 0.02-1.2) was barely significant (p = 0.056). Summarizing, our data indicated a non-significant trend toward increased ovarian cancer risk in the Val/Val homozygosity, especially in women aged above 50 years. Further large-cohort studies focusing on the role of the HER2 codon 655 Val allele are needed.

Ile655Val of the HER2 gene and its possible predictive value in patients with hereditary breast and ovarian cancer syndrome

“…The frequency of isoleucine-valine heterozygotes and valine-valine homozygotes in Chinese women was 21.7% and 0.3% respectively, which are percentages well below those reported in Caucasian women (40% and 12%, respectively). These data are consistent with observations reported in other studies indicating that Chinese women have a low risk for developing breast cancer in comparison with Caucasian women, which shows once again that allelic frequencies are different according to the studied population [9][10][11][12][13][14][15][16][17][18][19][20][21][22] ; therefore, the results of a studied population cannot be extrapolated to others. The truth is that, with regard to HER2 polymorphisms, the results have been conflicting and have even been inversely related to the risk of breast cancer, especially in older women (> 45 years) 23 .…”

“…Xie D et al 9 suggest that the polymorphism in HER2 gene codon 655 is associated with an increased risk for breast cancer, particularly in young women (< 45 years) and, in a meta-analysis, lower risk was observed in oriental women in comparison with a higher risk in western women 10 , which suggests that it can be used as an indicator of genetic susceptibility for breast cancer. However, this polymorphism was not associated with poor prognosis in a study conducted in Australian patients with ovarian cancer 11 . The polymorphism in codon 655 12 specifically results from the change of an isoleucine (ATC) for a valine (GTC).…”

“…The HER2 gene is located at chromosome 17 (q11. [2][3][4][5][6][7][8][9][10][11][12] and encodes a 1,255-amino acid (185 Kd) transmembrane glycoprotein that activates tyrosine kinase.…”

Ile655Val del gen HER2 y su posible valor predictivo en pacientes con síndrome de cáncer de mama y ovario hereditario

“…Xie D, et al 9 sugieren que el polimorfismo en el codón 655 del gen HER2 está asociado a un aumento en el riesgo de cáncer mamario, particularmente en mujeres jóvenes (<45 años) y en un metaanálisis se observó un menor riesgo en mujeres orientales en comparación con el riesgo mayor de las mujeres occidentales 10 , y que se puede utilizar como indicador de susceptibilidad genética para el cáncer mamario. Sin embargo, este mismo polimorfismo no resultó asociarse a mal pronóstico en un estudio realizado en pacientes australianas con cáncer de ovario 11 . El polimorfismo en el codón 655 12 específicamente resulta del cambio a una valina (GTC) de una isoleucina (ATC), este codón se encuentra localizado en la región transmembrana y estudios in vitro de este polimorfismo han demostrado que puede afectar la función del gen HER2 cuando se encuentra el alelo mutado valina, incrementando la activación cinasa de la proteína de HER2, siendo contrario el efecto cinasa decreciente con el alelo leucina 13 .…”

“…La frecuencia del heterocigotos de isoleucina-valina y del homocigoto valina-valina en mujeres chinas fue del 21.7 y del 0.3% respectivamente, porcentajes muy por debajo de los reportados en mujeres caucásicas (40 y 12%, respectivamente). Estos datos coinciden con las observaciones reportadas en otros estudios de que las mujeres chinas presentan un bajo riesgo de padecer cáncer de mama con respecto a las mujeres caucásicas, lo que nos demuestra una vez más que las frecuencias alélicas son diferentes según la población que se estudie [9][10][11][12][13][14][15][16][17][18][19][20][21][22] ; por lo tanto, los resultados de una población estudiada no se pueden transpolar a otras. Lo cierto es que con respecto a los polimorfismos de HER2 los resultados han sido contradictorios e incluso se han relacionado inversamente con el riesgo de cáncer de mama, sobre todo en mujeres mayores (> 45 años) 23 .…”