Release date: 2018-04-12
Breast cancer is the most common cancer among women worldwide [1]. The incidence of breast cancer has increased year by year in the Chinese population. Now the annual incidence rate has reached 60/100,000. It has become the most common malignant tumor in China, which seriously endangers the physical and mental health of Chinese women.
The PI3K/AKT signaling pathway is widely activated in breast cancer, especially PIK3CA, PIK3R1, PTEN, AKT and other genes have high frequency mutations in breast cancer (in which PIK3CA gene is mutated in about 36% of breast cancer), Breast cancer development, development and drug resistance are closely related [2,3]. Our existing breast cancer multi-omics data are from Western populations, and there is no systematic and complete study on the mutations and functions of PI3K/AKT pathway genes in Chinese breast cancer population. There may be large differences in genetics and etiology between the East and West, so it is necessary to systematically study the mutational lineage of the PI3K signaling pathway in breast cancer patients in China.
On April 10th, Professor Shao Zhimin, director of the Department of Breast Surgery of Fudan University Cancer Hospital and director of the Institute of Cancer Research at Fudan University, and research team led by Associate Professor Hu Xin published a report entitled "Characterization of PIK3CA and PIK3R1 somatic mutations in online". The Chinese breast cancer patients' research paper reveals for the first time the mutational lineage characteristics of PI3K/AKT signaling in Chinese breast cancer population, and uses the self-developed high-throughput screening system Recombination-based mutation barcoding (ReMB) for PI3K function. Sexual mutations were systematically interpreted and identified. This work is of great significance for the implementation of the "precise interpretation" of PI3K gene functional mutations in breast cancer, and further guides the "precise treatment" of the PI3K/AKT pathway.
In the latest study, Professor Shao Zhimin's team targeted the exon of mutations in the PI3K/AKT signaling pathway genes (PIK3CA, PIK3R1, AKT1, AKT2, AKT3, PTEN, PDK1, etc.) in breast cancer based on the Fudan cohort. Sequencing, obtained a mutational lineage of this pathway gene based on Chinese breast cancer population.
Mutation map of PI3K/AKT signaling pathway in breast cancer in Chinese population
The study found that PIK3CA has the highest mutation frequency (44%), similar to the Western population in the US Tumor and Cancer Gene Map (TCGA) and the Tumor Cellular Mutation Catalog (COSMIC) database; the mutation frequency of PIK3R1 (17%) is significantly higher than that in the West. crowd. Moreover, PIK3CA and PIK3R1 have a higher proportion of multiple mutations (9%). In addition, in addition to validating some hotspot mutations in breast cancer, such as PIK3CA E545K and H1047R, the study also found a number of new mutations unique to breast cancer in China.
Gene mutations are widespread in tumors, and some mutations (with mutations) do not affect gene function, while some mutations (functional mutations) determine tumor progression and resistance. At present, there is a lack of systematic interpretation of the study of PI3K gene mutations in breast cancer. Except for some high frequency mutations (E542K, E545K and H1047R in PIK3CA gene), the functions of most low frequency mutations and even newly discovered mutations are clear. still uncertain.
ReMB Functional Mutation Screening System
The researchers combined the information in Fudan breast cancer data, the TCGA database and the COSMIC database to construct a library that currently covers most of the reported PIK3CA and PIK3R1 gene mutations. The self-developed ReMB functional mutation screening system was used to systematically interpret and identify PIK3CA and PIK3R1 gene mutations, and found functional mutations with potential carcinogenic properties or chemoresistance characteristics.
The study also found that a number of low-frequency, rare mutations also have important biological functions, such as E39K, G1049R, N345I, N345K, M1043V, H1047T of PIK3CA gene; E160D, Q329L, D560Y of PIK3R1 gene. These mutations are closely related to the malignant transformation of breast cancer, the chemotherapy drug doxorubicin and the resistance of the PI3K pathway inhibitor BKM120. The researchers also found that the functional mutations of PIK3CA and PIK3R1 are mostly located in the mutual binding region of the two or the other domain of PIK3CA and the kinase domain, and found that the functional mutations of PIK3CA and PIK3R1 are mutually exclusive, thereby regulating the PI3K pathway. Activity.
In summary, the major finding of the study was that it first mapped the mutation profile of the PI3K/AKT pathway in Chinese breast cancer populations and demonstrated functional mutations in breast tumors that drive activation of this pathway. In breast cancer, PI3K signaling pathway regulates malignant transformation and drug resistance of tumors, which is one of the key factors for the success of breast cancer treatment. On the other hand, this pathway is also an important target in the treatment of breast cancer. The study provides a large-scale functional annotation for each mutation, enabling accurate interpretation of PI3K functional mutations in breast cancer, providing more support for clinical drug use, drug development, and clinical trial design, for future implementation. Accurate treatment of breast cancer has important value in transformation applications.
It is reported that the co-first authors of the paper are Dr. Chen Li, Dr. Yang Liu and Dr. Yao Ling, and Professor Shao Zhimin and Associate Professor Hu Xin are co-authors.
Introduction to Professor Shao Zhimin
Doctoral tutor, Distinguished Professor of Changjiang Scholars, Distinguished Professor of Fudan University and winner of the National Outstanding Youth Fund. He is currently the director of the Institute of Oncology at Fudan University, the director of the Breast Cancer Research Institute, the director of the Department of Breast Surgery of the Affiliated Tumor Hospital of Fudan University and the director of the Breast Surgery, the Honorary Chairman of the Breast Cancer Committee of the China Anti-Cancer Association, and the Vice Chairman of the Oncology Branch of the Chinese Medical Association. Chairman of the 8th Asian Breast Cancer Association and a member of the St. Gallen Breast Cancer Congress. He has long been engaged in the clinical and basic research of breast cancer, and has made major breakthroughs in the field of clinical multidisciplinary comprehensive treatment mode, system optimization and popularization of individualized targeted therapy, basic research of clinical application and basic research. It has taken the lead in establishing the standard and prevention and treatment system for breast cancer diagnosis and treatment, and has widely promoted and applied it. The patient's overall survival rate and tumor-free survival rate have reached the international advanced level, focusing on the improvement of patients' quality of life and achieving remarkable economic and social benefits. In the molecular typing, invasion and metastasis of breast cancer, the interaction between microenvironment and breast cancer target organophilic metastasis, the establishment of tumor recurrence and metastasis regulation network and the establishment of early warning system, the international advanced research results and innovative findings have been obtained. A distinctive research system. In the past five years, more than 80 SCI papers have been published in the journals of Nat Rev Cancer, Lancet Oncol, Nat Commun, Plos Genet and Cancer Res, and four books have been edited.
Associate Professor Hu Xin
In 2003, he obtained a bachelor's degree in medicine from Fudan University; in 2008, he received a doctorate in medicine from Fudan University; from 2009 to 2012, he completed a postdoctoral research at the Department of Genetics, MD Anderson Cancer Center, University of Texas, USA. Since 2012, he has worked at Fudan University Affiliated Tumor Hospital and is currently an associate researcher and master tutor. He is mainly engaged in the research of breast tumor genomics, breast cancer resistance, high-throughput library screening, etc. The main results are published in international journals such as Cell, Nature Commun, Hepatology, Cancer Res and JBC.
references:
1. Torre, LA et al. Global cancer statistics, 2012. CA Cancer J. Clin. 65, 87–108 (2015).
2. Liu, P. et al. Oncogenic PIK3CA-driven mammary tumors frequently recur via PI3K pathway-dependent and PI3K pathway-independent mechanisms. Nat. Med. 17, 1116–1120 (2011).
3. Fruman, DA & Rommel, C. PI3K and cancer: lessons, challenges and opportunities. Nat. Rev. Drug Discov. 13, 140–156 (2014).
Source: BioArt
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