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Genetron Health Joins Hands with Peking University Cancer Hospital to Explore the Clonal Origin

Release Time: 2017-04-27

Thyroid papillary carcinoma is the commonest thyroid malignancy in adults, which often presents as multiple anatomically distinct nodules in thyroid, that is, multifocal thyroid papillary carcinoma (MPTC). Clinically, MPTC accounts for about 20 to 40% of all cases of thyroid cancer. The molecular pathogenesis, prognosis and optimization management protocol of MPTC are still controversial, although the multifocal frequency is its common clinical feature.

The origin of multiple nodules is one of the most controversial questions about the pathogenesis of MPTC, that is, whether multiple anatomically distinct tumor nodules are derived from the same clonal source or from different clonal populations. Recently, MPTC genomics research results achieved by the assistance of Genetron Health (Beijing) Co., Ltd. led by Peking University Cancer Hospital have been published in the international academic journal titled Journal of Pathology.

Studies have demonstrated that the mechanism of MPTC might originate from intrahepatic metastasis and spread of single malignant clone, or from multiple independent clones of different nature accompanied by intrahepatic metastasis and spread. The identification of the pathogenesis of MPTC will be helpful to provide guidelines for the development of clinical treatment regimens and provide clues to the common recurrence mechanism. Meanwhile, the next-generation sequencing technology (NGS) that has been widely used in cancer genomics provides a new technical approach and prospective view in conducting in-depth studies on clonal correlations between multiple independent tumor lesions in the same thyroid.

Description of next-generation sequencing technology:

Many techniques have been used in previous studies to explore the origin of MPTC clones, such as X-chromosome inactivation (XCI); BRAF gene mutation and RET gene rearrangement and other genetic variation information; LOH detection or allele imbalance detection of different cancer lesions. However, no consistent conclusion has been drawn since the comparative trials often present conflicting results due to technical limitations.

NGS technology can overcome the technical limitations of traditional genetic mapping and provide higher genomic resolution to make a more comprehensive portrait of individual cancer genes. The high-throughput sequencing technique with high-precision allows us to discover the genetic relevance between multiple co-existing tumor nodules and the unique genetic background and evolution of different clonal populations. We hope to further explore the clonal ability of these nodules by analyzing the independent mutation map of multiple MPTC tumor nodules, thus solving the question about the origin of multi-focal tumors.


Fig.1:Genetic variation map of 8 cases of multifocal papillary thyroid carcinoma

Among all eight patients with multifocal papillary thyroid carcinoma (MPTC) who were included in this study, the mutations and genetic rearrangement and other variations of non-synonymous sites in multiple independent lesions of the thyroid were analyzed with whole-exome sequencing combined with regional targeting sequencing. 


Fig.2:Samples from patients with MPTC1 show genetic and pathological characteristics of multiple independent clonal origins

The mutations of malignant nodules in thyroid of patients with MPTC1 were completely different from those of patients with MPTC5, suggesting that these malignant nodules originated from independent and different precursor cells.


Fig.3: Samples from patients with MPTC2 is a typical example of multiple independent clonal origin

In patients with MPTC2, 6, and 8, only BRAF V600E mutation concurred in different lesions of the thyroid, suggesting the mutations tend to be originated from independent and different clones.


Fig.4:Samples from patients with MPTC4 present molecular characteristics of single common clonal origin

In contrast, the mutations in different lesions were almost identical between patients with MPTC3 and those with MPTC 4, suggesting the same clonal origin.


Fig.5:Samples from MPTC7 patients also show multiple independent clonal origins accompanied by intrahepatic metastasis and spread of the same origin

Seven focal nodules were found in the thyroid of the patient with MPTC7, two of which showed the mutation consistency up to 66.7%, and the other five showed a completely different non-synonymous mutation, suggesting that multiple focal clones of different origins were accompanied by intrahepatic metastasis and spread of the same clonal origin in the patient.

In this study, 75% of MPTC cases that were derived from independent and different precursor tumor cells have been demonstrated, which was consistent with "cancer domain hypothesis" of multi-focal malignant lesions that was proposed by the previous studies. The mechanism of MPTC may originate from intrahepatic metastasis and spread of single malignant clones, or from multiple independent clones of different nature accompanied by intrahepatic metastasis and spread.

As a pioneer focusing on the clinical transformation of cancer genomics, Genetron Health always plays an active role at the forefront of clinical research. In the field of science and technology, Genetron Health, relying on high-quality sequencing platform and the ability to interpret big data, has successfully found PPM1D mutation that was an important factor contributing to the pathogenesis of brain stem glioma; participated in and completed the largest international study on the molecular pathology of Cushing disease that utilized the most definitive genetic mechanism; participated in and completed the largest study on the exome sequencing of esophageal squamous cell carcinoma to illustrate the histone modification as well as clinical significance of genetic variations of Hippo signal pathway-related genes; participated in and completed the largest-scale important scientific studies on the molecular typing of glioma using IDH and TERT promoter mutation for the Chinese population up to date.

In the clinical field, Genetron Health has successfully developed a number of precise medical products for patients with cancer, and built clinical laboratories covering a total area of 8,000 sq. m in Beijing, Shanghai and Hangzhou. In the future, Genetron Health will exert its utmost strength to serve cancer patients in China and throughout the world with its professional marketing, product, medical and research team, its sales network covering east, south, west and north China, its powerful cancer genomic techniques and efficient transformation of such technologies to clinical applications.

References:

Clonality analysis of multifocal papillary thyroid carcinoma by using genetic profiles

Other co-published literatures from Genetron Health:

[1]Exome sequencing identifies somaticgain-of-function PPM1D mutations in brainstem gliomas

[2]Genetic landscape of esophageal squamouscell carcinoma

[3]Recurrent gain-of-function USP8 mutationsin Cushing’s disease

[4]TERT promoter mutations contribute to IDHmutations in predicting differential responses to adjuvant therapies in WHO grade II and III diffuse gliomas

[5]Prevalence of deleterious ATM germlinemutations in gastric cancer patients

[6]Recurrent TERT promoter mutationsidentified in a large-scale study of multiple tumor types are associated withincreased TERT expression and telomerase activation

[7]The genome-wide mutational landscape of pituitary adenomas.

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