Sunday, February 18, 2024

Genetic Testing For Thyroid Cancer

Gene Mutations: Braf And Ras

Genetic Testing and Screening in Medullary Thyroid Cancer

The most prevalent and studied mutation in thyroid cancer is the T1799A point mutation of the BRAF gene. This activating gain-of-function mutation results from a thymine to adenine transversion at the nucleotide position 1799, ensuing in the substitution of valine by glutamate at codon 600 in exon 15 . The unimpaired expression of BRAFV600E mutant protein causes the constitutive activation of the MAPK pathway.8 The BRAF mutation occurs in approximately 45% of PTCs. Mutant BRAF is required to sustain tumor growth and is associated with poor clinical outcome as detailed below. Some thyroid nodules have been found to exhibit intra-tumor heterogeneity of the BRAF genotype, with a minority of cells harboring the BRAF mutation while the majority of cells express the wild-type BRAF .9

Second in prevalence in thyroid cancer are RAS mutations. Mutant RAS proteins lose their intrinsic GTPase activity. These proteins bind GTP but are unable to execute their GTPase activity by hydrolyzing GTP to GDP. Thereby the mutant RAS proteins are frozen in a permanent, constitutive on state, irrelevant of whether a cognate ligand is around or not.

Genes Associated With Thyroid Cancers

Nodules are usually detected during a routine physical exam. This is the first step into diagnosing thyroid cancer. Next, ultrasound imaging, blood testing, and fine-needle aspiration biopsies can help plan better treatments according to the level of malignancy of the nodule.

Molecular markers found through these procedures can help predict how aggressive the disease is and predict the efficacy of therapeutic agents for each particular case.

Thyroid tumors may have some gene mutations. The following are some of the most relevant:

BRAF: Mutations in this specific gene are the most common and are typically found in papillary thyroid cancers. A BRAF mutation means that the risk of PTC is almost 100%. This gene alteration is also associated with aggressive forms of thyroid cancer and usually represents a higher risk of recurrence.

RAS: This is the second most common mutation and is usually associated with papillary or follicular thyroid cancer.

RET: Approximately 2 out of 10 medullary thyroid carcinomas result from inheriting a damaged RET gene. These cases are known as familial medullary thyroid carcinomas . The combination of FMTC and tumors in other endocrine glands is called multiple endocrine neoplasia type 2 .

PAX8-PPAR: Mutation in this gene is associated with follicular thyroid carcinoma.

PTEN:Changes in the gene PTEN cause Cowden disease, which puts patients at a higher risk of developing papillary or follicular thyroid carcinomas.

Impact On Surgical Decision Making

One of the first studies to specifically investigate molecular testings impact on surgical management was a retrospective study performed by Aragon Han and colleagues in 2014 . Here, the authors compared management recommendations based on pre-operative molecular testing results to the treatment strategy recommended by a surgical management algorithm. The algorithm was based on clinical parameters developed by experts at a high-volume, tertiary academic institution and in incorporated into a calculator. They found that the strategy influenced by molecular testing differed from the recommendations of the clinical management algorithm in only 10% of the patients . Furthermore, in 6 out these 9 patients the molecular testing driven strategy was incorrect and led to overtreatment. Similar results were subsequently observed during two successive investigations by Noureldine and colleagues . In one, the authors specifically looked at the appropriateness and impact of Afirma-GEC on management of 273 patients using a similar strategy to Aragon Han et al. and found that the GEC results changed management strategy in just 23 out of 273 patients and led to overtreatment in most of these . These results were echoed by a subsequent prospective study by the same group where molecular testing only changed management plan in 7.9% patients, out of whom 91% were overtreated .

Table 1 Summary of investigations evaluating impact of molecular testing on surgical management and outcomes.

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Do You Need Genetic Testing For Breast Cancer

For people who have been diagnosed with breast cancer, genetic testing can clarify which treatments to pursue. A risk of recurrence could compel someone to pursue surgery, for instance. And for those with a family history of the disease, checking for genetic risk factors can help guide preventive measures.

If you have a family history of breast cancer, an at-home genetic test can tell you if you carry certain key mutations in the BRCA1 or BRCA2 genes. But at-home test results need to be verified with a lab test. A genetic counselor can help you decide whether testing is necessary and make sense of the results.

Screening For Thyroid Cancer

Genetic Basis and Gene Therapy Trials for Thyroid Cancer

There is no national screening programme in the UK for thyroid cancer.

If your doctor suspects that you might have a high risk of thyroid cancer, they will refer you to a genetic clinic for advice. Some people with a significant family history of thyroid cancer may be tested to find out if they have an inherited gene fault. Depending on the results, they may be offered surgery to remove their thyroid gland.

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Genetic Testing For Thyroid Cancer

Several genetic testing techniques can be applied depending on the type of tumor and suspected mutation. Some of these tests are:

Sanger Dideoxy Sequencing

This is the most widely used method to detect single nucleotide variants. Through this next generation sequencing technique, technicians copy target DNA sequences many times to create DNA fragments that are later separated.

Polymerase Chain Reaction

This method is used to amplify a DNA sequence. This sequence is then used to identify markers at specific positions to confirm the presence of a mutation.

Fluorescence In Situ Hybridization

This technique uses a tag with a fluorescent probe on DNA sequences of interest. These are then viewed under fluorescent microscopy.

Multiplex Ligation-Dependent Probe Amplification

This is a specialized form of PCR that identifies point mutations.

Afirma Gene Expression Classifier

This new technology uses microarray technology to analyze messenger RNA expression of over 150 genes and was designed as a rule out test to more accurately diagnose patients and allow more patients to avoid surgery.

Advancing Molecular Testing In Thyroid Patients

As the field continues to evolve, molecular testing is poised to provide even more precise and clinically valuable diagnostic information to guide appropriate treatment for patients with thyroid nodules. In addition to refining physicians ability to resolve indeterminate thyroid nodules, molecular testing will likely increase in use to inform optimal therapy and measure therapy response, among other uses.

As a physician who has been managing patients with thyroid nodules for over 15 years, I believe the opportunity to provide excellent patient care has never been greater than it is now.

Dr. Shank reported receiving research funding from Veracyle and he is on their speaker’s bureau.

  • Haugen BR, et al. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2015 26:1-202.
  • NCCN Clinical Practice Guidelines in Oncology: Thyroid Carcinoma. National Comprehensive Cancer Network. Version 2.2017 – May 17, 2017. Accessed 1/3/18.
  • Gharib H et al. American Association of Clinical Endocrinologists, American College of Endocrinology, and Associazione Medici Endocrinologi Medical Guidelines for Clinical Practice for the Diagnosis And Management of Thyroid Nodules 2016 Update. Endocr Pract. 2016 22.
  • Hegedus L 2004 Clinical practice. The thyroid nodule. N Engl J Med. 2004 351:17641771.
  • Stoll SJ, et al. Thyroid hormone replacement after thyroid lobectomy. Surgery. 2009 146:554-560.
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    What Is Cancer Screening

    Screening means testing people for early stages of a disease. This is before they have any symptoms. For screening to be useful the tests:

    • need to be reliable at picking up cancers
    • overall must do more good than harm to people taking part
    • must be something that people are willing to do

    Screening tests are not perfect and have some risks. The screening programme should also be good value for money for the NHS.

    Magnetic Resonance Imaging Scan

    Genetic Testing in Thyroid Cancer Diagnosis and Treatment.

    MRI scans use magnets instead of radiation to create detailed cross-sectional images of your body. MRI can be used to look for cancer in the thyroid, or cancer that has spread to nearby or distant parts of the body. But ultrasound is usually the first choice for looking at the thyroid. MRI can provide very detailed images of soft tissues such as the thyroid gland. MRI scans are also very helpful in looking at the brain and spinal cord.

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    Types Of Genetic Testing For Thyroid Cancer

    There are a few commercially available genetic testing companies that test potentially dangerous nodules. The physician sends the nodule cells to these companies for genetic testing. This will help determine if the nodule is benign or malignant.

    Quest Diagnostics

    The objective of this company is to help physicians decide if there is a presence of thyroid cancer and if it needs surgical removal. This test consists of a panel with four gene markers:

    • BRAF Mutation Analysis, Papillary Thyroid Cancer
    • RAS Mutation Analysis, Thyroid Cancer
    • RET/PTC Rearrangement, Thyroid Cancer

    NeoGenomics

    NeoGenomics offers its molecular testing services to patients with the advanced condition. They perform this under The Thyroid Cancer Testing Program sponsored by Lilly Oncology, a company that provides financial assistance to patients.

    Patients eligible for this testing must be 12 years or older and have any of the following:

    • Advanced or metastatic medullary thyroid cancer
    • Advanced or metastatic non-medullary thyroid cancer

    ThyroSeq

    This is one of the most well-known genomic tests of this type. Branded as ThyroSeq Genomic Classifier, it distinguishes between benign and cancerous thyroid nodules using a tiny sample. The test aims to help avoid unnecessary diagnostic surgery.

    If the test is positive, the report provides valuable information about the nodule to help the patient and physician decide on a customized treatment plan.

    Veracyte

    Asuragen

    The Afirma Thyroid Fna Analysis

    An overview for patients A novel patient-centric approach to thyroid nodule managementThe Afirma Thyroid FNA Analysis, offered by Veracyte, is a novel approach used by physicians to assess whether a lump in a thyroid gland is likely to be benign or malignant . Although most thyroid nodules are benign, the only way to be sure is to look closely at the cells that make up a nodule. Many physicians have chosen to use the Afirma Thyroid FNA Analysis to assist them in their assessment of thyroid nodules given its significant benefits for patients, including the ability to:

    • Keep patients from unnecessary thyroid surgery2-4
    • Provide an actionable diagnosis from a single patient visit5
    • Have their nodule cells examined by specialized cytopathology5
    • Utilize powerful genomic technology to better characteriize nodules nodules challenging to diagnose by cytopathology assessement alone 2,5,6

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    Clarifying Indeterminate Thyroid Nodules

    The most common application of molecular testing in thyroid nodule assessment is to guide care for patients with indeterminate nodules. Cytopathology examination of ultrasound-guided fine needle aspiration biopsies is the standard preoperative tool for evaluating thyroid nodules larger than one cm. However, in 15-30% of nodule aspirates, the results are indeterminate.

    Based on the Bethesda System for Reporting Thyroid Cytopathology, indeterminate thyroid nodules encompass atypia of undetermined significance/follicular lesion of undetermined significance follicular neoplasm or suspicious for a follicular neoplasm and suspicious for malignancy . Indeterminate nodules have a high enough risk of cancer to warrant additional evaluation.¹

    Traditionally, most patients with cytologically indeterminate nodules have been referred for diagnostic surgery, even though 70% to 80% of these nodules ultimately prove to be benign by surgical histopathology meaning the surgery was unnecessary. Further, patients with confirmed thyroid cancer may not receive the surgery they need. For example, Esfandiari et al reported that over 40% of patients with medullary thyroid cancer did not undergo a total thyroidectomy and central neck dissection, which this diagnosis would typically require. These patients may require a second surgery to complete the thyroidectomy.

    European Perspective On The Use Of Molecular Tests In The Diagnosis And Therapy Of Thyroid Neoplasms

    University of Toronto

    Magorzata Oczko-Wojciechowska1, Agnieszka Kotecka-Blicharz2, Jolanta Krajewska2, Dagmara Rusinek1, Marcin Barczyski3, Barbara Jarzb2, Agnieszka Czarniecka4

    1 Department of Nuclear Medicine and Endocrine Oncology, Laboratory of Molecular Diagnostic and Functional Genomics, 2 Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Institute-Oncology Center, Gliwice Branch, Gliwice 3Department of Endocrine Surgery, Third Chair of General Surgery, Jagiellonian University Medical College 4The Oncologic and Reconstructive Surgery Clinic, Maria Sklodowska-Curie Institute-Oncology Center, Gliwice Branch, Gliwice , Poland

    Contributions: Conception and design: M Oczko-Wojciechowska, A Czarniecka Administrative support: M Oczko-Wojciechowska Provision of study materials or patients: All authors Collection and assembly of data: All authors Data analysis and interpretation: All authors Manuscript writing: All authors Final approval of manuscript: All authors.

    Correspondence to:

    Keywords: Thyroid nodules indeterminate cytology molecular classifier

    Submitted Oct 18, 2019. Accepted for publication Oct 30, 2019.

    doi: 10.21037/gs.2019.10.26

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    Can Genetic Tests Detect Breast Cancer Risks Accurately

    Humans have more than 20,000 genes. When just one amino acid in these genes is swapped out for another, thats called a mutation, or variation.

    Genetic variation is extremely common in the human species, , medical oncologist and Chief of the Breast Cancer Medicine Center at Memorial Sloan Kettering Cancer Center.

    When studying genetic variants that may be linked to cancer, scientists rate them on a five-point scale, from “benign” to “pathogenic.” Robson said that with more research, scientists might find that most VUS are likely noncancerous.

    Due to the uncertainty about their role in breast cancer, VUS are not usually considered actionable,” according to the American College of Medical Genetics and Genomics. That means clinicians should not take preventive actions, like recommending a mastectomy, based solely on the detection of a VUS.

    Some clinical lab tests have the capacity to detect as many as 84 different variants implicated in breast and ovarian cancer. Sharing a positive test result may give just enough information to worry patients, but not enough for clinicians to feel confident taking drastic action, Robson said.

    Robson said he falls on the conservative end of the spectrum of cancer geneticists. Although hes not opposed to encouraging a patient with a VUS to receive more frequent screening, recommending a preventive surgery based on an uncertain risk factor could have severe consequences.

    Gene Amplifications And Copy

    These genetic alterations cause the replication of a specific genomic sequence leading to increased copies of a gene. This was shown to be the case for genes encoding PI3K pathway components, including PIK3CA, PIK3CB, 3-phosphoinositide-dependent protein kinase 1 , AKT1, and AKT2. Activation of this pathway was found to be related to development of FTA and FTC. Overall, genetic copy-number gain in these genes is more prevalent in ATC than in DTC, suggesting that these genetic changes play an important mechanistic role in the progression of thyroid cancer.15

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    Increased Molecular Testing Accelerates Precision Thyroid Nodule Management Cancer Care

    View Issue Disclosures: We were unable to process your request. Please try again later. If you continue to have this issue please contact .

    Thyroid nodules are common. Each year, approximately 600,000 U.S. residents with nodules undergo a fine-needle aspiration biopsy in which cells are extracted and examined to determine whether the nodule is benign or cancerous.

    Fine-needle aspiration, or FNA, biopsy is mostly accurate and most nodules are benign. However, in approximately 20% to 25% of cases, the test returns an indeterminate finding, meaning there was not a conclusive identification of benign or malignant thyroid disease. Only a decade ago, most of these patients would go on to diagnostic surgery, with approximately 60% overtreated or undertreated, based on the surgery that they receive.

    Ten or 15 years ago, when someone had indeterminate cytology for their nodule, there were really only two options to watch the nodule conservatively or to surgically remove it,Erik K. Alexander, MD, chief of the thyroid section at Brigham and Womens Hospital and professor of medicine at Harvard Medical School, told Endocrine Today. The problem, of course, is most patients do not want to watch things when there is a potential risk for cancer, so we were doing a lot more surgery, much of it unnecessary and much of it for benign disease.

    Beyond the microscope

    Comparing options

    More data needed

    The lack of clarity has been disappointing for some endocrinologists, Lee said.

    Genetics Inheritance And Genetic Testing

    Genetic Testing and Screening in Advanced Medullary Thyroid Cancer

    The CDKN1B variant codes for p27Kip1 , a putative tumor suppressor gene that regulates cell cycle progression. Alterations in this gene lead to a decrease in expression of p27 protein, triggering uncontrolled cell cycle progression. Although the loss of one allele of p27 is a frequent event in many human cancers, the remaining allele is rarely mutated or lost by loss of heterozygosity in human cancers. Somatic mutations or germline pathogenic variants in CDKN1B have also been identified in patients with sporadic PHPT, small intestinal NETs, lymphoma, and breast cancer. These findings demonstrate a novel role for CDKN1B as a tumor susceptibility gene in other neoplasms.

    To date, only 19 cases having CDKN1B germline variants have been reported in the medical literature. Thirteen pathogenic germline variants that have been frameshift, nonsense, or missense variants have been described.

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    Cytological And Pathological Data

    From a cytological point of view, 37 patients had a nodule scored class III, 84 class IV and 10 class V . Central review confirmed the IC status in all 131 nodules.

    Fig. 1

    Molecular alterations in patients with malignant or benign nodules for each cytological subgroup . WT wild-type, PTC papillary thyroid cancer, FVPTC papillary thyroid cancer with follicular variant, FTC follicular thyroid carcinoma, HCC Hürthle-cell carcinoma, PDTC poorly differentiated thyroid carcinoma

    Genetic Techniques Used For Evaluation Of Dtc

    The identification of genetic changes thought to have a role in the evolution and progress of DTC and the attempt to understand their clinical relevancehas set the stage for using molecular markers for the diagnosis and treatment of DTC. The first step in this process was to design a diagnostic platform that is able to identify genetic changes and to report their presence with acceptable validity. Next, an algorithm for the interpretation of large sets of data had to be developed and applied. Further studies were performed to evaluate the ability of the results to improve care of DTC patients. Samples for genetic testing are obtained from cytopathology and pathology specimens. Extracted DNA and/or RNA are used for analysis . The currently available methods are discussed below.

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