RAB6C is an independent prognostic factor of estrogen receptor-positive/progesterone receptor-negative breast cancer

Abstract

The majority of breast cancer tumors are estrogen receptor-positive (ER⁺) and can be treated with endocrine therapy. However, certain patients may exhibit a good prognosis without systemic treatment. The aim of the present study was to identify novel prognostic factors for patients with ER⁺ breast cancer tumors using gene copy data, and to investigate if these factors have prognostic value in subgroups categorized by progesterone receptor status (PR). Public data, including the whole genome gene copy data of 199 systemically untreated patients with ER⁺ tumors, were utilized in the present study. To assess prognostic value, patients were divided into two groups using the median gene copy number as a cut-off for the SNPs that were the most variable. One SNP was identified, which indicated that the Ras-related protein Rab-6C (RAB6C) gene may exhibit prognostic significance. Therefore, RAB6C protein expression was subsequently investigated in a second independent cohort, consisting of 469 systematically untreated patients (of which 310 were ER⁺) who received long term follow-up. In the public data set, a distant recurrence risk reduction of 55% was determined for copy numbers above the median value of RAB6C compared with numbers below [multivariable adjusted hazard ratio (HR), 0.45; 95% CI 0.28-0.72; P=0.001)]. It was also more pronounced in the ER⁺/PR^- subgroup (HR, 0.15; 95% CI, 0.05-0.46; P=0.001). In the second cohort, patients of the ER⁺/PR^- subgroup who exhibited high RAB6C expression had a reduced distant recurrence risk (HR, 0.17; 95% CI, 0.05-0.60; P=0.006). However, this was not identified among ER⁺/PR⁺ tumors (HR, 1.31; 95% CI, 0.69-2.48; P=0.41). The results of the present study indicated that RAB6C serves as an independent prognostic factor of distant recurrence risk in systemically untreated patients with an ER⁺/PR^- tumor.

Keywords: Ras-related protein Rab-6C; breast neoplasm; estrogen receptor; gene copy number; progesterone receptor; prognostic.

Figure 1.

Consort diagram of the independent cohort. RAB6C, Ras-related protein Rab-6C; TMA, tissue microarray.

Figure 2.

Cumulative distant recurrence risk in relation to the gene copy number of RAB6C in patients of the public dataset. (A) ER⁺. HR, 0.44 (95% CI, 0.28–0.71; P=0.001). (B) ER⁺/PR⁻. HR, 0.23 (95% CI, 0.08–0.61; P=0.003). (C) ER⁺/PR⁺. HR, 0.55 (95% CI, 0.32–0.96; P=0.03). ER, estrogen receptor; HR, hazard ratio; PR progesterone receptor; RAB6C, Ras-related protein Rab-6C.

Figure 3.

Cumulative distant recurrence risk in relation to the protein expression of RAB6C in patients of the independent cohort. (A) ER⁺. HR, 0.77 (95% CI, 0.48–1.22; P=0.27). (B) ER⁺/PR⁻. HR, 0.24 (95% CI, 0.09–0.66; P=0.005). (C) ER⁺/PR⁺. HR, 1.20 (95% CI, 0.66–2.19; P=0.55). ER, estrogen receptor; HR, hazard ratio; PR, progesterone receptor; RAB6C, Ras-related protein Rab-6C.