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Nature sub-journal: Significant breakthrough achieved in cancer genomics

On May 25th 2018, the world's authoritative academic journal Nature Communications published The Genomic Landscape of TERT Promoter Wildtype-IDH Wildtype Glioblastoma, an online paper about the latest study achievements on glioblastoma. The study was led by Professor Yan Hai, a professor at Duke University, co-founder and chief scientist of Genetron Health, and collaboratively carried out by research teams from Duke University, Johns Hopkins University and Genetron Health scientists.

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 tumors and benefit more patients.

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 supports for improving clinical treatment and prognosis.

Completing the genetic map of glioblastoma

As a pioneer in molecular classification of brain glioma studies, from 2008 to 2009, scientists from Genetron Health led a 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, scientists from Genetron Health 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 in 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, scientists from Genetron Health 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, Scientists of Genetron Health and collaborative partners first used whole genome sequencing (WGS) to define the genetic map of 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 tumors 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.

With findings of IDH mutation and TERT promoter mutation, the study basically completed the gene mapping 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 an 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," a scientists from Genetron Health said.

Focusing on clinical transformation of cancer genomics

Genetron Health has an expert team which with academic backgrounds of multiple complementary disciplines. The team has been focusing on clinical transformation 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 glioma, which was published in Nature Genetics;

In 2016, established complete gene mapping of pituitary tumor cell was constructed for the first time, and several potential drug routes for targeted therapy of pituitary tumor were excavated, which was published in 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 in 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 explore key mechanisms of cancer development.

Taking advantage of cancer molecular studies, Genetron Health has been speeding up technological applications and achieved multiple milestones in the journey of precision medicine:

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 509 panel, 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 the market. It was mainly used in liquid biopsy to provide LDT services targeting more than 50 loci 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 the tumor detection industry. For developing individualized drug therapy to a large extent, Genetron Health will be providing more diversified clinical options to meet various demands of patients.



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