Scientists of Genetron Health Again Define Key Pathogenic Gene for Malignant Gliomas

Release time:2018-06-01

Nature sub-journal: On May 25, the world’s authoritative academic journal Nature Communications published an online paper about the latest study achievements on glioblastoma. The study was collaboratively carried out by researchers at Duke University and The Johns Hopkins University and Genetron Health scientists.


Scientists of Genetron Health Again Define Key Pathogenic Gene for Malignant Gliomas


The research first defined two novel molecular classifications of glioblastoma, thus completing the genetic map of TERTpWT-IDHWT (TERT promoter wildtype-IDH wildtype) glioblastoma. The ground-breaking findings are likely to facilitate development of targeted therapies for fatal brain tumor and benefit more patients.


Scientists of Genetron Health Again Define Key Pathogenic Gene for Malignant Gliomas


Pic: The novel subtypes of glioblastoma in molecular classification of adult diffuse gliomas


Glioblastoma is the most common and deadly primary malignant brain tumor found in adult patients. The median overall survival is less than 15 months despite aggressive treatment. The analysis of genetic map of glioblastoma and the development of molecular classification system have provided important support for improving clinical treatment and prognosis.


Complete the genetic map of glioblastoma


As a pioneer in molecular classification of brain glioma studies, from 2008 to 2009, Professor Yan led his team to collaborate with many researchers and first defined the important role of IDH1/2 mutations in brain glioma, with study findings being published in Science and The New England Journal of Medicine respectively. In 2013, Professor Yan found that TERT promoter mutation is a key driver event in many common tumors thus providing another important basis for molecular classification of brain glioma. These findings were published on PNAS. Subsequent studies have shown that IDH gene mutations and TERT promoter mutations can be used for molecularly classification for about 80% of brain glioma patients.


Based on this, at the invitation of WHO in 2016, the professor at Duke University participated in compiling guidance on new WHO Classification of Tumors of the Central Nervous System, introducing molecular classification standards for brain tumors, such as IDH1/2, which set a record in human history to use molecular classification as a gold standard for brain tumor diagnosis. Soon after that, Genetron Health started to translate scientific achievements into clinical applications and, in 2018, developed Genetron Health IDH1/TERT genetic testing kit for glioma, the only product of such being approved in China.


However, about 20% of glioblastomas patients have no TERT promoters and IDH mutations or 1p19q loss, who often suffer from the worst prognosis conditions. These tumors, known as TERTpWT-IDHWT glioblastomas, or “triple negative” glioma, do not have well-established genetic biomarkers, thus cannot be classified with objective biomarkers.


In the latest paper published in 2018, Professor Yan and collaborative partners first used whole genome sequencing (WGS) to define the genetic map of TERTpWT-IDHWT glioblastoma.


Scientists of Genetron Health Again Define Key Pathogenic Gene for Malignant Gliomas


Pic: Mutation map of somatic coding alterations in TERTpWT-IDHWT glioblastoma


Researchers found that TERTpWT-IDHWT tumors are actually comprised of two subgroups which utilize different mechanisms of telomere maintenance, i.e., lengthening of telomere due to concurrent loss-of-function mutations in SMARCAL1, and telomere activation due to rearrangement of TERT upstream chromosomes. According to these two novel mechanisms of telomere maintenance, TERTpWT-IDHWT tumor can be further classified into two subgroups: a telomerase-positive subgroup driven by TERT-structural rearrangements (IDHWT-TERTSV), and an ALT-positive subgroup (IDHWT-ALT) with mutations in ATRX or SMARCAL1.


Scientists of Genetron Health Again Define Key Pathogenic Gene for Malignant Gliomas


Pic: In TERTpWT-IDHWT glioblastoma, concurrent loss-of-function mutations in SMARCAL1 and ATRX, and TERT upstream rearrangement are very common, which are relevant to different mechanisms of telomere maintenance.


With findings of IDH mutation and TERT promoter mutation, the study basically completed the genetic map of glioblastoma, which will again update molecular classification standards of glioblastoma. Studying tumor molecular mechanism is not only human’s endeavor in further exploring pathogenesis, but also of clinical significance. The findings can be translated into clinical measures to bring forward hope and benefits to patients, which is exactly the mission and commitment of Genetron Health.


Also, researchers found that BRAF is frequently mutated in young adult diagnosed with TERTpWT-IDHWT glioblastomas, which provides an opportunity to use targeted BRAF V600E/MEK for treatment.


However, immune escape and survival mechanisms of cancer have always been a bothering issue. “Even though being located, tumor cells are still very cunning and often disguise or alter themselves. Therefore, studying their immune escape and survival mechanisms means a lot for developing cancer medicines. We need to deepen our understanding of genetic signs and pathways of tumor mutations to identify the principles of such mechanisms and find solutions,” said Professor Yan.


Focus on clinical translation of cancer genomics


Genetron Health has an expert team which is led by Professor Yan and with academic backgrounds of multiple complementary disciplines. The team has been focusing on clinical translation of cancer genomics from the very beginning. The team has published more than 10 papers on the world’s authoritative academic journals including Nature Genetics. Papers about brain tumors include:


In 2014, collaborated with Beijing Tian Tan Hospital and found that PPM1D mutations being a key pathogenic genetic factor for brainstem gliomas, which was published in Nature Genetics;


In 2016, established complete genetic map of somatic mutations in pituitary adenoma and performed association study of gene pathways of pituitary adenoma subgroups, and found several pathways for potential targeted therapy, which was published on Cell Research online;


In 2017, first found that CDH23 is not only a genetic predisposing factor for familial pituitary adenoma, but also a susceptibility gene for sporadic pituitary adenoma, which was published on American Journal of Human Genetics.


Since its inception, Genetron Health has been committed to gaining insights into genetic secrets and achieving technological innovations and development, striving to trace the sources of cancer genes and disclose the root causes of tumor and key mechanisms for their development.


Taking advantages of cancer molecular studies, Genetron Health has been speeding up technological application and achieved multiple milestones in the journey of conquering the grand ocean of genetics:


In 2015, Genetron Health released 6 detection products for brain glioma, which covers all genes of molecular classification of glioma recommended by WHO and NCCN guidelines;


In September, 2016, Genetron Health released 509panel, which can be used for overall guidance of precision classification prognosis, targeted therapy and immunotherapy guidance and genetic risks prediction for primary brain tumor and brain metastases;


In April, 2017, 68 gene panel specific for precision diagnosis and treatment of brain tumor and China’s first pediatric medulloblastoma molecular classification detection product were launched into the market;


In August, 2017, Genetron Health released the cerebrospinal fluid (CSF) ctDNA detection product for brain tumor diagnosis, which provided another weapon for liquid biopsy;


In December, 2017, Genetron Health’s independently developed biochip reader GENETRON 3D (Registration No.: YXZZ 20172400136) was approved to be launched into market. It was mainly used in liquid biopsy to provide LDT services targeting more than 50 locus in lung cancer, breast cancer, colorectal cancer and gastric cancer, etc.;


In 2018, Genetron Health released IDH1/TERT genetic testing kit for gliomas, the first of such being approved in China, which provides important reference information for deciding pathological classification for gliomas patients.


With practical actions, Genetron Health has achieved innovations and breakthroughs in tumor genetic detection industry. By providing diversified clinical options that meet personalized demands of patients, Genetron Health has been leading the trend of personalized medical care for cancer patients.


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