Driver mutations in thyroid cancer

Many of these cancers have changes in specific parts of the ret gene. Ret is a transmembrane receptor protein kinase, signaling through downstream pathways including. Whats really remarkable is that in every single one of these cases, we were able to find the driver mutation the actual genetic change that caused the cancer, he says. As insilico analysis suggested these variants to be potentially pathogenic, we recapitulated mutations from tcga. Oncogenic tshr mutation in papillary thyroid cancer. Cote, phd presented, ras mutations in medullary thyroid cancer. In total, 53 genes were determined as driver candidates by oncodrivefm. Why ret alteration is an attractive target for therapy.

Thyroid cancers contain oncogenic mutations that are considered driver mutations because they play a key role in the disordered proliferation and metastasis of the cancer. Tcga finds thyroid cancer drivers, subtypes cancer discovery. In papillary thyroid cancer, a htert mutation has been more frequently found in advanced tumors and in tumors with a braf p. The cancer genome atlas, 3rd symposium, integrated genomic characterization, papillary thyroid carcinoma, thomas giordano created date. They are usually indolent tumors that harbor mutually exclusive mutations in braf, ras, or fusions of ret, ntrk, or braf. Mutations of ras genes have recently risen as second drivers found in 1015% of mtc cases. Several dna mutations changes have been found in papillary thyroid cancer. But in lung cancer we see ret fusions, kif5b being the most common fusion. In medullary thyroid cancer mtc, the calcitoninproducing cells, or c cells, account for approximately 2% to 4% of the thyroid gland and mtc accounts for about 2% to 4% of all thyroid cancers. An indepth conversation regarding the importance of identifying driver mutations before initiating immunotherapy in patients with tumors who express greater than 50% pdl1 positivity.

It usually develops in only 1 of the 2 lobes of the thyroid gland and often spreads to lymph nodes in the neck. The prevailing theory of cancer progression is that driver mutations, mostly acquired somatically, confer a growth advantage to the tumour, enabling outgrowth of neoplastic clones. Oncogenic driver mutations in lung cancer springerlink. Papillary carcinomas ptc are the most common type of thyroid cancer. Among them, braf, nras, hras, kras, ppm1d and eif1ax are known recurrently mutated driver genes in thyroid cancer, with mutation frequencies of 59. The incidence of thyroid cancer is rapidly increasing worldwide. Based on hypothesisdriven research, the classic view of thyroid cancer pathogenesis considers thyroid carcinomas as tumors accumulating mutations that drive. A comprehensive analysis of oncogenic driver genes and mutations in 9,000 tumors across 33 cancer types highlights the prevalence of clinically actionable cancer driver events in tcga tumor samples. Tumors were prescreened for common known mutations believed to be driver events in thyroid cancer braf, nras, hras, kras, retptc, and pax8ppar. Genetic landscape of somatic mutations in a large cohort of. Although a large number of driver mutations have been identified through the efforts of the cancer genome atlas tcga, some tumor types have not been characterized deeply enough to reach that level of discovery. In addition to serving as a driver mutation in papillary thyroid cancer, activation of the mapk pathway via braf mutations results in decreased expression of. A comprehensive analysis of the genomes of nearly 500 papillary thyroid carcinomas ptc the most common form of thyroid cancer has provided new insights into the roles of frequently mutated cancer genes and other genomic alterations that drive disease development.

Novel driver mutations in thyroid cancer recurrence. Drugs that target mek which shares a signaling pathway with braf and ras or vegf vascular endothelial growth factor also have shown promise against. To study the role of this mutation in the growth of thyroid cancer, we developed a model system on the basis of thyroid epithelial cell line nthyori 31 transduced by a lentiviral vector containing the nras gene with the q61r mutation. Identification of the transforming strnalk fusion as a. Mar 10, 2020 the classical view of thyroid cancer pathogenesis considers thyroid carcinomas as tumors accumulating mutations that drive progression through a dedifferentiation process, giving rise initially to. The standard therapy for radioactive iodinerefractory papillary thyroid cancer is sorafenib or lenvatinib, lin said, although neither of these agents have demonstrated papillary thyroid activity in a subpopulation driven by ntrk, ros1, alk, or other driver mutations. Efficacy of combination therapy for anaplastic thyroid cancer. The reported mutations were of the missense type ga substitution in positions. Cancers with braf changes tend to grow and spread to other parts of the body more quickly. The main oncogenic drivers associated with welldifferentiated thyroid cancer ptc. As such, we run the model three times for each cancer type, which corresponds to setting n g p at 2, 3, or 4. The altered form of this gene, known as the ptc oncogene, is found in about 10% to 30% of papillary thyroid cancers overall, and in a larger percentage of these cancers in children andor linked with. Pdf mapping driver mutations to histopathological subtypes in.

However, the diversity of driver mutations in cancer related genes increased over time. Study reveals genetic causes for thyroid cancer increase. The cancer genome atlas tcga study of ptc identified additional driver alterations present at lower frequency in genes including eif1ax, ppm1d, and chek2. Next, we focused on the consequences of the driver mutations.

Mapping cancer genomic evolution national cancer institute. This plot shows the most recurrently mutated cancer driver genes. Jun 27, 2018 while some tumors in the tcga data have over 10 mutations in the putative cancer genes, a recent study showed that most cancer types only require 3 driver mutations tomasetti et al. Oct 28, 2019 braf mutations are not found in follicular thyroid cancer, medullary carcinomas, or benign tumors, so the presence of the mutation can help distinguish different types of thyroid cancer. Driver mutations in cancer related genes which promote the development and spread of tumors, including tp53 and kras, were very likely to occur early in cancer development, regardless of cancer type. Jun 29, 2015 and when you go in sequence cancer, and compare sequence of a cancer cell from a patient with the sequence of a normal tissue from the same patient you can see tens of thousands of mutations specific to cancer. Investigation of the relationship between radiation dose and. Ret fusion as a novel driver of medullary thyroid carcinoma.

Novel driver mutations in thyroid cancer recurrence sfebes2017. Poorly differentiated thyroid carcinoma pdtc is a rare malignancy with higher. Tert promoter mutations in thyroid cancer request pdf. Update on fundamental mechanisms of thyroid cancer. By sequencing larger numbers of cases, cddp will have the statistical power to discover recurrent mutations in genes that may drive the oncogenic process. For advanced thyroid cancers, particularly anaplastic thyroid cancers atc, the responsiveness to immune checkpoint blockage agents has been poor, to date. Although ret point mutation has been identified as a driver of tumorigenesis in medullary thyroid carcinoma mtc, no fusions have been described to date. Pdf papillary thyroid carcinoma ptc is the most common subtype of thyroid cancers and informative biomarkers are critical for risk stratification. Oncogenic ret tyrosine kinase gene fusions and activating mutations have recently been identified in lung cancers, prompting initiation of targeted therapy trials in this disease. The presence of oncogenic driver mutations leads to a phenomenon called oncogene addiction wherein tumor cells tend to be dependent on the specific mutant. Discovery of pathogenic and driver mutations in thyroid cancer. Despite this remarkable progress, algorithms do not entirely agree on certain candidate cancer driver genes and mutations, necessitating expert curation to filter likely false positive findings. The reality of our lung cancer population is that only a minority of patients currently have identifiable driver mutations where we have the ability to take action in used.

For these reasons, one could assume that certain driver mutations are. Evidence for differential selection between mutations in the same driver gene. About half of ptcs harbor brafv600e and 10%15% have ras mutations. Dec 22, 2012 the mutations in nras typically associated with melanomas, multiple myelomas, acute myelogenous leukemia, and thyroid cancer were, in both cases, the q61r hotspot mutation in the ras domain. Defining driver mutations in the genomic landscape of. Still, approximately half of sporadic mtc tumors have no identified mechanism of tumorigenesis. Mutations in ret are much more common within thyroid cancer. Driver mutations trump pdl1 expression in lung adenocarcinoma. The p53 signaling genes were also determined as driver genes. To a large extent, the oncogenes implicated were ones that were already known to play a role in thyroid cancer. Braf mutations are present in a large number of anaplastic thyroid cancers a very aggressive tumor that has been challenging to treat, and up to half of papillary thyroid cancers. The 20 discovery of tert promoter mutations chr5, 1,295,228 ct c228t and 1,295,250 ct c250t in thyroid cancer represents an important event in the thyroid cancer field and much progress.

Further elucidation of the molecular causes of cancer through deeper characterization of tumors is expected to yield insights into tumor biology, leading to better treatment options. According to the american cancer society, in 2014, there are 2,500 mtc cases in the united states us and 12,500 cases worldwide. Notable in this case of papillary thyroid cancer is the absence of other oncogenic mutations, commonly identified by other groups through nextgeneration sequencing, including braf v600e, nras, hras, and select fusions. The q61r mutation of the nras gene is one of the most frequent driver mutations of thyroid cancer. Applying a deep convolutional neural network by peiling tsou and changjiun wu department of genomic medicine, university of texas, md anderson cancer center, 1901 east road, 3scr5. Together, these studies have confirmed the role of oncogenic mutations of mapk pathway as key drivers of differentiated thyroid cancer braf, ras, and that additional genetic alterations in the pi3k pathway, tp53, and the tert promoter are necessary for anaplastic transformation. For each mutation, the maximum likelihood estimate of relative risk compared to kras g12r is shown. Concordance between mutations in the primary papillary thyroid carcinoma ptc and the paired x lymph node metastasis may elucidate the potential role of molecular targeted therapy in advanced stages. Thyroid cancer is a genetically simple disease with a relatively low number of mutations in each tumor driver mutations and gene fusions are identified in over 90% of thyroid cancers, making it one of the best molecular characterized malignancies in humans. We developed a gene expression signature of samples with these mutations and characterized tumors based on this signature. Evolution and impact of subclonal mutations in papillary. Tert encodes the reverse transcriptase component of telomerase, which adds telomere repeats to chromosome ends, thereby enabling cell replication. We applied mathematical methods for network analysis to identify distinct modules linking tumors to driver mutations. Driver and passenger mutation in cancer serious science.

We applied oncodrivefm to identify driver genes in thyroid cancer. Ret is a transmembrane receptor protein kinase, signaling through downstream pathways including the mitogen activated protein kinase mapk cascade involving rasrafmekerk. Mutpanning is a new method to detect cancer driver genes that identifies genes with an excess of mutations in unusual nucleotide contexts. Identification of cancer driver genes based on nucleotide. Intogen cancer driver mutations in thyroid adenocarcinoma. Targeted nextgeneration sequencing of cancer genes in poorly. Tcga study improves understanding of genetic drivers of. Table 1 lists these four molecular targets with their respective detection methods and inhibitors. Cancermutation network and the number and specificity of. The braf mutation is less common in thyroid cancers in children and in cancers thought to develop because of exposure to radiation. Comprehensive characterization of cancer driver genes and. Sporadic medullary thyroid carcinoma smtc is a rare but. Both the kit and nras mutations were overlooked as driver mutations by the frequencybased approach additional file 7. Dabrafenib and trametinib treatment in patients with.

The most common sporadic types of thyroid tumors of follicular origin. Male thyroid cancer rates have doubled since 1975 whereas female rates have tripled 6. Integrated genomic characterization of papillary thyroid carcinoma author. The identification of driver mutations in epidermal growth factor receptor, anaplastic lymphoma kinase, the braf and ros1 genes and subsequent successful clinical development of kinase inhibitors not only significantly improves clinical outcomes but also facilitates the discovery of other novel driver mutations in nonsmall cell lung cancer. Papillary thyroid carcinoma ptc this type of thyroid cancer is responsible for approximately 80% of all thyroid cancer cases and tends to grow very slowly and is rarely fatal. With papillary thyroid cancer, the presence of a braf mutation is associated with a higher risk of recurrence and spread to lymph nodes. The classical view of thyroid cancer pathogenesis considers thyroid carcinomas as tumors accumulating mutations that drive progression through a.

Immunotherapy plus targeted therapy for anaplastic thyroid. Tumors with this mutation are characterized by invasion into. Immunotherapy plus targeted therapy for anaplastic thyroid cancer. This driver cloud represents the most recurrently mutated cancer driver genes in thca. The incidence of thyroid cancer has increased 3fold over the past 30 years 1, and it is estimated by the national institutes of health that in 2018 more than 53,000 new cases of thyroid cancer and more than 2000 deaths from these diseases occurred in the united states. Thyroid cancers of follicular origin in a genomic light.

Alk gene rearrangements are mutually exclusive with all other known thyroid cancer driver mutations and have been reported in up to 2. Clinical utility of tert promoter mutations and alk. Braf mutations are not found in follicular thyroid cancer, medullary carcinomas, or benign tumors, so the presence of the mutation can help distinguish different types of thyroid cancer. Mapping driver mutations to histopathological subtypes in papillary thyroid carcinoma. This driver cloud represents the most recurrently mutated cancer driver genes. However, most of the driver candidates were not frequently mutated in thyroid cancer fig.

Combination immunotherapy to treat advanced thyroid cancers. The first evidence to conclusively link genomic alterations to tc came with the appreciation that mtc occurs in a heritable form linked to gainoffunction activating germ line mutations in ret rearranged during transfection. Only a small portion of somatic mutations are cancer drivers that confer clonal fitness and are positively selected over the course of tumor evolution. However, we know that mutations and neoantigen burden predict response in general 4,5 said dr.

Whilst outcome in thyroid cancer is generally good, up to 25% of patients develop recurrence, and have a significantly reduced life expectancy. Cancer driver discovery program cddp aims to identify driver mutations in as few as 2% of patients. Papillary thyroid carcinoma ptc is the most common malignant thyroid cancer, accounting for 1. And in medullary thyroid cancer there can be those mutations in 2.

He also noted that the safety profiles of these agents are not trivial. The application of wes in thyroid cancer was also reported in the previous tumor researches. Driver mutations are typically not found in the germline noncancer genome of the host and are usually mutually exclusive ie, a cancer is unlikely to have more than one driver mutation. The effects of mutational processes and selection on. Thyroid cancer development is driven by known point mutations or gene fusions found in. Activating point mutations occurring in the ret gene have been identified as the oncogenic driver in all cases of hereditary medullary thyroid carcinoma mtc and approximately 40% of sporadic mtc cases. Mutations in this gene, most commonly the v600e mutation, are the most frequently identified cancer causing mutations in melanoma, and have been identified in various other cancers as well, including nonhodgkin lymphoma, colorectal cancer, thyroid carcinoma, nonsmall cell lung carcinoma, hairy cell leukemia and adenocarcinoma of lung. Intogen collects and analyses somatic mutations in thousands of tumor genomes to identify cancer driver genes.

Braf and nras mutations in papillary thyroid carcinoma and. At the joint meetings of the international congress of endocrinology and the endocrine society held june 2124, 2014 in chicago, gilbert j. Recent novel findings have linked the high mutational burden. In early thyroid cancer, mapk pathway is motivated by mutations in braf and ras or by ret ptc rearrangements. Integrated genomic characterization of papillary thyroid. In a recent study by gerber and colleagues targeted ngs was employed to detect genetic mutations in poorly differentiated thyroid cancer. The size of the gene symbol is relative to the count of samples with pams. An integrated analysis of cancer genes in thyroid cancer. Thada fusion is a mechanism of igf2bp3 activation and.

Molecular therapeutics for anaplastic thyroid cancer. In our study, alk rearrangement was not identified in any thyroid cancers. Significance of oncogenic driver mutations in lung cancer severity and therapy. The findings also may help improve diagnosis and treatment. Subcellular localisation, proliferation, cellular migration and invasion were investigated in cell lines which represent the most common background driver mutations of papillary thyroid cancer tpc1. High incidence of flt3 mutations in follicular thyroid cancer. Melanoma is a cancer that starts most of the time in the skin and actually gets induced, we think, by uv exposure, which leads to a lot of mutations. Comprehensive characterization of cancer driver genes. Driver mutations are typically transformative, which means that they initiate the evolution of. Mapping driver mutations to histopathological subtypes in.

In addition to serving as a driver mutation in papillary thyroid cancer, activation of the mapk pathway via braf mutations results in decreased expression of sodium iondine symporter, tsh receptor, and thyroglobulin, resulting in a relative iodine refractory state ricartefilho et al. V600e mutation, and the rate of recurrence is 8 times greater in tumors with both mutations, as compared to patients who lack both mutations liu et al. Ret point mutations, which are just a single mutation in a gene sequence, are usually associated with medullary thyroid cancer. The insulinlike growth factor 2 mrnabinding protein 3 igf2bp3 plays an important role in cancer, yet the mechanisms of its activation in cancer cells remain poorly understood.

We hypothesise those thyroid tumours which subsequently recur display a distinct pattern of driver. Anaplastic thyroid carcinomas atcs are rare, highly aggressive, undifferentiated tumors and patients diagnosed with atcs have a median survival of 5 to 12 months and a 1year overall survival of 20% to 40%. Hannah nieto1, alice fletcher1, rebecca thompson1, kate baker1, mohammed alshahrani1, albert nobre. About 27% of the tumors belong to such modules, whereas the rest form a. The size of the gene symbol is relative to the count of samples with mutation in that gene. Eif1ax and ras mutations cooperate to drive thyroid. To search for novel driver gene fusions in thyroid cancer, we studied a group of 446 ptc cases with snapfrozen tumor tissue available. This paper shows that specific mutations in tert are frequently found. Jun 26, 2018 cancer genomics yields a wealth of information on cancer associated mutations in various cancer types, but current understanding of the number and tissue specificity of the driver mutations remains limited. The profile of genetic mutations in papillary thyroid cancer. The cancer genome atlas 3rd annual scientific symposium keywords. Additional drivers such as mutations in tert promoter, dna repair genes.

The incidence of thyroid cancer has increased 3fold over the past 30 years, and it is estimated by the national institutes of health that in 2018 more than 53,000 new cases of thyroid cancer and more than 2000 deaths from these diseases occurred in the united states. Adar1mediated rna editing is a novel oncogenic process in. As 5year survival rates after thyroid cancer are in excess of 90%. We hypothesise those thyroid tumours which subsequently recur display a distinct pattern of driver events. Many papillary thyroid cancers have a mutated braf gene. Atcs comprise 1% to 2% of all thyroid cancers in the united states and 1% to 10% of thyroid cancers worldwide. Tc is a genetically simple disease with a relatively low somatic mutation burden in each tumor. Thyroid cancer is the most common form of endocrine malignancy. Findings from the study of nearly 500 papillary thyroid carcinomas ptc suggest that tumors harboring the two main drivers of ptcsbraf primarily v600e and ras mutations are more genetically complex than previously thought and have distinct subtypes and signaling pathways cell 2014. Identification of alk fusions in thyroid cancer using rnaseq. Novel driver mutations in thyroid cancer recurrence ece2019.

The most common driver mutations for anaplastic thyroid cancer occur in the braf or ras genes, and drugs that target the braf kinase have had higher response rates than cytotoxic chemotherapy. Ret and ras mutations have been confirmed as the major drivers in sporadic. Papillary thyroid carcinoma ptc is the most common subtype of thyroid cancers and informative biomarkers are critical for risk stratification and treatment guidance. Pdf papillary thyroid carcinoma ptc is the most common subtype of thyroid cancers and informative biomarkers are critical for risk. Tumors with this mutation are characterized by invasion. And in medullary thyroid cancer there can be those mutations in. For example, half of all early driver mutations occurred.