Histone demethylase GASC1--a potential prognostic and predictive marker in invasive breast cancer

Abstract

Background: The histone demethylase GASC1 (JMJD2C) is an epigenetic factor suspected of involvement in development of different cancers, including breast cancer. It is thought to be overexpressed in the more aggressive breast cancer types based on mRNA expression studies on cell lines and meta analysis of human breast cancer sets. This study aimed to evaluate the prognostic and predictive value of GASC1 for women with invasive breast cancer.

Methods: All the 355 cases were selected from a cohort enrolled in the Kuopio Breast Cancer Project between April 1990 and December 1995. The expression of GASC1 was studied by immunohistochemistry (IHC) on tissue microarrays. Additionally relative GASC1 mRNA expression was measured from available 57 cases.

Results: In our material, 56% of the cases were GASC1 negative and 44% positive in IHC staining. Women with GASC1 negative tumors had two years shorter breast cancer specific survival and time to relapse than the women with GASC1 positive tumors (p=0.017 and p=0.034 respectively). The majority of GASC1 negative tumors were ductal cases (72%) of higher histological grade (84% of grade II and III altogether). When we evaluated estrogen receptor negative and progesterone receptor negative cases separately, there was 2 times more GASC1 negative than GASC1 positive tumors in each group (chi2, p= 0.033 and 0.001 respectively). In the HER2 positive cases, there was 3 times more GASC1 negative cases than GASC1 positives (chi2, p= 0.029). Patients treated with radiotherapy (n=206) and hormonal treatment (n=62) had better breast cancer specific survival, when they were GASC1 positive (Cox regression: HR=0.49, p=0.007 and HR=0.33, p=0.015, respectively). The expression of GASC1 mRNA was in agreement with the protein analysis.

Conclusions: This study indicates that the GASC1 is both a prognostic and a predictive factor for women with invasive breast cancer. GASC1 negativity is associated with tumors of more aggressive histopathological types (ductal type, grade II and III, ER negative, PR negative). Patients with GASC1 positive tumors have better breast cancer specific survival and respond better to radiotherapy and hormonal treatment.

Figure 1

Expression of GASC1 in invasive breast carcinoma of ductal type. (A) Positive immunostaining in nuclei of epithelial cells (arrows; immunoscores: 3 for the nuclear number and 3 for intensity of nuclear staining), positive staining visible in cytoplasm was not taken into account. Original magnification of x200. (B) Negative GASC1 immunostaining in nuclei of epithelial carcinoma cells. Original magnification of x200.

Figure 2

Breast cancer specific survival by Kaplan-Meier analysis. Overall, the patients with GASC1 immunopositive tumors have better survival than the patients with GASC1 negative tumors (p=0.017 Log Rank; p=0.012, Breslow; p=0.013, Tarone-Ware).

Figure 3

Breast cancer specific survival analysis by Cox regression. After adjusting the model to confound for the age at diagnosis, nodal status, size of tumor, and clinical stage, GASC1 positive patients have better survival than GASC1 negative. The p-value for the model is 0.000 and for the GASC1 status 0.001.

Figure 4

Time to relapse by Kaplan-Meier analysis. Overall, the patients with GASC1 immunopositive tumors have a longer time to relapse than the patients with GASC1 negative tumors (p=0.034, Log Rank; p=0.005, Breslow; p=0.010 Tarone-Ware).

Figure 5

Time to relapse analysis by Cox regression. GASC1 negative cases have a shorter time to relapse than GASC1 positive cases. The following covariates were included into the model: age at diagnosis, nodal status, size of tumor, clinical stage and GASC1 status. The p-value for the model is 0.000 and for the GASC1 status 0.002.

Figure 6

Breast cancer specific survival by Kaplan-Meier analysis. Overall, the patients with high expression of GASC1 mRNA in tumors have a better survival than patients with low GASC1 mRNA expression (p = 0.152, Log Rank).

Figure 7

Graph showing GASC1 mRNA expression in tumors of different histological grades. Boxes represent the 25–75th percentile; whiskers: range; black line: median; black dots: outliers. The highest GASC1 mRNA expression is detected in tumors of grade I (GR I; 0.761±0.099). Tumors of grade II (GR II; 0.510±0.070) and III (GR III; 0.510±0.069) show lower GASC1 mRNA expression than tumors of grade I. There is no difference in GASC1 mRNA expression between tumors of grade II and III. Kruskal-Wallis test, p=0.02. Mann–Whitney test: grade I versus II - p=0.006; grade I versus III - p=0.019, grade II versus III - p=0.821.

Figure 8

Graphs showing GASC1 mRNA expression according to progesterone receptor (PR) and HER2 status. (A) GASC1 mRNA relative level is lower in tumors showing negative or weak expression of PR (0.483±0.051) compared with tumors showing high PR expression (0.691±0.092; Mann–Whitney: p=0.016). (B) GASC1 mRNA relative level is higher in HER2 negative tumors (0.599±0.055) than in HER2 positive tumors (0.326±0.054; Mann–Whitney: p=0.004).