Hereditary Medullary Thyroid Cancer Research Articles

30years of prophylactic thyroidectomy for hereditary medullary thyroid cancer : Amilestone in translational medicine

Medullary thyroid cancer (MTC) is the most frequent manifestation of multiple endocrine neoplasia type 2 (MEN2) that determines the oncological outcome. Germline mutations in the rearranged during transfection (RET) protooncogene, atumor suppressor gene on chromosome 10q11.2, were identified 30 years ago as the genetic basis of MEN2 and published in 1993 and 1994. These seminal findings gave rise to the concept of prophylactic thyroidectomy for asymptomatic gene mutation carriers based on apositive RET gene test, which has become the standard of care ever since. Clinical genetic investigations showed genotype-phenotype correlations with respect to the individual gene mutation regarding the penetrance and onset of MTC and to alesser extent also with respect to the other components of MEN2, pheochromocytoma and primary hyperparathyroidism. From this a clinically relevant risk stratification could be derived. Initially, the optimal timing of prophylactic thyroidectomy was primarily based on the RET genotype alone, which was not sufficient for a precise age recommendation and subsequently required additional consideration of calcitonin serum levels for fine tuning. Calcitonin levels first show the risk of lymph node metastasis when they exceed the upper normal limit of the assay independent of carrier age and RET mutation. Routine calcitonin screening of patients with nodular thyroid disease, screening of families on identification of MEN2 index patients, and pre-emptive thyroidectomy in carriers of gene mutations with normal calcitonin levels have led to the fact that nowadays, 30years after the first description of the gene mutations causing the disease, the life-threatening hereditary MTC has become curable: ashining example for the success of translational transnational medical research for the benefit of patients.

Medullary Thyroid Cancer: Epidemiology and Characteristics According to Data From the Marne-Ardennes Register 1975-2018.

Medullary thyroid cancer (MTC) is a rare disease. The main objective of our study was to analyze the incidence evolution of MTC with a follow-up of more than 40 years. Further, a descriptive and survival analysis was performed according to the Kaplan-Meier analysis. This is a retrospective epidemiological study using data from the Marne-Ardennes registry from 1975 to 2018. Two hundred sixty patients with MTC were included. The incidence was calculated in the territory of the register (Marne and Ardennes departments of France) and standardized on the demographic structure of France. Patient and tumor characteristics were described. An analysis in a subgroup comparing hereditary and sporadic forms was performed. An analysis of survival was performed. The standardized incidence shows an increasing trend over time. The incidence increased significantly from 0.41 to 0.57/100 000 person-years between 1986 and 1996 and 2008 and 2018. The MTC was hereditary in 21.2% of cases. The sex ratio (males:females) was 0.73. The average age at diagnosis was 53 years. Ninety-seven patients (37.3%) were N1, 26 (10%) were M1, and 56 (21.5%) developed metastases during the follow-up. Complete remission was obtained in 58.5% of patients. The disease was refractory for 18.1% of patients. The 5-year survival rate was 88.4%. Sporadic cases had a poorer prognosis than hereditary MTC. Our study demonstrates a moderate increase in the incidence of MTC between 1975 and 2018. The prognosis remains worse for sporadic MTC than for hereditary MTC.

Latest Progress in Risk-Adapted Surgery for Medullary Thyroid Cancer.

(1) Background: The wider adoption of a preoperative ultrasound and calcitonin screening complemented by an intraoperative frozen section has increased the number of patients with occult sporadic medullary thyroid cancer (MTC). These advances offer new opportunities to reduce the extent of the initial operations, minimizing operative morbidity and the risk of postoperative thyroxin supplementation without compromising the cure. (2) Methods: This systematic review of the international literature published in the English language provides a comprehensive update on the latest progress made in the risk-adapted surgery for sporadic and hereditary MTC guided by an intraoperative frozen section. (3) Results: The current evidence confirms the viability of a hemithyroidectomy for desmoplasia-negative sporadic MTC. To add an extra safety margin, the hemithyroidectomy may be complemented by a diagnostic ipsilateral central node dissection. Despite the limited extent of the surgery, all the patients with desmoplasia-negative sporadic tumors achieved a biochemical cure with excellent clinical outcomes. A hemithyroidectomy decreases the need for postoperative thyroxine substitution, but a total thyroidectomy may be required for bilateral nodular thyroid disease. Hereditary MTC is a different issue. Because each residual thyroid C cell carries its own risk of malignant progression, a total thyroidectomy remains mandatory for hereditary MTC. (4) Conclusion: In experienced hands, a hemithyroidectomy, which minimizes morbidity without compromising the cure, is an adequate therapy for desmoplasia-negative sporadic MTC.

Individualization of treatment in sporadic and hereditary medullary thyroid cancer

Routine preoperative assessment of the tumor marker calcitonin for medullary thyroid cancer (MTC) and the generally improved diagnostics with high-resolution ultrasound, elastography and Doppler function as well as functional imaging, enable the earlier detection of organ-limited, non-metastasized MTC. Thereby, anew treatment option arises for surgical de-escalation in sporadic MTC, moving from routine thyroidectomy with bilateral central lymph node dissection towards unilateral thyroidectomy with ipsilateral central lymph node dissection. A search was carried out in PubMed for surgical approaches and selection of publications with results from limited resection in sporadic MTC. In selected patient cohorts limited resection surgery can achieve adequate oncological results but requires long-term follow-up. When sporadic unifocal primary tumors are identified and intraoperative frozen section pathological investigation is consistently employed for assessing the grade of desmoplasia and breach of the tumor capsule, the extent of resection can be intraoperatively adapted. Pivotal prerequisites for this personalized concept include consideration of preoperative clinical criteria and intraoperative surgical assessment in conjunction with the intraoperative frozen section examination in order to achieve an adequate oncological tumor resection and a biochemical cure.

Sexual dimorphism in medullary thyroid cancer aggressiveness.

Thyroid cancer is the only nonreproductive cancer with striking female predominance, although men with thyroid cancer develop more aggressive disease. This study aimed to quantify sex-specific differences in medullary thyroid cancer (MTC) spread after controlling for primary thyroid tumor size. Included in this retrospective analysis were all patients with unilateral solitary MTC who underwent initial neck surgery at a tertiary referral center. A total of 565 patients, 255 men and 310 women, were identified, of whom 467 had sporadic and 98 hereditary MTC. When stratified by sex, and after correction for multiple testing, men had higher preoperative basal calcitonin levels (medians of 655 vs 181 pg/mL; P < 0.001), more frequent extrathyroid extension (25 vs 9%; P < 0.001) and node metastasis (53 vs 27%; P < 0.001) with more involved nodes (medians of 2 vs 0 nodes; P < 0.001) than women but achieved less often biochemical cure (53 vs 74%; P < 0.001). Although absent in patients with very small (≤5 mm) thyroid tumors, sex disparities were immediately apparent in patients with 5.1-40 mm (node metastasis and biochemical cure) and 10.1-40 mm (extrathyroid extension) large thyroid tumors but were lost in patients with thyroid tumors >40 mm as women caught up. Sex disparities were strongest for node metastasis with a 27-41% (overall 24.0%) point difference, followed by biochemical cure with a -15-35% (overall -20.3%) point difference and extrathyroid extension with a 17-24% (14.2% overall) point difference. These findings indicate that the male predominance in MTC aggressiveness is largely biologically driven, warranting further research.

Comparing nodal with primary tumor desmoplasia uncovers metastatic patterns in multiple endocrine neoplasia 2B.

While primary tumor desmoplasia is a powerful biomarker of node metastases in sporadic medullary thyroid cancer (MTC), information for hereditary MTC is sparse. This proof-of-concept study, comprising 3 consecutive children with multiple endocrine neoplasia 2B, evaluated simultaneously the metastatic behavior of multiple primary thyroid tumors of disparate size and extent of desmoplasia within patients. Altogether, MTC typically involved the ipsilateral central neck before spreading to the ipsilateral lateral and the contralateral neck. Medullary thyroid cancer in the upper thyroid lobe leaped the ipsilateral central neck to invade the ipsilateral lateral neck. Unlike the desmoplasia-positive 6-mm high-grade and 7-mm low-grade primary thyroid tumors, the desmoplasia-negative 8-, 11-, and 16-mm low-grade primary thyroid tumors did not spread to ipsilateral neck nodes. With extranodal growth, the extent of nodal desmoplasia was greater than with intranodal growth. This proof-of-concept study suggests that primary tumor desmoplasia is an equally powerful biomarker of node metastasis in hereditary MTC.

Challenges in the care of patients with RET-altered thyroid cancer: a multicountry mixed-methods study

BackgroundThe discovery of driver oncogenes for thyroid carcinomas and the identification of genomically targeted therapies to inhibit those oncogenes have altered the treatment algorithm in thyroid cancer (TC), while germline testing for RET mutations has become indicated for patients with a family history of RET gene mutations or hereditary medullary TC (MTC). In the context of an increasing number of selective RET inhibitors approved for use, this paper aims to describe challenges and barriers affecting providers’ ability to deliver optimal care for patients with RET-altered TC across the patient healthcare journey.MethodsA mixed-method educational and behavioral needs assessment was conducted in Germany (GER), Japan (JPN), the United Kingdom (UK), and the United States (US) prior to RET-selective inhibitor approval. Participants included medical oncologists (MO), endocrinologists (EN) and clinical pathologists (CP) caring for patients affected with TC. Data collection tools were implemented in three languages (English, German, Japanese). Qualitative data were coded and thematically analyzed in NVivo. Quantitative data were analyzed via frequency and crosstabulations in SPSS. The findings presented here were part of a broader study that also investigated lung cancer challenges and included pulmonologists.ResultsA total of 44 interviews and 378 surveys were completed. Suboptimal knowledge and skills were self-identified among providers, affecting (1) assessment of genetic risk factors (56%, 159/285 of MOs and ENs), (2) selection of appropriate genetic biomarkers (59%, 53/90 of CPs), (3) treatment plan initiation (65%, 173/275 of MOs and ENs), (4) management of side effects associated with multitargeted tyrosine kinase inhibitors (78%, 116/149 of MOs and ENs), and (5) transfer of patients into palliative care services (58%, 160/274 of MOs and ENs). Interviews underscored the presence of systemic barriers affecting the use of RET molecular tests and selective inhibitors, in addition to suboptimal knowledge and skills necessary to manage the safety and efficacy of targeted therapies.ConclusionThis study describes concrete educational needs for providers involved in the care of patients with RET-altered thyroid carcinomas. Findings can be used to inform the design of evidence-based education and performance improvement interventions in the field and support integration into practice of newly approved RET-selective inhibitors.

Temporal trends in referrals of RET gene carriers for neck surgery to a tertiary surgical center in the era of international management guidelines.

Thirty years into the genomic era, this study sought to explore events that helped transform the clinical landscape of hereditary medullary thyroid cancer (MTC). This retrospective analysis of prospectively collected data included all RET carriers referred to a tertiary center for neck surgery that was performed between 1986 and 2021, using descriptive statistics and Poisson regression analysis. Altogether, 496 RET carriers were referred for thyroidectomy (388 carriers) or neck reoperation (108 carriers). Of these, 44 carriers had highest risk mutations (p.Met918Thr), 164 carriers high risk mutations (p.Cys634Arg/Gly/Phe/Ser/Trp/Tyr/insHisGluLeuCys), 116 carriers moderate-high risk mutations (p.Cys609/611/618/620/630Arg/Gly/Phe/Ser/Tyr) and 172 carriers low-moderate risk mutations (p.Glu768Asp, p.Leu790Phe, p.Val804Leu/Met, or p.Ser891Ala). Three event clusters drove referral numbers upward: a string of first reports of causative RET mutations between 1993 and 1998; the international consensus guidelines for diagnosis and therapy of MEN type 1 and type 2 in 2001; and the revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma in 2015. Referrals for neck reoperation declined sluggishly over 30 years, ending in 2018. Index patients continued to be referred into 2021. Referrals for thyroidectomy, grouped in 5-year increments, peaked in 1996-2000 for carriers of highest and high risk mutations, and in 2006-2010 for carriers of moderate-high and low-moderate risk mutations, some 10 years later. International management guidelines are critical in building and increasing the pressure towards screening of sporadic-appearing disease and offspring of known gene families by encompassing the complete disease spectrum early on.

Prospective study on the clinical relevance of 18F-DOPA positron emission tomography/computed tomography in patients with medullary thyroid carcinoma.

18F-DOPA Positron Emission Tomography/Computed Tomography (18F-DOPA PET/CT) is a sensitive functional imaging method (65-75%) for detecting disease localization in medullary thyroid cancer (MTC). We aimed: (i) to assess the clinical usefulness of 18F-DOPA PET/CT in patients with MTC and elevated calcitonin (Ctn) and CEA levels and, (ii) to evaluate changes in disease management secondary to the findings encountered with this methodology. Thirty-six patients with MTC and Ctn levels ≥150 pg/ml were prospectively included. Neck ultrasound, chest contrast-enhanced CT, liver magnetic resonance imaging/abdominal three-phase contrast-enhanced CT and bone scintigraphy were carried out up to 6 months before the 18F DOPA PET/CT. Seventy eight percent of patients were female and 27% had hereditary MTC. Median Ctn level was 1450 pg/ml [150-56620], median CEA level 413 ng/ml [2.9-7436]. Median Ctn DT was 37.5 months [5.7-240]; median CEA DT was 31.8 [4.9-180]. 18F-DOPA PET/CT was positive in 33 patients (91.6%); in 18 (56%) uptake was observed in lymph nodes in the neck or mediastinum, in seven cases (22%) distant metastases were diagnosed, and in eight additional patients (24%) both locoregional and distant sites of disease were found. Ctn and CEA levels were higher in patients with ≥3 foci of distant metastases. In 14 patients (38.8%), findings on 18F-DOPA PET/CT led to changes in management; surgery for locoregional lymph nodes was the most frequent procedure in 8 patients (22%). 18F-DOPA PET/CT was useful for the detection of recurrent disease in MTC, providing incremental value over conventional imaging procedures that led to modification in treatment strategies in nearly 40% of patients.

Exceptionality of Distant Metastasis in Node-Negative Hereditary and Sporadic Medullary Thyroid Cancer: Lessons Learned.

Risk factors of lymph node and distant metastases have rarely been analyzed in hereditary and sporadic medullary thyroid cancer (MTC) using large genetic-clinical data sets. This comprehensive investigation aimed to explore risk factors of lymph node and distant metastases and interdependencies between age at thyroidectomy, primary tumor size, lymph node metastasis, and distant metastasis in patients with hereditary and sporadic MTC. We performed comparative analyses of risk factors of metastasis, stratified by hereditary MTC (4 mutational risk categories) and sporadic MTC. There were 1115 patients with hereditary MTC (307 patients) or sporadic MTC (808 patients). Age at thyroidectomy increased proportionately from 12.2, 22.7, 34.3, and 49.8 years for patients with decreasing mutational risk, compared with 52.1 years for patients with sporadic MTC. Metastatic primary tumors overall were 10.7 to 19.4 mm larger in node-positive patients and 15.9 to 19.3 mm larger in distant metastatic patients at thyroidectomy than nonmetastatic tumors. Distant metastases were noted in 13% to 50% of node-positive vs 0% of node-negative hereditary MTC, and in 23.5% of node-positive vs 1.7% of node-negative sporadic MTC. In multivariable logistic regression analysis for sporadic MTC, lymph node metastasis contributed to distant metastasis (odds ratio 12.4) more than primary tumor size (odds ratios of 7.8, 5.5, and 2.4 for tumors measuring >60, 41-60, and 21-40 mm, respectively). When thyroidectomy is performed before lymph node metastases have developed, distant metastases are exceptional, both in patients with hereditary MTC (irrespective of mutational risk level) and patients with sporadic MTC.

Lymph node metastasis in hereditary medullary thyroid cancer is independent of the underlying RET germline mutation

Although the onset of hereditary medullary thyroid cancer (MTC) depends on mutational risk, the impact of that risk on lymph node metastasis is unclear.Included in this investigation were 387 carriers of RET germline mutations with node-negative MTC (201 carriers) or node-positive MTC (186 carriers).Age at thyroidectomy increased significantly from highest (p.Met918Thr; 45 carriers), high (p.Cys634Arg/Gly/Phe/Ser/Trp/Tyr; 138 carriers) and moderate-high risk (p.Cys609/611/618/620Arg/Gly/Phe/Ser/Trp/Tyr; 93 carriers) to low-moderate risk (p.Glu768Asp, p. Leu790Phe, p. Val804Leu/Met, p. Ser891Ala; 111 carriers).In contrast, tumor progression to lymph node metastasis was similar, taking 8.6–9.1 years with moderate risk mutations and 13.6–14.5 years with high and highest risk mutations. Primary tumor size across the mutational risk spectrum changed little, measuring 18.1–22.1 mm with and 2.7–7.3 mm without lymph node metastasis.Because the biological behavior of hereditary MTC is similar after disease onset, equal treatment of comparable tumors is warranted regardless of the underlying RET mutation.

Clinical utility of genetic diagnosis for sporadic and hereditary medullary thyroid carcinoma

Medullary thyroid cancer (MTC) is a rare thyroid tumor whose prevalence is 3–5% among all thyroid tumors. The pathogenesis of MTC is mainly related to germline or somatic RET activating point mutations that are causative of hereditary and sporadic cases, respectively. Hereditary MTC can occur as multiple endocrine neoplasia type 2A (MEN 2A), type 2B (MEN 2B) and familial MTC (FMTC) that differ for the association with other endocrine neoplasia. Germline RET point mutations are prevalently localized in exons 5, 8, 10–11, 13–16 and a significant genotype-phenotype correlation has been observed. RET genetic screening is mandatory in all patients with a diagnosis of MTC regardless from their apparent sporadic origin. The identification of RET germline mutation in an apparently sporadic case is of great clinical utility because it allows the identification of those subjects who will develop the tumor. RET positive relatives must undergo clinical and biochemical tests to verify if the MTC is already present and, according to the type of RET mutation, they have to be screened for the presence of pheochromocytoma and/or hyperparathyroidism. If a MTC is already present patients must be surgically treated. If MTC is not yet present subjects will be followed up with basal and stimulated calcitonin serum measurement, which is the serum marker of MTC. Indeed, RET negative subjects can be reassured that they do not run any risk to develop the disease as well as their children. In conclusions RET genetic screening allows the identification of the hereditary/sporadic nature of MTC and of a relevant percentage of hidden familial MTC. Furthermore, it favors the early diagnosis of MTC in RET positive subjects. RET positive patients and no clinical evidence of MTC can be followed and surgical treatment can be delayed. Finally RET negative relatives do not need to be further monitored.

Serum calcitonin nadirs to undetectable levels within 1 month of curative surgery in medullary thyroid cancer.

Because serum calcitonin (CT) is a reliable marker of the presence, volume, and extent of disease in medullary thyroid cancer (MTC), both the ATA and NCCN guidelines use the 2-3 month post-operative CT value as the primary response to therapy variable that determines the type and intensity of follow up evaluations. We hypothesized that the calcitonin would nadir to undetectable levels within 1 month of a curative surgical procedure. This retrospective review identified 105 patients with hereditary and sporadic MTC who had at least two serial basal CT measurements done in the first three months after primary surgery. When evaluated one year after initial surgery, 42 patients (42/105, 40%) achieved an undetectable basal calcitonin level without additional therapies and 56 patients (56/84, 67%) demonstrated a CEA within the normal reference range. In patients destined to have an undetectable CT as the best response to initial therapy, the calcitonin was undetectable by 1 month after surgery in 97% (41/42 patients). Similarly, in patients destined to have a normalize their CEA, the CEA was within the reference range by 1 month post-operatively in 63% and by 6 months in 98%. By 6 months after curative initial surgery, 100% of patients had achieved a nadir undetectable calcitonin, 98% had reached the CEA nadir, and 97% had achieved normalization of both the calcitonin and CEA. The 1 month CT value is a reliable marker of response to therapy that allows earlier risk stratification than the currently recommended 2-3 month CT measurement.

Genetic characterization of medullary thyroid cancer in childhood survivors of the Chernobyl accident

BackgroundRadiation-associated fusion oncogenes play a direct role in papillary thyroid cancer development and pathogenic fusions have recently been reported in medullary thyroid cancer. To date, no studies have evaluated oncogenic events in medullary thyroid cancer in a radiation-exposed population. MethodsSomatic and germline alterations, including RET fusions, were evaluated in paired medullary thyroid cancer tumor and normal samples from the Chernobyl Tissue Bank, a heavily screened population affected by the Chernobyl disaster. ResultsTissue was available for 49 individuals. The median age of diagnosis was 26 years (range 9 to 43 years); 16 were radiation-exposed at a median age of 6 (range 2 days to 17 years). A total of 21 patients harbored germline RET mutations (codons 634[13], 918[5], 790[1], 609[1], and 620[1]); 4 had family history. Sporadic medullary thyroid cancer was identified in 27 patients (RET[18], KRAS[1], RET+KRAS[1], TP53[1], wild type [6]), with 1 RET fusion (1/49;2%). The age at operation for patients with hereditary medullary thyroid cancer was not different than sporadic medullary thyroid cancer (23.5 vs 28 years, P = .063). In sporadic medullary thyroid cancer, radiation was not associated with a difference in age at operation, tumor size, or tumor stage (P > .05). ConclusionIn a heavily screened cohort, genetic analysis revealed germline RET mutations in previously unrecognized probands and a remarkable number of sporadic medullary thyroid cancer cases with a young age at presentation.

Genotype-specific progression of hereditary medullary thyroid cancer.

Although already 25 years into the genomic era, age-related progression of hereditary medullary thyroid cancer (MTC), the prevalence of which is estimated at one in 80,000 inhabitants, remains to be delineated for most unique RET (REarranged during Transfection) mutations. Included in this study were 567 RET carriers. The age-related progression of MTC across histopathological groups (normal thyroid/C-cell hyperplasia; node-negative MTC; node-positive MTC) was statistically significant for 13 unique RET mutations (p.Cys611Phe/c.1832G>T; p.Cys611Tyr; p.Cys618Ser/c.1852T>A; p.Cys620Arg; p.Cys634Arg; p.Cys634Phe; p.Cys634Ser; p.Cys634Tyr; p.Glu768Asp; p.Leu790Phe/c.2370G>T; p.Val804Met; p.Ser891Ala; p.Met918Thr), whereas two unique RET mutations (p.Cys618Phe; p.Cys634Gly) trended toward statistical significance. When grouped by mutational risk (highest; high; moderate-high; low-moderate; polymorphism), the age-related progression of MTC was significant for all four categories of RET mutations, which differed significantly across and within the three histopathological groups. For high, for moderate-high, and for low-moderate risk RET mutations, the age-related progression of MTC by mutated codon was broadly comparable across and within the three histopathological groups, and essentially unaffected by the amino acid substitutions examined. These data argue in favor of splitting the American Thyroid Association's moderate-risk category into moderate-high and low-moderate risk categories, while emphasizing the need to contradistinguish the latter from rare nonpathogenic polymorphisms.

Medullary thyroid cancer: strategy, pitfalls and technical aspects with emphasis on remedial surgery

Medullary thyroid cancer (MTC) is a rare neuroendocrine tumor that has specific diagnostic and therapeutic requireents. Currently, imaging tools show great limits to localize all residual MTC foci. Non-invasive imaging is helpful but far from perfect for guiding the re-exploration for loco regional residual MTC. The therapeutic approach is different between sporadic and hereditary MTC. In order to obtain the biochemical and anatomical control the first surgical resection is critical. Calcitonin (Ctn) rate used for MTC recurrence detection as serum marker is definite. Yet it poses a unique challenge notwithstanding its ability in detecting microscopic subclinical disease; it is not clear if patients with evident biological signs of residual MTC should be closely observed when MTC is finally found out through different investigations that localize it, or if a different aggressive approach is necessary including central neck dissection, whether or not associated with ipsilateral or bilateral lateral neck dissection. In all phases of the disease, the co-treatment by physicians with experience in MTC therapy should be sought.

Educational Case: Endocrine Neoplasm: Medullary Thyroid Carcinoma

Medullary thyroid cancer is a rare neuroendocrine tumor that arises the neural crest-derived parafollicular C cells and accounts for approximately 5% to 10% of thyroid cancers worldwide. These tumor can occur sporadically or as part of hereditary tumor syndromes, such as multiple endocrine neoplasia 2 and familial medullary thyroid cancer. The most common clinical presentation is a solitary thyroid nodule. The genetic defect in these disorders involves the RET proto-oncogene which is important for diagnosis of medullary thyroid cancer (including screening for hereditary medullary thyroid cancer) and for treatment guidance. This review summarizes the molecular basis and clinicopathologic features of medullary thyroid carcinoma.

Differences in the transcriptome of medullary thyroid cancer regarding the status and type of RET gene mutations

Medullary thyroid cancer (MTC) can be caused by germline mutations of the RET proto-oncogene or occurs as a sporadic form. It is well known that RET mutations affecting the cysteine-rich region of the protein (MEN2A-like mutations) are correlated with different phenotypes than those in the kinase domain (MEN2B-like mutations). Our aim was to analyse the whole-gene expression profile of MTC with regard to the type of RET gene mutation and the cancer genetic background (hereditary vs sporadic). We studied 86 MTC samples. We demonstrated that there were no distinct differences in the gene expression profiles of hereditary and sporadic MTCs. This suggests a homogeneous nature of MTC. We also noticed that the site of the RET gene mutation slightly influenced the gene expression profile of MTC. We found a significant association between the localization of RET mutations and the expression of three genes: NNAT (suggested to be a tumour suppressor gene), CDC14B (involved in cell cycle control) and NTRK3 (tyrosine receptor kinase that undergoes rearrangement in papillary thyroid cancer). This study suggests that these genes are significantly deregulated in tumours with MEN2A-like and MEN2B-like mutations; however, further investigations are necessary to demonstrate any clinical impact of these findings.

Cirugía profiláctica en cáncer medular de tiroides hereditario

IntroductionApproximately 5-10% of global cancer has a genetic base. Nowadays it is possible to identify those who have a genetic predisposition for some cancers, so they can be treated in short term. ObjectivesEvaluate how useful is prophylactic surgery on hereditary Medullary Thyroid Cancer. Materials and methodsThis investigation is a literature review of different research papers from electronic databases such as Scientific Electronic Library Online (SciELO), MedLine-PubMed and UpToDate. The research was made with clinical queries and MeSH terms, specially focused on hereditary Medullary Thyroid Cancer. ResultsThis research shows that prophylactic Thyroidectomy with cervical lymph node resection is the only effective and curative treatment for hereditary Medullary Thyroid Cancer. ConclusionsProphylactic surgery has proof an important role decreasing the risk on Hereditary Thyroid cancer Syndrome and in RET carriers surgery is considered a must.

Cytotoxic and targeted therapy for hereditary cancers.

There is a number of drugs demonstrating specific activity towards hereditary cancers. For example, tumors in BRCA1/2 mutation carriers usually arise via somatic inactivation of the remaining BRCA allele, which makes them particularly sensitive to platinum-based drugs, PARP inhibitors (PARPi), mitomycin C, liposomal doxorubicin, etc. There are several molecular assays for BRCA-ness, which permit to reveal BRCA-like phenocopies among sporadic tumors and thus extend clinical indications for the use of BRCA-specific therapies. Retrospective data on high-dose chemotherapy deserve consideration given some unexpected instances of cure from metastatic disease among BRCA1/2-mutated patients. Hereditary non-polyposis colorectal cancer (HNPCC) is characterized by high-level microsatellite instability (MSI-H), increased antigenicity and elevated expression of immunosuppressive molecules. Recent clinical trial demonstrated tumor responses in HNPCC patients treated by the immune checkpoint inhibitor pembrolizumab. There are successful clinical trials on the use of novel targeted agents for the treatment or rare cancer syndromes, e.g. RET inhibitors for hereditary medullary thyroid cancer, mTOR inhibitors for tumors arising in patients with tuberous sclerosis (TSC), and SMO inhibitors for basal-cell nevus syndrome. Germ-line mutation tests will be increasingly used in the future for the choice of the optimal therapy, therefore turnaround time for these laboratory procedures needs to be significantly reduced to ensure proper treatment planning.