Characterization of PIK3CA and PIK3R1 somatic mutations in Chinese breast cancer patients

Li Chen; Liu Yang; Ling Yao; Xia-Ying Kuang; Wen-Jia Zuo; Shan Li; Feng Qiao; Yi-Rong Liu; Zhi-Gang Cao; Shu-Ling Zhou; Xiao-Yan Zhou; Wen-Tao Yang; Jin-Xiu Shi; Wei Huang; Xin Hu; Zhi-Ming Shao

doi:10.1038/s41467-018-03867-9

Characterization of PIK3CA and PIK3R1 somatic mutations in Chinese breast cancer patients

Nat Commun. 2018 Apr 10;9(1):1357. doi: 10.1038/s41467-018-03867-9.

Authors

Li Chen^{1

2}, Liu Yang^{1

2}, Ling Yao¹, Xia-Ying Kuang³, Wen-Jia Zuo^{1

2}, Shan Li¹, Feng Qiao¹, Yi-Rong Liu^{1

2}, Zhi-Gang Cao¹, Shu-Ling Zhou^{2

4}, Xiao-Yan Zhou^{2

4}, Wen-Tao Yang^{2

4}, Jin-Xiu Shi⁵, Wei Huang⁵, Xin Hu^{6

7}, Zhi-Ming Shao^{8

9}

Affiliations

¹ Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
² Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
³ Department of Breast Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China.
⁴ Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
⁵ Department of Genetics, Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center and Shanghai Industrial Technology Institute (SITI), Shanghai, 201206, China.
⁶ Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. [email protected].
⁷ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. [email protected].
⁸ Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. [email protected].
⁹ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. [email protected].

Abstract

Deregulation of the phosphoinositide 3-kinase (PI3K) pathway contributes to the development and progression of tumors. Here, we determine that somatic mutations in PIK3CA (44%), PIK3R1 (17%), AKT3 (15%), and PTEN (12%) are prevalent and diverse in Chinese breast cancer patients, with 60 novel mutations identified. A high proportion of tumors harbors multiple mutations, especially PIK3CA plus PIK3R1 mutations (9.0%). Next, we develop a recombination-based mutation barcoding (ReMB) library for impactful mutations conferring clonal advantage in proliferation and drug responses. The highest-ranking PIK3CA and PIK3R1 mutations include previously reported deleterious mutations, as well as mutations with unknown significance. These PIK3CA and PIK3R1 impactful mutations exhibit a mutually exclusive pattern, leading to oncogenesis and hyperactivity of PI3K pathway. The PIK3CA impactful mutations are tightly associated with hormone receptor positivity. Collectively, these findings advance our understanding of PI3K impactful mutations in breast cancer and have important implications for PI3K-targeted therapy in precision oncology.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / pharmacology
Binding Sites
Breast Neoplasms / genetics*
Breast Neoplasms / metabolism
Breast Neoplasms / pathology
Cell Line, Tumor
Class I Phosphatidylinositol 3-Kinases / chemistry
Class I Phosphatidylinositol 3-Kinases / genetics*
Class I Phosphatidylinositol 3-Kinases / metabolism
Class Ia Phosphatidylinositol 3-Kinase
Doxorubicin / pharmacology
Female
Gene Expression Regulation, Neoplastic*
Genetic Predisposition to Disease
Humans
Models, Molecular
Mutation*
PTEN Phosphohydrolase / genetics
PTEN Phosphohydrolase / metabolism
Phosphatidylinositol 3-Kinases / chemistry
Phosphatidylinositol 3-Kinases / genetics*
Phosphatidylinositol 3-Kinases / metabolism
Protein Binding
Protein Conformation, alpha-Helical
Protein Conformation, beta-Strand
Protein Interaction Domains and Motifs
Proto-Oncogene Proteins c-akt / genetics
Proto-Oncogene Proteins c-akt / metabolism
Receptor, ErbB-2 / genetics
Receptor, ErbB-2 / metabolism
Receptors, Estrogen / genetics
Receptors, Estrogen / metabolism
Receptors, Progesterone / genetics
Receptors, Progesterone / metabolism
Recombinant Proteins / chemistry
Recombinant Proteins / genetics
Recombinant Proteins / metabolism
Retrospective Studies
Signal Transduction

Substances

Antineoplastic Agents
Receptors, Estrogen
Receptors, Progesterone
Recombinant Proteins
Doxorubicin
PIK3R1 protein, human
Class I Phosphatidylinositol 3-Kinases
Class Ia Phosphatidylinositol 3-Kinase
PIK3CA protein, human
ERBB2 protein, human
Receptor, ErbB-2
Proto-Oncogene Proteins c-akt
PTEN Phosphohydrolase
PTEN protein, human