Significance of molecular detection in clinical laboratory in accurate diagnosis and treatment of malignant tumor
Author: Zhao Xiaotao 1 Cong Yulong 2
SETTING: 1. Clinical Laboratory of Peking University People’s Hospital, 2. Clinical Laboratory Center of PLA General Hospital.
Zhao Xiaotao
Deputy Director, Laboratory Department, Peking University People’s Hospital
Chief physician/professor, master tutor. Engaged in clinical molecular detection and related basic research. As the project leader, he was supported by the National Natural Science Foundation of China and the Beijing Natural Science Foundation, and published many core journals and articles in SCI as the first or correspondent author. Major social workers are members (and secretaries) of the Department of Medical Laboratory in peking university health science center; Standing Committee member (and Secretary-General) of Clinical Microbiology and Infection Branch of China Health Care International Exchange Promotion Association; Deputy head of the special working group on scientific research and postgraduate training of Beijing Inspection Society of Chinese Medical Association; Member of Molecular Diagnosis Group of Laboratory Medicine Branch of Chinese Medical Association; Director of Laboratory Specialist Branch of Beijing Medical Doctor Association; Member of the Special Committee of Laboratory Medicine of China Association of Integrated Traditional Chinese and Western Medicine; Standing Committee of Laboratory Medicine Committee of Beijing Society of Integrated Traditional Chinese and Western Medicine; Member of Laboratory Medicine Branch of China Medical Equipment Association; Member of China Medical and Health Care International Exchange Promotion Association, grassroots inspection technology standardization branch, etc.
Malignant tumor is an important disease endangering human life and health, and its incidence has long been at the forefront of disease spectrum and death spectrum, which is a disease of universal concern. The online cloud live broadcast mode was launched for the first time in the 26th National Cancer Prevention Publicity Week held from April 15th to 21st, 2020, and 21.456 million people watched the live broadcast nationwide. This shows that the national medical and health field and the whole society pay attention to the prevention and treatment of malignant tumors. At present, the burden of malignant tumor is still rising in China, which seriously affects people’s health and social life. In recent 10 years, the incidence of malignant tumors in China has increased by about 3.9% every year, and the mortality rate has increased by 2.5% every year. According to the data released by the National Cancer Center in 2019, there were about 3.929 million cases of malignant tumors and 2.338 million deaths in China in 2015. The top five cancers in China are lung cancer, gastric cancer, colorectal cancer, liver cancer and breast cancer, among which lung cancer and breast cancer rank first among men and women in China respectively. At present, the five-year survival rate of cancer patients in China is about 40%, which is 10% higher than that of ten years ago, but there is still a certain gap compared with developed countries. The reason is that early diagnosis, early treatment and precise medical treatment are the key to prevent and cure tumors, and one of its important means is the extensive and effective application of molecular biological diagnosis technology in clinical laboratories.
1. The development of medical molecular biology promotes the wide application of molecular diagnosis technology in precision medicine.
Medical molecular biology refers to the study of the structure and function of biological macromolecules at the molecular level, so as to clarify the nature of life phenomena. In recent years, with the emergence of new technologies in the field of medical molecular biology and the continuous improvement of bioinformatics data, the level of molecular diagnosis in clinical laboratories has been greatly promoted, and the progress of medical science has been promoted, so that the diagnosis and treatment of diseases in clinical medicine has risen to a brand-new realm, from morphological or cellular level to the explanation of the mechanism and accurate diagnosis and treatment of malignant tumor diseases from gene level and molecular level, so as to achieve early diagnosis and even susceptibility assessment of diseases, and to evaluate the stages, types, treatment effects and prognosis of diseases. Molecular biology has become an important development direction of modern medicine and precision medicine.
In the field of clinical medicine, the application scope of molecular biology technology and methods is expanding day by day, and its research content and technical means are deepening. At present, it has penetrated into all fields of medicine, including molecular detection of pathogenic microorganisms, genetic detection and diagnosis of congenital diseases and hereditary diseases, genetic detection and diagnosis of malignant tumors, as well as individual drug use gene detection that affects drug metabolism, drug resistance and toxic side effects, individual identification, gene detection related to transplant matching, non-invasive prenatal detection (NIPT) and embryo implantation. Among them, gene detection related to targeted therapy of malignant tumor, multi-locus tumor-related gene detection related to heredity, susceptibility, treatment and prognosis, and whole exon gene detection play an important role in accurate diagnosis, prevention and treatment of malignant tumor.
Second, tumor molecular diagnostic markers and new detection technologies provide an important basis for clinical risk assessment of malignant tumors.
In clinical research, it is the direction of clinical medicine, especially clinical tumor research and basic research, to continuously discover new diagnostic markers of malignant tumors and further explore and study the pathological mechanism of malignant tumors. From the discovery of Bence-Jones protein in the urine of patients with multiple myeloma by Henry Bence-Jones in 1846, which was used as the first tumor marker for the diagnosis of multiple myeloma, up to now, more than 100 tumor markers have been discovered, including protein tumor markers, sugar tumor markers and enzyme tumor markers. With the development of molecular biotechnology, there are more and more categories of tumor biomarkers, such as specific gene mutation, which can affect the effect of tumor-targeted drug therapy, genes related to cell growth and differentiation, oncogenes, tumor suppressor genes and their products that play a key role in the occurrence and development of tumors, and single nucleotide polymorphism, genome, transcriptome and proteome can all be used as tumor biomarkers. From tumor-related chromosomal abnormalities to tumor-related genetic abnormalities, from tumor-related single nucleotide polymorphisms to tumor-related epigenetic abnormalities, and the study of new molecular markers such as miRNA and LncRNA provide powerful tools for accurate diagnosis and treatment of malignant tumors in clinic. By detecting these molecular markers, we can assess the risk of cancer and make early diagnosis, monitoring, early warning, intervention,Reduce the risk of cancer and improve the treatment effect, slow down the development of cancer and even prevent the intervention of cancer.
Due to the rapid development of molecular biology technology, the detection of molecular markers of malignant tumors is more and more accurate and efficient. From the discovery of nuclein by F.Miescher in 1868 to the discovery of double helix structure of deoxyribonucleic acid (DNA) by Watson and Crick in 1953, from the invention of polymerase chain reaction (PCR) by Mullis in 1985 to the wide application of NGS NGS((Next-generation sequencing, also known as second-generation sequencing) technology developed in recent years, from the technical means, At present, the Amplified Arrested Mutation System (AMRs) is applied in clinic, which can be used to detect low-frequency mutations and detect 1% mutations in tissues and cells. More sensitive digital PCR technology can detect 0.1% mutation. For the traditional Sanger sequencing, although it is less sensitive, it has advantages in detecting germline mutations, high-frequency mutations, unknown mutations, clear target genes and few genes. NGS technology has the advantage of Qualcomm, which can sequence hundreds of genes, whole exons and whole genomes at one time. With the maturity of technology, more standardized management, continuous improvement and updating of biological information database, and perfection of data interpretation, combined with technologies such as detecting tumor cells in peripheral blood and free nucleic acids in peripheral blood, through overcoming the heterogeneity of malignant tumors,It will greatly promote the development of this technology and have a broader clinical application prospect.
Third, with the diagnosis of cancer patients tailored to provide the best solution for accurate diagnosis and treatment of malignant tumors.
At present, with the continuous development of molecular biology technology and the popularization of molecular diagnosis technology in clinical laboratories, the clinical oncology is increasingly widely used in individualized medicine, precision medicine and targeted therapy. Therefore, the concept of companion diagnostics (CDx) came into being. Adjoint diagnosis is an in vitro diagnostic technique related to special drugs, which can identify the best drug users by detecting the variation of proteins and genes in human body and the expression level of genes. The application of CDx in patients with malignant tumor can not only screen out effective treatment schemes for patients, save the time and cost of ineffective treatment, but also improve the compliance of patients taking drugs and reduce unnecessary toxic and side effects.
The development of accompanying diagnosis shows that the correlation between the expression of estrogen receptor and the efficacy of endocrine therapy in breast cancer patients has been studied since 1970s, from protein level to molecular gene level. Herceptin, the first adjoint diagnostic reagent approved by FDA in September, 1998, was used to detect people who used anticancer drug Herceptin, a humanized monoclonal antibody targeting the extracellular structural region of HER-2 receptor tyrosine kinase. As the driving gene of non-small cell lung cancer, epidermal growth factor receptor (EGFR) has a sensitive mutation rate of 30%~40% in Asian population. TKI (tyrosine kinase inhibitor) is used as a targeted therapy for such non-small cell lung cancer patients, and their survival time is significantly prolonged, and their tolerance and quality of life are higher than those of traditional chemotherapy. Up to now, FDA has approved NGS associated diagnosis and detection products with multiple genes and cancers, covering 324 genes, including microsatellite instability (MSI) and tumor mutation load (TMB). At present, most of the applications of adjoint diagnosis are used in tumors, mainly including clinical management of non-small cell lung cancer, melanoma, breast cancer, colorectal cancer and ovarian cancer. Adjoint diagnosis plays an indispensable role in precision medicine, and its application scope is gradually expanding. It is predicted that it will be developed in the fields of pharmacogenomics, autoimmune diseases, cardiovascular diseases, central nervous system, infection and so on.
Four, clinical laboratory molecular diagnosis quality assurance and technical specifications and market supervision has a long way to go.
The market demand and development potential of cancer medical treatment promote the development and application of In Vitro Diagnosis (IVD) instruments and reagents, and new technologies emerge one after another. On the other hand, institutions for tumor genetic testing have also flourished. The results of tumor detection are related to the diagnosis, treatment and prognosis of the disease, which can be said to be related to the existence of a life. However, due to the high sensitivity and diversity of molecular detection technology, as well as the complexity and uncertainty of specimens and experimental operations, the quality assurance of tumor-related molecular detection is particularly important. From the research and development of reagents and equipment, to the determination of expected clinical use, the establishment and optimization of methods, from the range control of indications to the selection of detection items, methods adopted, the performance confirmation of LDTs or the performance verification of kits, from the selection of specimen types to the collection and transportation of specimens, from the design and layout of space environment to the qualification of personnel, equipment, reagents and technical specifications, from bioinformatics analysis to the interpretation of genetic variation in tumor molecular detection reports, and so on. In order to standardize the medical behavior in the field of tumor genetic testing, the health administrative department has successively issued a number of rules and regulations, and clinical and laboratory experts have also actively formulated national or industry standards, written relevant guidelines, expert consensus, etc., coordinated supervision and liberalization, and jointly promoted the orderly and healthy development of the field of tumor molecular testing.Effectively serve the accurate diagnosis and treatment of clinical malignant tumors.
With the completion of the human genome project and the post-genome era, as well as the completion of genome-wide association study () of all malignant tumors, more new molecular targets of malignant tumors will be continuously discovered and applied to clinical diagnosis and treatment. At the same time, with the continuous introduction of the application management policy of molecular diagnostic technology and the improvement of supervision, many genetic tests related to malignant tumors will gradually move from basic scientific research to clinical application. The joint application of various molecular biological detection technology platforms, the in-depth study of various new targets, and the intersection and penetration with other disciplines make molecular biological detection play an increasingly important role in the diagnosis, prevention, treatment, drug research and development of malignant tumors. Molecular detection technology in clinical laboratories will help promote the accurate detection, accurate diagnosis, accurate treatment, accurate prediction and accurate prevention of malignant tumors, so that it can serve human health more efficiently and push medical science forward continuously.
Note:This article comes from the topic "Tumor and Adjoint Diagnosis" in the 5th issue of Clinical Laboratory in 2020.
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Title map | veer.com
Original release date | May 8, 2020
Clinical Laboratory is a journal of medical laboratory technology, with 12 issues a year, each with different topics, tracking industry hotspots, capturing industry direction and paying attention to development frontiers. The electronic version is updated in real time every month, and colleagues are welcome to follow up.





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