A major breakthrough in cancer genomics! Pan-scientific scientists once again discover the key pathogenic genes of malignant glioma | Nature

June 04, 2018 Source: Biological Exploration

On May 25th, a new achievement on glioblastoma was published online in the internationally leading academic journal Nature Communications. The research was led by Professor Duke University professor of the University of Duke, and the co-founder and chief scientist of the Pan-Effective Professor, Dr. Hai Hai. The researchers at Duke University and Johns Hopkins University, together with the team of the team of students.

The study first discovered two new glioblastoma molecular typing, thus completing the mapping of TERTpWT-IDHWT (TERT promoter wild-IDH wild type) glioblastoma gene map. This breakthrough discovery is expected to develop targeted therapies for lethal brain tumors that will benefit more patients.

Figure: New genotype of glioblastoma in global molecular typing of adult diffuse glioma

Glioblastoma is the most common and fatal primary malignant brain tumor in adults. Despite active treatment, the median overall survival was less than 15 months. The analysis of its gene profile and the development of molecular typing provide important support for improving the clinical treatment level and improving the prognosis of glioblastoma.

1. Complete the complete mapping of the glioblastoma gene map

As a pioneer in molecular typing research of glioma, from 2008 to 2009, Professor Bohai team and collaborators discovered the important role of IDH1/2 gene mutation in glioma for the first time. The results were published in Science. In the New England Journal of Medicine, in 2013, he found that the TERT promoter mutation is a key driver of many common tumors and can be used as another important basis for molecular typing of glioma. The results were published in PNAS. Subsequent studies have shown that mutations in the IDH gene and mutations in the TERT promoter can be molecularly typed in approximately 80% of glioma patients.

Based on this, in 2016, Professor Bohai was invited by the World Health Organization to participate in the preparation of the new WHO Classification of Central Nervous System Tumors, introducing molecular classification criteria for brain tumors such as IDH1/2, which is the first time in human history. Classification is included in the gold standard for brain tumor diagnosis. Immediately afterwards, the Panzozis carried out clinical transformation of scientific research results, and in 2018 launched the only domestically approved IDH1/TERT gene detection kit for glioma.

However, there are still about 20% of glioma patients without TERT promoter, IDH mutation and 1p19q deletion, and these patients usually have the worst prognosis. This part of the tumor is named TERTpWT-IDHWT glioblastoma, or three. Negative gliomas, which do not have mature genetic biomarkers, cannot be classified by objective biomarkers.

In the latest study published in 2018, Professor Bohai and his collaborators first mapped the gene profile of TERTpWT-IDHWT by whole-genome sequencing.

Figure: Mutation map of somatically encoded changes in TERTpWT-IDHWT glioblastoma cells

The investigators found that TERTpWT-IDHWT tumors are actually composed of two subpopulations associated with telomere maintenance, namely telomere elongation caused by inactivating mutations in SMARCAL1 and telomere activation by chromosomal rearrangements upstream of TERT. Based on these two newly discovered mechanisms of telomere maintenance, the TERTpWT-IDHWT tumor can be divided into two molecular subtypes. That is, the telomerase-positive subtype (IDHWT-TERTSV) caused by rearrangement of the TERT structure and the ALT-positive subtype (IDHWT-ALT) caused by the ATRX or SMARCAL1 mutation.

Figure: Inactivating mutations of SMARCAL1 and ATRX and rearrangement upstream of TERT in TERTpWT-IDHWT glioblastoma are common and are associated with different telomere maintenance mechanisms

After the discovery of the IDH mutation and the TERT promoter mutation, the study completed the mapping of the glioblastoma gene map. Based on this finding, the molecular typing criteria for glioblastoma will be updated. The study of the molecular mechanism of tumors is not only a deeper exploration of the mechanism of disease occurrence, but also can be transformed into the clinic, bringing hope and gospel to patients. This is the mission and original intention of the pan-child.

In addition, the researchers found that high-frequency mutations in the BRAF gene were found in younger adult patients with TERTpWT-IDHWT glioblastoma, which provided a basis for the use of targeted drugs against BRAF V600E/MEK.

However, the escape and survival mechanism of tumors also plague us. Professor Bohai said: "Even if locked, tumor cells tend to camouflage or change. Therefore, study the mechanism of escape and survival for tumors. Drug development is of great significance. We need to understand more about the signaling pathways of tumor mutant genes to explore the principles of these mechanisms and find ways to deal with them."

2 , focus on the clinical transformation of cancer genomics

The multi-disciplinary team of experts, centered on Professor Bohai, has been focused on the clinical transformation of cancer genomics since its inception. He has published more than 10 research results in world-renowned authoritative academic journals such as Nature Genetics, including in the field of brain tumors:

In 2014, in cooperation with Beijing Tiantan Hospital, PPM1D mutation, another important cause of brain stem glioma, was successfully discovered. The results were published in Nature Genetics;

In 2016, a complete map of the somatic tumor cell mutated gene was constructed, and gene pathway association analysis was performed on each subtype of pituitary tumor, and several potential targeted therapeutic pathways were discovered. The results were published online in Cell Research.

In 2017, it was first discovered that the CDH23 gene is not only a genetic causative gene of familial pituitary tumor (FPA) but also a susceptibility gene for sporadic pituitary tumors. The results were published in the American Journal of Human Genetics.

Since its establishment, the Pan-son has focused on the mystery of genetics and the development of technological innovation. It is committed to trace the roots of cancer genes and reveal the root causes of tumors and the key mechanisms for their development.

With the molecular research of cancer as the paddle, the pan-progenitor has accelerated the landing of technology, and has thrown the giant anchor of clinical transformation in the gene navigation:

• In 2015, Panzoko launched six detection products for glioma, covering the glioma molecular typing test genes recommended by the WHO and NCCN guidelines;
• In September 2016, Panson has launched 509panel, which can be used to comprehensively guide the accurate prognosis, targeting and immunotherapy guidance and genetic risk prediction of primary brain tumors and brain metastases;
• In April 2017, the 68 gene panel for brain tumor precision diagnosis and treatment and the first domestic pediatric medulloblastoma molecular typing test product were launched;
• In August 2017, Panson launched a cerebrospinal fluid ctDNA test for brain tumor diagnosis, adding a tool for liquid biopsy;
• In December 2017, the biochip reader GETENRON 3D (Registration No.: 注机械注准20172400136), which was independently developed by the Panshengzi, was approved for marketing, and focused on the development of lung cancer, breast cancer, colorectal cancer, stomach cancer, etc. in the field of liquid biopsy. More than 50 sites to detect LDT services;
• In 2018, the only domestically approved IDH1/TERT gene detection kit for glioma was introduced, which provides important reference information for pathological typing of glioma patients.

Through the practical action, the pan-son has achieved innovative breakthroughs in the tumor gene detection industry, and has provided a diversified and clinically appropriate choice for clinical treatment, leading to the development trend of individualized medical cancer.

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