Background: Experimental studies indicate that neuroendocrine pathways might play a role in progression of breast cancer. We aim to test the hypothesis that somatic mutations in the genes of neuroendocrine pathways influence breast cancer prognosis, through dysregulated gene expression in tumor tissue. Methods: We conducted an extreme case–control study including 208 breast cancer patients with poor invasive disease-free survival (iDFS) and 208 patients with favorable iDFS who were individually matched on molecular subtype from the Breast Cancer Cohort at West China Hospital (WCH; N = 192) and The Cancer Genome Atlas (TCGA; N = 224). Whole exome sequencing and RNA sequencing of tumor and paired normal breast tissues were performed. Adrenergic, glucocorticoid, dopaminergic, serotonergic, and cholinergic pathways were assessed for differences in mutation burden and gene expression in relation to breast cancer iDFS using the logistic regression and global test, respectively. Results: In the pooled analysis, presence of any somatic mutation (odds ratio = 1.66, 95% CI: 1.07–2.58) of the glucocorticoid pathway was associated with poor iDFS and a two-fold increase of tumor mutation burden was associated with 17% elevated odds (95% CI: 2–35%), after adjustment for cohort membership, age, menopausal status, molecular subtype, and tumor stage. Differential expression of genes in the glucocorticoid pathway in tumor tissue (P = 0.028), but not normal tissue (P = 0.701), was associated with poor iDFS. Somatic mutation of the adrenergic and cholinergic pathways was significantly associated with iDFS in WCH, but not in TCGA. Conclusion: Glucocorticoid pathway may play a role in breast cancer prognosis through differential mutations and expression. Further characterization of its functional role may open new avenues for the development of novel therapeutic targets for breast cancer.
Bibliographical noteFunding Information:
Open access funding provided by Karolinska Institute. This work was supported by grants awarded to KH by the China Scholarship Council (No. 201806240005); to FF by the Swedish Cancer Society (20 0846 PjF); to DL by the National Natural Science Foundation of China (No. 8187111500) and the Swedish Research Council (2018–00648). The funding bodies did not play any role in the design of the study and collection, analysis, or interpretation of data or in writing the manuscript.
We thank the West China Biobank, Department of Clinical Research Management, West China Hospital, Sichuan University for the bio-sample storage. We thank Dr. Jianming Zeng (University of Macau) and his team biotrainee for generously sharing their experiences and codes. The results shown here are in part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga. This work was presented as an e-Poster (215P) in ESMO Congress 2021, 16-21 September 2021.
© 2022, The Author(s).
- Breast cancer
- Differential expression
- Somatic mutation