Age is the number one risk factor for breast cancer development. The breast cancer incidence rate increases with age, following beta distribution, which is approximately linear in range from 30 to 70 years old [1]. Transcriptome alterations have been shown to promote tumorigenesis for many types of cancers. Therefore, we hypothesize that the genes with altered expression during aging may promote breast cancer development and/or progression. Using The Cancer Genome Atlas data, we extracted whole transcriptome profiling data of matched normal tissues from 82 female patients with age at diagnosis and menopausal status available. First, we applied simple linear regression to study the association between gene expression level and age at diagnosis on all the 82 patients. 258 upregulated and 240 downregulated genes are identified, which are associated with age. Secondly, 493 upregulated and 254 downregulated genes are identified that are altered by menopause by comparing post-menopausal to pre-menopausal patients (FDR < 0.05). Exclusion of these menopause affected genes from those genes affected by age (258 upregulated and 240 downregulated) results in 148 upregulated and 189 downregulated genes during aging. Thirdly, by comparing matched tumor and adjacent normal samples, 3356 upregulated and 3124 downregulated genes are found to be associated with tumorigenesis. Overlapping of tumorigenesis associated genes with age dependent genes result in 14 upregulated and 24 downregulated genes that are both age and tumorigenesis associated. This discovery is being validated with normal breast tissues from donors in GTEx cohort. Experimental manipulation of the upregulated genes in seven breast cancer cell lines, representing five subtypes of breast cancer, demonstrated their essential role in promoting tumor malignancy, suggesting the upregulation is not merely passenger event. In a large mixed cohort, this panel of genes have significant predictive value in relapse free survival of breast cancer patients.

Funding: CPRIT Research Training Award (RP140105); NIH R01CA192564

Reference:

Francesco Pompei and Richard Wilson (2001). Age Distribution of Cancer: The incidence Turnover at Old Age. Human and Ecological Risk Assessment: Vol. 7, No. 6, pp. 1619-1650.

Citation Format: Gu X, Zhu H, Sun L. Identification of tumor-promoting and tumor-inhibiting genes with age dependent expression in breast cancer patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-08-08.