scholarly journals Whole Genome Sequencing of Familial Non-Medullary Thyroid Cancer Identifies Germline Alterations in MAPK/ERK and PI3K/AKT Signaling Pathways

2019 ◽  
Author(s):  
Aayushi Srivastava ◽  
Abhishek Kumar ◽  
Sara Giangiobbe ◽  
Elena Bonora ◽  
Kari Hemminki ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Whole Genome Sequencing ◽  
Signaling Pathways ◽  
Genome Sequencing ◽  
Tyrosine Kinases ◽  
Medullary Thyroid Cancer ◽  
Familial Cancer ◽  
Whole Genome ◽  
Medullary Thyroid ◽  
Genetic Burden

Evidence of familial inheritance in non-medullary thyroid cancer (NMTC) has accumulated over the last few decades. However, known variants account for a very small percentage of the genetic burden. Here, we focused on the identification of common pathways and networks enriched in NMTC families to better understand its pathogenesis with the final aim of identifying one novel high/moderate-penetrance germline predisposition variant segregating with the disease in each studied family. We performed whole genome sequencing on 23 affected and 3 unaffected family members from five NMTC-prone families and prioritized the identified variants using our Familial Cancer Variant Prioritization Pipeline (FCVPPv2). In total, 31 coding variants and 39 variants located in upstream, downstream, 5′ or 3′ untranslated regions passed FCVPPv2 filtering. Altogether, 210 genes affected by variants that passed the first three steps of the FCVPPv2 were analyzed using Ingenuity Pathway Analysis software. These genes were enriched in tumorigenic signaling pathways mediated by receptor tyrosine kinases and G-protein coupled receptors, implicating a central role of PI3K/AKT and MAPK/ERK signaling in familial NMTC. Our approach can facilitate the identification and functional validation of causal variants in each family as well as the screening and genetic counseling of other individuals at risk of developing NMTC.

scholarly journals Whole Genome Sequencing of Familial Non-Medullary Thyroid Cancer Identifies Germline Alterations in MAPK/ERK and PI3K/AKT Signaling Pathways

Biomolecules ◽  
2019 ◽  
Vol 9 (10) ◽  
pp. 605 ◽  
Author(s):  
Aayushi Srivastava ◽  
Abhishek Kumar ◽  
Sara Giangiobbe ◽  
Elena Bonora ◽  
Kari Hemminki ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Whole Genome Sequencing ◽  
Signaling Pathways ◽  
Genome Sequencing ◽  
Tyrosine Kinases ◽  
Medullary Thyroid Cancer ◽  
Familial Cancer ◽  
Whole Genome ◽  
Medullary Thyroid ◽  
Genetic Burden

Evidence of familial inheritance in non-medullary thyroid cancer (NMTC) has accumulated over the last few decades. However, known variants account for a very small percentage of the genetic burden. Here, we focused on the identification of common pathways and networks enriched in NMTC families to better understand its pathogenesis with the final aim of identifying one novel high/moderate-penetrance germline predisposition variant segregating with the disease in each studied family. We performed whole genome sequencing on 23 affected and 3 unaffected family members from five NMTC-prone families and prioritized the identified variants using our Familial Cancer Variant Prioritization Pipeline (FCVPPv2). In total, 31 coding variants and 39 variants located in upstream, downstream, 5′ or 3′ untranslated regions passed FCVPPv2 filtering. Altogether, 210 genes affected by variants that passed the first three steps of the FCVPPv2 were analyzed using Ingenuity Pathway Analysis software. These genes were enriched in tumorigenic signaling pathways mediated by receptor tyrosine kinases and G-protein coupled receptors, implicating a central role of PI3K/AKT and MAPK/ERK signaling in familial NMTC. Our approach can facilitate the identification and functional validation of causal variants in each family as well as the screening and genetic counseling of other individuals at risk of developing NMTC.

scholarly journals Whole Genome Sequencing Prioritizes CHEK2, EWSR1, and TIAM1 as Possible Predisposition Genes for Familial Non-Medullary Thyroid Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Aayushi Srivastava ◽  
Sara Giangiobbe ◽  
Diamanto Skopelitou ◽  
Beiping Miao ◽  
Nagarajan Paramasivam ◽  
...  
Keyword(s):  
Dna Damage ◽  
Thyroid Cancer ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Medullary Thyroid Cancer ◽  
Familial Cancer ◽  
Whole Genome ◽  
Polygenic Inheritance ◽  
Medullary Thyroid ◽  
Probable Case

Familial inheritance in non-medullary thyroid cancer (NMTC) is an area that has yet to be adequately explored. Despite evidence suggesting strong familial clustering of non-syndromic NMTC, known variants still account for a very small percentage of the genetic burden. In a recent whole genome sequencing (WGS) study of five families with several NMTCs, we shortlisted promising variants with the help of our in-house developed Familial Cancer Variant Prioritization Pipeline (FCVPPv2). Here, we report potentially disease-causing variants in checkpoint kinase 2 (CHEK2), Ewing sarcoma breakpoint region 1 (EWSR1) and T-lymphoma invasion and metastasis-inducing protein 1 (TIAM1) in one family. Performing WGS on three cases, one probable case and one healthy individual in a family with familial NMTC left us with 112254 variants with a minor allele frequency of less than 0.1%, which was reduced by pedigree-based filtering to 6368. Application of the pipeline led to the prioritization of seven coding and nine non-coding variants from this family. The variant identified in CHEK2, a known tumor suppressor gene involved in DNA damage-induced DNA repair, cell cycle arrest, and apoptosis, has been previously identified as a germline variant in breast and prostate cancer and has been functionally validated by Roeb et al. in a yeast-based assay to have an intermediate effect on protein function. We thus hypothesized that this family may harbor additional disease-causing variants in other functionally related genes. We evaluated two further variants in EWSR1 and TIAM1 with promising in silico results and reported interaction in the DNA-damage repair pathway. Hence, we propose a polygenic mode of inheritance in this family. As familial NMTC is considered to be more aggressive than its sporadic counterpart, it is important to identify such susceptibility genes and their associated pathways. In this way, the advancement of personalized medicine in NMTC patients can be fostered. We also wish to reopen the discussion on monogenic vs polygenic inheritance in NMTC and instigate further development in this area of research.

scholarly journals Efficacy of vandetanib in the treatment of medullary thyroid cancer: literature review and case report

2019 ◽  
Vol 9 (3) ◽  
pp. 38-48
Author(s):  
А. М. Mudunov ◽  
Yu. V. Alymov ◽  
I. S. Romanov ◽  
S. О. Podvyaznikov ◽  
А. V. Ignatova
Keyword(s):  
Clinical Trials ◽  
Thyroid Cancer ◽  
Tyrosine Kinases ◽  
Medullary Thyroid Cancer ◽  
Locally Advanced ◽  
Distant Metastases ◽  
Individual Characteristics ◽  
Medullary Thyroid ◽  
Mechanisms Of Carcinogenesis ◽  
Thyroid Malignancies

Medullary thyroid cancer (MTC) is a rare disorder that accounts for approximately 1.7 % of all thyroid malignancies. MTC is usually detected at early stages; however, approximately 10–15 % of patients are diagnosed with locally advanced MTC and distant metastases. Treatment of such patients is challenging due to biological characteristics of the disease and very few effective treatment approaches available. The investigation of mechanisms of carcinogenesis, as well as advances in pharmacology, allowed the development of a new group of targeted drugs, namely tyrosine kinases, which efficacy against progressive unresectable locally advanced or metastatic MTC has been demonstrated in multiple clinical trials. Vandetanib has been registered for MTC treatment in the Russian Federation. MTC is very rare, thus, each case of vandetanib use for its treatment is particularly interesting. Moreover, since the approval of this drug in 2011 by the U. S. Food and Drug Administration (FDA), new data on the clinical use of vandetanib have been accumulated. Importantly, clinical trials are usually well designed and conducted in near-ideal conditions, whereas the real conditions can be different and patients may have individual characteristics. Therefore, the aim of this study was to update the information on the efficacy and safety of vandetanib by retrospective analysis of available publications and to report a case of MTC treated with vandetanib.

RNAi Screening of the Tyrosine Kinome Identifies Therapeutic Targets in Leukemia Patients

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 758-758
Author(s):  
Jeffrey W Tyner ◽  
Marc Loriaux ◽  
Stephanie G Willis ◽  
Bill Chang ◽  
Vincent T Bicocca ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Tyrosine Kinases ◽  
White Blood Cells ◽  
Functional Assay ◽  
Functional Screening ◽  
Whole Genome ◽  
Primary Cells ◽  
Gene Target

Abstract A large percentage of cancer cases present without knowledge of the causative genetic events. Tyrosine kinases are frequently implicated in the pathogenesis of cancer, but identification of specific tyrosine kinases as cancer targets has been a slow process. In the near future, whole-genome sequencing will enable vast amounts of sequence data to be collected, however clinical application of this information will require a detailed understanding of the functional consequences of each sequence change. Here, we present an RNAi-assisted protein target identification (RAPID) assay by which cells from leukemia patients are functionally screened with siRNA to determine tyrosine kinases that constitute amenable targets for therapeutic intervention. These data have led to identification of novel oncogenic anomalies in cancer patients. Combination of the RAPID screen with whole-genome sequencing promises to yield a powerful synthesis of methodologies by which both functional targets and genetic lesions can be rapidly determined. Methods: To detect targets necessary for viability of malignant cells, we screened primary cells from 75 patients with AML, ALL, CMML, and other MPD as well as white blood cells from healthy individuals by electroporating siRNAs individually targeting each member of the tyrosine kinase family. Four days later, we determined the cell viability and tabulated sensitivity of the cells to any individual tyrosine kinase. Where possible, results were confirmed by treating samples with small-molecule inhibitors with activity against the genes identified by the assay. In addition, the mechanism of oncogenesis was investigated for each positive result. Results: We demonstrate that siRNA screening can identify known oncogenic lesions such as K-RasG13D and JAK2V617F in primary cells from leukemia patients. The RAPID screen has also directed us towards a novel insertional mutation in the thrombopoietin receptor, MPL (1886InsGG). Additionally, we have detected FLT3 sensitivity in patients with FLT3-ITD and loss of heterozygosity, although not in FLT3-ITD heterozygous patients. In total, of 75 patients screened, this assay has yielded 25 cases that exhibit sensitivity to one or more tyrosine kinases. The mechanism of oncogenesis and its relation to the gene target has been established in select other samples with genetic abnormalities including evidence of chromosomal rearrangements as well as gene overexpression and mis-spicing events. Conclusions: We demonstrate that RNAi functional screening can determine sensitivity to individual tyrosine kinases in primary samples. Thus, this technique offers the potential to match specific therapies for targeted intervention with individual patients based on a functional assay. Additionally, in many cases, combination of the RAPID screen with whole-genome sequencing will enable efficient discovery of the genetic etiology of cancer.

Effect of sorafenib in symptomatic metastatic medullary thyroid cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14065-14065 ◽  
Author(s):  
F. Kober ◽  
M. Hermann ◽  
A. Handler ◽  
G. Krotla
Keyword(s):  
Thyroid Cancer ◽  
Side Effects ◽  
Tyrosine Kinases ◽  
Medullary Thyroid Cancer ◽  
Serum Levels ◽  
Primary Objective ◽  
Medullary Thyroid ◽  
Severe Diarrhea ◽  
Metastatic Lesions ◽  
Octreotide Therapy

14065 Background: RET receptor tyrosin kinase activity plays a major role in medullary thyroid cancer (MTC) tumor growth. Sorafenib is an oral agent that selectively targets RET tyrosine kinases. Methods: 5 patients (pts) with metastatic MTC with excessive elevation of calcitonin(CTN) serum levels entered this pilotstudy. Hypercalcitonemia-related symptoms were present in all pts (3 severe diarrhea, 2 moderate) and metastasis- related symptoms were present in 4 pts (2 severe pain, 2 moderate). All pts had had prior thyreoidectomy and cervical +- mediastinal lymphnode dissection, 4 pts had prior octreotide therapy, 3 prior chemotherapy. Pts received 800 mg or 400 mg (weight < 50 kg) Sorafenib as a starting dose. According to the protocol, the dose was reduced gradually in 200 mg scale when pts revealed therapy induced side effects to avoid worsening of quality of life. Sorafenib has to be administered at least 3 months, the scheduled duration of therapy was 6 months. Physical examination, calcitonin and CEA levels were monitored every 4 weeks, measurable metastatic lesions were controlled by appropriate means 3 and 6 months after starting therapy. Primary objective was to assess the effect on CTN dependent symptoms, second objectives included assessments of tumor response (RECIST) and biochemical response. Results: After 2–3 months CTN decreased to levels >50% of baseline in all pts, to levels >90% in 2 pts. According to that all pts were free of CTN related symptoms after 4 weeks. In 4 pts CEA levels reacted in a similar way. After 6 months controls of metastatic lesions were classified as CR-1 pt, PR-1 pt, NC-3 pts. 2 pts with severe metastasis-related pain were off analgesics after 3 months of treatment. Due to side effects Sorafenib dosage was reduced to 50% of the initial dose in all patients. Interestingly marked TSH - elevations were observed in 3 pts which indicates a direct influence to the hypothalamic-pituary-axis. Conclusion: Sorafenib has to be considered as an effective teatment of symptomatic, metastatic MTC. No significant financial relationships to disclose.

Whole‐genome sequencing of synchronous thyroid carcinomas identifies aberrant DNA repair in thyroid cancer dedifferentiation

2019 ◽  
Vol 250 (2) ◽  
pp. 183-194 ◽  
Author(s):  
Johan O Paulsson ◽  
Samuel Backman ◽  
Na Wang ◽  
Adam Stenman ◽  
Joakim Crona ◽  
...  
Keyword(s):  
Dna Repair ◽  
Thyroid Cancer ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Whole Genome ◽  
Thyroid Carcinomas

Vandetanib in metastatic hereditary medullary thyroid cancer: Follow-up results of an open-label phase II trial

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 6018-6018 ◽  
Author(s):  
S. A. Wells ◽  
J. E. Gosnell ◽  
R. F. Gagel ◽  
J. F. Moley ◽  
D. G. Pfister ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Disease Control ◽  
Phase Ii ◽  
Tyrosine Kinases ◽  
Medullary Thyroid Cancer ◽  
Phase Ii Trial ◽  
Locally Advanced ◽  
Disease Control Rate ◽  
Clinical Activity ◽  
Medullary Thyroid

6018 Background: Medullary thyroid cancer (MTC) is the most common cause of death in patients with hereditary syndromes caused by activating mutations in the RET protooncogene. RET activation is the initial oncogenic event, with the activity of other receptor tyrosine kinases, including VEGFR and EGFR, likely to contribute to tumor growth and metastasis. Vandetanib (ZD6474) is a once- daily oral agent that selectively targets RET, VEGFR and EGFR tyrosine kinases. Methods: Eligible patients had unresectable, measurable, locally advanced or metastatic hereditary MTC and a RET germline mutation. Patients received vandetanib 300 mg/day until disease progression or any other withdrawal criteria. The primary objective was to assess the objective tumor response (RECIST every 3 months). Secondary assessments included disease control rate, biochemical response (determined by decrements in plasma levels of calcitonin, a tumor marker for MTC) and safety and tolerability. Results: Thirty patients (21 female; median age 50 years) received initial treatment with vandetanib 300 mg. At data cut-off (20 Nov 2006), the median duration of treatment was 172 days. Based on site investigator assessments, 20% (6/30) of patients experienced a partial response (duration of response 59–260 days) and another 30% (9/30) of patients experienced stable disease =24 weeks, yielding a disease control rate of 50% (15/30). Centralized independent confirmation of response is planned. In 19 patients, plasma calcitonin levels showed a =50% decrease from baseline that was maintained for at least 6 weeks. Adverse events (AEs) occurring in >50% of patients were rash (73%), diarrhea (67%), fatigue (57%) and nausea (53%). Most AEs were grade 1 or 2; grade 3 AEs included asymptomatic QTc prolongation (n=5), rash and diarrhea (both n=3), all of which were manageable. Conclusions: Vandetanib has demonstrated clinical activity in this phase II study in metastatic hereditary MTC, and the safety profile is generally consistent with previous vandetanib monotherapy studies. Accrual is now complete (30 patients), and an updated analysis will be performed in April 2007. An international, randomized, placebo-controlled phase II trial of vandetanib in MTC is now recruiting patients. # No significant financial relationships to disclose.

scholarly journals Identification of Familial Hodgkin Lymphoma Predisposing Genes Using Whole Genome Sequencing

2019 ◽  
Author(s):  
Aayushi Srivastava ◽  
Sara Giangiobbe ◽  
Abhishek Kumar ◽  
Dagmara Dymerska ◽  
Wolfgang Behnisch ◽  
...  
Keyword(s):  
B Cell ◽  
Whole Genome Sequencing ◽  
Hodgkin Lymphoma ◽  
Genome Sequencing ◽  
Pathway Analysis ◽  
Cell Activation ◽  
Familial Cancer ◽  
Amino Acid Sequences ◽  
Clear Understanding ◽  
Whole Genome

AbstractHodgkin lymphoma (HL) is a lymphoproliferative malignancy of B-cell origin that accounts for 10% of all lymphomas. Despite evidence suggesting strong familial clustering of HL, there is no clear understanding of the contribution of genes predisposing to HL. In this study, whole genome sequencing (WGS) was performed on 7 affected and 9 unaffected family members from three HL-prone families and variants were prioritized using our Familial Cancer Variant Prioritization Pipeline (FCVPPv2). WGS identified a total of 98564, 170550 and 113654 variants which were reduced by pedigree-based filtering to 18158, 465 and 26465 in families I, II and III, respectively. In addition to variants affecting amino acid sequences, variants in promoters, enhancers, transcription factors binding sites and microRNA seed sequences were identified from upstream, downstream, 5’ and 3’ untranslated regions. A panel of 565 cancer predisposing and other cancer-related genes and of 2383 high-risk HL genes were also screened in these families to aid further prioritization. Pathway analysis of segregating genes with CADD (Combined Annotation Dependent Depletion Tool) scores > 20 was performed using Ingenuity Pathway Analysis software which implicated several candidate genes in pathways involved in B-cell activation and proliferation and in the network of “Cancer, Hematological disease and Immunological Disease”. We used the FCVPPv2 for further in silico analysis and prioritized 45 coding and 79 non-coding variants from the three families. Further literature-based analysis allowed us to constrict this list to one rare germline variant each in families I and II and two in family III. Functional studies were conducted on the candidate from family I in a previous study, resulting in the identification and functional validation of a novel heterozygous missense variant in the tumor suppressor gene DICER1 as potential HL predisposition factor. We aim to identify the individual genes responsible for predisposition in the remaining two families and will functionally validate these in further studies.

scholarly journals Whole Genome Sequencing Illuminates the Developmental Signatures of Human Language Ability

2021 ◽  
Author(s):  
Tanner Koomar ◽  
Lucas Casten ◽  
Taylor R Thomas ◽  
Jin-Young Koh ◽  
Dabney Hofamann ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Language Ability ◽  
Whole Genome ◽  
Ancestral State ◽  
Region Gene ◽  
Related Proteins ◽  
Genetic Burden ◽  
Functional Profiles ◽  
Human Specific

Language is the foundation of human social interaction, education, commerce, and mental health. The heritability underlying language is well-established, but our understanding of its genetic basis - and how it compares to that of more general cognitive functioning - remains unclear. To illuminate the language-specific contributions of rare and common variation, we performed whole genome sequencing in N=350 individuals, who were characterized with seven latent language phenotypes. We conducted region, gene, and gene set-based analyses to identify patterns of genetic burden that disproportionately explained these language factors compared to nonverbal IQ. These analyses identified language-specific associations with NDST4 and GRIN2A, with common variant replication of NDST4 in an independent sample. Rare variant burden analyses revealed three distinct functional profiles of genes that make contributions to language: a prenatally-expressed profile with enrichment for chromatin modifiers and broad neuropsychiatric risk, a postnatal cortex-expressed profile with enrichment for ion channels and cognitive/neuropsychiatric associations, and a postnatal, subcortically-expressed profile with enrichment of cilium-related proteins. Compared to a profile strongly associated with nonverbal IQ, these language-related profiles showed less intolerance to damaging variation, suggesting that the selection patterns acting on language differ from patterns linked to intellectual disability. Furthermore, we found evidence that rare potential reversions to an ancestral state are associated with poorer overall specific language ability. The breadth of these variant, gene, and profile associations suggest that while human-specific selection patterns do contribute to language, these are distributed broadly across numerous key mechanisms and developmental periods, and not in one or a few "language genes".

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