2. Academic Validation
  3. Genomic and transcriptomic analysis of breast cancer identifies novel signatures associated with response to neoadjuvant chemotherapy

Genomic and transcriptomic analysis of breast cancer identifies novel signatures associated with response to neoadjuvant chemotherapy

  • Genome Med. 2024 Jan 12;16(1):11. doi: 10.1186/s13073-024-01286-8.
Gengshen Yin 1,  Liyuan Liu 1 2 3,  Ting Yu 4,  Lixiang Yu 1 2 3,  Man Feng 5,  Chengjun Zhou 6,  Xiaoying Wang 6,  Guoxin Teng 6,  Zhongbing Ma 1 2 3,  Wenzhong Zhou 1 2 3,  Chunmiao Ye 1 2 3,  Jialin Zhang 1,  Changhua Ji 6,  Linfeng Zhao 2 7,  Peng Zhou 1,  Yaxun Guo 1,  Xingchen Meng 8,  Qinye Fu 1 2 3,  Qiang Zhang 1 2 3,  Liang Li 1 2 3,  Fei Zhou 1 2 3,  Chao Zheng 1 2 3,  Yujuan Xiang 1 2 3,  Mingming Guo 1 2 3,  Yongjiu Wang 1 2 3,  Fei Wang 9 10 11,  Shuya Huang 12 13 14,  Zhigang Yu 15 16 17
Affiliations

Affiliations

  • 1 Department of Breast Surgery, The Second Hospital of Shandong University, Jinan, 250033, China.
  • 2 Institute of Translational Medicine of Breast Disease Prevention and Treatment, Shandong University, Jinan, 250033, China.
  • 3 Shandong Provincial Engineering Laboratory of Translational Research On Prevention and Treatment of Breast Disease, Jinan, 250033, China.
  • 4 Research Center for Mathematics and Interdisciplinary Sciences, Shandong University, Qingdao, 266237, China.
  • 5 Department of Pathology, The Third Affiliated Hospital of Shandong First Medical University (Affiliated Hospital of Shandong Academy of Medical Sciences), Jinan, 250031, China.
  • 6 Department of Pathology, The Second Hospital of Shandong University, Jinan, 250033, China.
  • 7 Institute of Medical Sciences, The Second Hospital of Shandong University, Jinan, 250033, China.
  • 8 Department of Breast Surgery, Weifang People's Hospital, Weifang, 261041, China.
  • 9 Department of Breast Surgery, The Second Hospital of Shandong University, Jinan, 250033, China. [email protected].
  • 10 Institute of Translational Medicine of Breast Disease Prevention and Treatment, Shandong University, Jinan, 250033, China. [email protected].
  • 11 Shandong Provincial Engineering Laboratory of Translational Research On Prevention and Treatment of Breast Disease, Jinan, 250033, China. [email protected].
  • 12 Department of Breast Surgery, The Second Hospital of Shandong University, Jinan, 250033, China. [email protected].
  • 13 Institute of Translational Medicine of Breast Disease Prevention and Treatment, Shandong University, Jinan, 250033, China. [email protected].
  • 14 Shandong Provincial Engineering Laboratory of Translational Research On Prevention and Treatment of Breast Disease, Jinan, 250033, China. [email protected].
  • 15 Department of Breast Surgery, The Second Hospital of Shandong University, Jinan, 250033, China. [email protected].
  • 16 Institute of Translational Medicine of Breast Disease Prevention and Treatment, Shandong University, Jinan, 250033, China. [email protected].
  • 17 Shandong Provincial Engineering Laboratory of Translational Research On Prevention and Treatment of Breast Disease, Jinan, 250033, China. [email protected].
PMID: 38217005 DOI: 10.1186/s13073-024-01286-8
Abstract

Background: Neoadjuvant chemotherapy (NAC) has become a standard treatment strategy for breast Cancer (BC). However, owing to the high heterogeneity of these tumors, it is unclear which patient population most likely benefit from NAC. Multi-omics offer an improved approach to uncovering genomic and transcriptomic changes before and after NAC in BC and to identifying molecular features associated with NAC sensitivity.

Methods: We performed whole-exome and RNA sequencing on 233 samples (including matched pre- and post-treatment tumors) from 50 BC patients with rigorously defined responses to NAC and analyzed changes in the multi-omics landscape. Molecular features associated with NAC response were identified and validated in a larger internal, and two external validation cohorts, as well as in vitro experiments.

Results: The most frequently altered genes were TP53, TTN, and MUC16 in both pre- and post-treatment tumors. In comparison with pre-treatment tumors, there was a significant decrease in C > A transversion mutations in post-treatment tumors (P = 0.020). NAC significantly decreased the mutation rate (P = 0.006) of the DNA repair pathway and gene expression levels (FDR = 0.007) in this pathway. NAC also significantly changed the expression level of immune checkpoint genes and the abundance of tumor-infiltrating immune and stroma cells, including B cells, activated dendritic cells, γδT cells, M2 macrophages and endothelial cells. Furthermore, there was a higher rate of C > T substitutions in NAC nonresponsive tumors than responsive ones, especially when the substitution site was flanked by C and G. Importantly, there was a unique amplified region at 8p11.23 (containing ADGRA2 and ADRB3) and a deleted region at 3p13 (harboring FOXP1) in NAC nonresponsive and responsive tumors, respectively. Particularly, the CDKAL1 missense variant P409L (p.Pro409Leu, c.1226C > T) decreased BC cell sensitivity to docetaxel, and ADGRA2 or ADRB3 gene amplifications were associated with worse NAC response and poor prognosis in BC patients.

Conclusions: Our study has revealed genomic and transcriptomic landscape changes following NAC in BC, and identified novel biomarkers (CDKAL1P409L, ADGRA2 and ADRB3) underlying chemotherapy resistance and poor prognosis, which could guide the development of personalized treatments for BC.

Keywords

Breast cancer; Genomic; Neoadjuvant chemotherapy; Pathological response; Prognosis; Transcriptomic.

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