Identification of a secondary RET mutation in a pediatric patient with relapsed acute myeloid leukemia leads to the diagnosis and treatment of asymptomatic metastatic medullary thyroid cancer in a parent: a case for sequencing the germline
Danielle PendrickJennifer A. ObergSusan J. HsiaoWendy K. ChungCarrie KovalAnthony SireciJennifer KuoPrakash SatwaniChana L. GlasserMaria Luisa SulisMahesh MansukhaniJulia L. Glade Bender
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Abstract:
The incorporation of tumor-normal genomic testing into oncology can identify somatic mutations that inform therapeutic measures but also germline variants associated with unsuspected cancer predisposition. We describe a case in which a RET variant was identified in a 3-yr-old male with relapsed leukemia. Sanger sequencing revealed the patient's father and three siblings carried the same variant, associated with multiple endocrine neoplasia 2A (MEN2A). Evaluation of the father led to the diagnosis and treatment of metastatic medullary thyroid carcinoma. Detection of RET mutations in families with hereditary MTC allows for genetic risk stratification and disease surveillance to reduce morbidity and mortality.Keywords:
Sanger sequencing
Medullary Thyroid Cancer
A New Germline Point Mutation in Ret Exon 8 (Cys515Ser) in a Family with Medullary Thyroid Carcinoma
Background: A novel Cys-Ser Ret germline point mutation in a 58-year-old woman with bilateral medullary thyroid carcinoma (MTC) prompted us to perform genetic analysis of the family and evaluate the biological consequences of such a mutation. Methods: Ret analysis by direct sequencing was performed in five family members. The biological activity and biochemical properties of the Ret- Cys515Ser mutant were analyzed in NIH-3T3 cells. Results: The proband's son, age 35, had the Ret- Cys515Ser mutation and the L769 CTT/CTG exon 13 polymorphic variant, which was also found in his father. Clinical evaluation of the son also revealed bilateral multifocal microscopic MTC and papillary thyroid carcinoma (PTC). In vitro and in vivo analysis indicated ligand-independent activation of the Ret-Cys515Ser mutant due to aberrant disulfide homodimerization, increased mitogenic activity, and ability to induce anchorage-independent growth in NIH-3T3 cells in comparison to wild-type Ret, suggesting a possible role of Cys515Ser in tumor development. Conclusions: The Cys515Ser mutation adds to cysteine substitution groups that have been described in association with MTC. Our data also highlight the importance of performing a complete genetic analysis in patients who present with MTC.
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Proto-Oncogene Proteins c-ret
Medullary carcinoma
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The incorporation of tumor-normal genomic testing into oncology can identify somatic mutations that inform therapeutic measures but also germline variants associated with unsuspected cancer predisposition. We describe a case in which a RET variant was identified in a 3-yr-old male with relapsed leukemia. Sanger sequencing revealed the patient's father and three siblings carried the same variant, associated with multiple endocrine neoplasia 2A (MEN2A). Evaluation of the father led to the diagnosis and treatment of metastatic medullary thyroid carcinoma. Detection of RET mutations in families with hereditary MTC allows for genetic risk stratification and disease surveillance to reduce morbidity and mortality.
Sanger sequencing
Medullary Thyroid Cancer
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Summary Objective Medullary thyroid carcinoma ( MTC ) is a rare disease that can be inherited or sporadic; its pathogenesis is related to activating mutations in the RET gene. Design This study describes our 20‐year experience regarding RET genetic screening in MTC . Patients and methods We performed RET genetic screening in 1556 subjects, 1007 with an apparently sporadic MTC , 95 with a familial form and 454 relatives of RET ‐positive patients with MTC . Results A germline RET mutation was found in 68 of 1007 (6·7%) patients with sporadic MTC , while 939 patients with MTC were negative for germline RET mutations. We then identified a total of 137 gene carriers ( GC ). These subjects initiated a clinical evaluation for the diagnosis of MEN 2. A total of 139 MEN 2 families have been followed: 94 FMTC , 33 MEN 2A and 12 MEN 2B. Thirty‐three different germline RET mutations were identified. Codon 804 was the most frequently altered codon particularly in FMTC (32/94, 34%), while codon 634 was the most frequently altered codon in MEN 2A (31/33, 94%); MEN 2B cases were exclusively associated with an M918T mutation at exon 16. Conclusions Our 20‐year study demonstrated that RET genetic screening is highly specific and sensitive, and it allows the reclassification as hereditary of apparently sporadic cases and the identification of GC who require an adequate follow‐up. We confirmed that FMTC is the most prevalent MEN 2 syndrome and that it is strongly correlated with noncysteine RET mutations. According to these findings, a new paradigm of follow‐up of hereditary MTC cases might be considered in the next future.
Medullary Thyroid Cancer
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Medullary Thyroid Cancer
Medullary carcinoma
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Germline RET variants are responsible for approximately 25% of medullary thyroid carcinoma (MTC) cases. Identification of RET variant carriers allows for the adoption of preventative measures which are dependent on the risk associated with the specific alteration. From 2002 to 2020, at our cancer genetics clinic, RET genetic testing was performed in 163 subjects (102 complete gene analyses and 61 targeted analyses), 72 of whom presented with MTC. A germline RET variant was identified in 31.9% of patients affected by MTC (93.8% of those having positive family history and 14.3% of clinically sporadic cases). Subsequent target testing in relatives allowed us to identify 22 asymptomatic carriers, who could undertake appropriate screening. Overall, patients with germline RET variants differed significantly from those who tested negative by family history (p < 0.001) and mean age at MTC diagnosis (44.45 vs. 56.42 years; p = 0.010), but the difference was not significant when only carriers of moderate risk variants were considered (51.78 vs. 56.42 years; p = 0.281). Out of 12 different variants detected in 49 patients, five (41.7%) were of uncertain significance (VUS). For two of these, p.Ser904Phe and p.Asp631_Leu633delinsGlu, co-segregation and genotype/phenotype analysis, matched with data from the literature, provided evidence supporting their classification in the moderate and the highest/high risk class (with a MEN2B phenotype), respectively.
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Thyroid carcinomas, the most common endocrine tumors in humans, have an increasing incidence in the U.S. and worldwide. There are four major types of thyroid cancers: papillary, follicular, anaplastic, and medullary carcinomas. In recent years, significant progress has been made in the identification of genetic alterations in thyroid carcinomas, particularly, papillary and medullary thyroid cancers. Mouse models of thyroid cancer are valuable tools in elucidating molecular genetic changes underlying thyroid carcinogenesis and in identifying potential molecular targets for therapeutic intervention. Representative mouse models of papillary, follicular, and medullary carcinomas are reviewed here with particular emphasis on those for follicular thyroid carcinomas. Challenges for further development in the modeling of thyroid cancer will also be discussed.
Medullary Thyroid Cancer
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The origins of medullary carcinoma (MTC) and papillary carcinoma (PTC) of the thyroid are embryologically different.Tumors showing concurrent medullary and papillary features are rare and they represent less than 1% of all thyroid malignancies.Hereditary MTC is an autosomal dominantly inherited disease which is genetically determined as part of the MEN 2A, MEN 2B, or variants of MEN 2A such as familial MTC.Germline mutations of the RET gene are the underlying cause of the majority of cases of hereditary medullary carcinomas.The pathogenesis of concurrent PTC with familial MTC has rarely been known.Genetic analysis of the RET oncogene has so far provided conflicting results.Here we describe a family whose sibling was affected by both PTC & MTC, and the family carried a germ-line point mutation in the RET extracellular domain that converted cysteine 634 into tryptophan (C634W).
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A quarter of patients with medullary thyroid carcinoma (MTC) have germline mutations in the RET proto-oncogene indicating MEN2. Therefore genetic testing is recommended for all patients presenting with MTC. Approximately 40% of MTCs have somatic RET mutations. Somatic mutations in the RAS genes are the next most common driver mutations and appear to be mutually exclusive with germline RET mutation. The single most common somatic RAS mutation is HRASQ61R (c.182A>G), reported in 4.6% to 11% of all MTCs. Mutation-specific immunohistochemistry (IHC) initially developed to identify the NRASQ61R mutation in melanoma (clone SP174) has proven highly sensitive and specific. Because the amino acid sequences for the HRAS and NRAS proteins at codon 61 are identical, we postulated that SP174 IHC would also identify the somatic HRASQ61R mutation. IHC with SP174 was performed on a tissue microarray of 68 patients with MTC including 13 (22.8%) with molecularly confirmed MEN2. Seven (10.3%) MTCs demonstrated positive staining. Six of these patients had already undergone germline RET mutation testing as part of clinical care and were all confirmed to be wild type, excluding the diagnosis of MEN2. All SP174 immunohistochemically positive MTCs were proven to have HRASQ61R mutation (and lack KRASQ61R and NRASQ61R) by Sanger sequencing. All MEN2 patients showed negative staining. We conclude that IHC with SP174 is highly specific for the HRASQ61R mutation in MTC. Because current data suggest that this mutation is mutually exclusive with germline RET mutation, IHC may also have a role in triaging formal genetic testing for MEN2.
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