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Aldosterone-producing adenomas (APAs) are found in 1.5–3.0% of hypertensive patients in primary care and can be cured by surgery. Elucidation of genetic events may improve our understanding of these tumors and ultimately improve patient care. Approximately 40% of APAs harbor a missense mutation in the KCNJ5 gene. More recently, somatic mutations in CACNA1D, ATP1A1 and ATP2B3, also important for membrane potential/intracellular Ca2 + regulation, were observed in APAs. In this study, we analyzed 165 APAs for mutations in selected regions of these genes. We then correlated mutational findings with clinical and molecular phenotype using transcriptome analysis, immunohistochemistry and semiquantitative PCR. Somatic mutations in CACNA1D in 3.0% (one novel mutation), ATP1A1 in 6.1% (six novel mutations) and ATP2B3 in 3.0% (two novel mutations) were detected. All observed mutations were located in previously described hotspot regions. Patients with tumors harboring mutations in CACNA1D, ATP1A1 and ATP2B3 were operated at an older age, were more often male and had tumors that were smaller than those in patients with KCNJ5 mutated tumors. Microarray transcriptome analysis segregated KCNJ5 mutated tumors from ATP1A1/ATP2B3 mutated tumors and those without mutation. We observed significant transcription upregulation of CYP11B2, as well as the previously described glomerulosa-specific gene NPNT, in ATP1A1/ATP2B3 mutated tumors compared to KCNJ5 mutated tumors. In summary, we describe novel somatic mutations in proteins regulating the membrane potential/intracellular Ca2 + levels, and also a distinct mRNA and clinical signature, dependent on genetic alteration.
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The prevalence of thyroid carcinoma is increasing and represents the most common endocrine malignancy, with papillary thyroid carcinoma (PTC) being the most frequent subtype. The genetic alterations identified in PTCs fail to distinguish tumors with different clinical behaviors, such as extra-thyroidal extension and lymph node metastasis. We hypothesize that the immune microenvironment may play a critical role in tumor invasion and metastasis. Computational immunogenomic analysis was performed on 568 PTC samples in The Cancer Genome Atlas using CIBERSORT, TIMER and TIDE deconvolution analytic tools for characterizing immune cell composition. Immune cell infiltrates were correlated with histologic type, mutational type, tumor pathologic T stage and lymph node N stage. Dendritic cells (DCs) are highly associated with more locally advanced tumor T stage (T3/T4, odds ratio (OR) = 2.6, CI = 1.4–4.5, P = 5.4 × 10−4). Increased dendritic cells (OR = 3.4, CI = 1.9–6.3, P = 5.5 × 10−5) and neutrophils (OR = 10.5, CI = 2.7–44, P = 8.7 × 10−4) significantly correlate with lymph node metastasis. In addition, dendritic cells positively correlate with tall cell morphology (OR = 4.5, CI = 1.6–13, P = 4.9 × 10−3) and neutrophils negatively correlate with follicular morphology (OR = 1.3 × 10−3, CI = 5.3 × 10−5–0.031, P = 4.1 × 10−5). TIDE analysis indicates an immune-exclusive phenotype that may be mediated by increased galectin-3 found in PTCs. Thus, characterization of the PTC immune microenvironment using three computational platforms shows that specific immune cells correlate with mutational type, histologic type, local tumor extent and lymph node metastasis. Immunologic evaluation of PTCs may provide a better indication of biologic behavior, resulting in the improved diagnosis and treatment of thyroid cancer.
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Recently, a somatic point mutation of the B-RAF gene (V600E) has been identified as the most common genetic event in papillary thyroid carcinoma (PTC), with a prevalence variable among different series. Since discordant data on the clinico-pathologic features of B-RAF mutated PTC are present in the literature, the aim of the present co-operative study was to establish the prevalence of this genetic alteration and to perform a genotype–phenotype correlation in a large cohort of patients with PTC. To this purpose, a series of 260 sporadic PTCs with different histological variants were included in the study. The mutational analysis of the B-RAF gene was performed either by RT-PCR followed by single-stranded conformational polymorphism or by PCR and direct sequencing. Statistical analyses were obtained by means of χ2/Fisher’s exact test and t-test. Overall, a heterozygous T > A transversion at nucleotide 1799 (V600E) was found in 99 out of 260 PTCs (38%). According to the histological type of the tumor, the B-RAF V600E mutation was present in 48.3% of cases of classic PTCs (85 out of 176), in 17.6% (nine out of 51) of follicular variants of PTCs, in 21.7% (five out of 23) in other PTC variants and in none of the ten poorly differentiated tumors. B-RAF V600E was significantly associated with the classic variant of PTC (P = 0.0001) and with an older age at diagnosis (P = 0.01). No statistically significant correlation was found among the presence of B-RAF V600E and gender, tumor node metastasis (TNM), multicentricity of the tumor, stage at diagnosis and outcome. In conclusion, the present study reports the prevalence of B-RAF V600E (38%) in the largest series of sporadic PTCs, including 260 cases from three different Italian referring centers. This prevalence is similar to that calculated by pooling together all data previously reported, 39.6% (759 out of 1914 cases), thus indicating that the prevalence of this genetic event lies around 38–40%. Furthermore, B-RAF V600E was confirmed to be associated with the papillary growth pattern, but not with poorer differentiated PTC variants. A significant association of B-RAF mutation was also found with an older age at diagnosis, the mutation being very rare in childhood and adolescent PTCs. Finally, no correlation was found with a poorer prognosis and a worse outcome after a median follow-up of 72 months.
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Laboratory of Translational Research, Arcispedale S. Maria Nuova – IRCCS, Department of Pharmacology and Biotechnology (FaBiT), University of Bologna, 40139, Pathology Unit, Department of Oncology, Arcispedale S. Maria Nuova – IRCCS, Department of Medicine (DIMES) – Anatomic Pathology Unit, Bellaria Hospital, University of Bologna, Viale Risorgimento 80, Reggio Emilia, 42123, Italy
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metastases and death among the overall PTC cases, and hence the difficulty in collecting large cohorts of PTCs that developed distant metastases (DM-PTCs), has been an important limitation for studies that attempted to correlate genetic alterations with
Department of Pathology, WRN219, Harvard Medical School, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts, 02114, USA
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known to be present in 27 of these patients while alive. In most patients, lung metastases are detected by chest X-ray ( Besic & Gazic 2013 ). Several genetic alterations are reported in the pathogenesis of ATC, including RAS , BRAF , TP53 , CTNNB1
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-induced colorectal cancer ( Valko et al . 2001 ). One potential consequence of this event may be DNA damage by ROS, resulting in mutagenic genetic alterations that can initiate carcinogenesis and development of cancer. Perhaps such genetic alterations could include
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Division of Endocrinology, University of Texas Medical Branch, Galveston, Texas, USA
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samples from November 2017 to December 2018 (within one year of TSv3 implementation) that on routine molecular testing revealed CNA as the only genetic alteration and had surgical outcomes available. Medical chart review and clinical features After
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Department of Clinical Therapeutics, Alexandra Hospital Athens University School of Medicine, Endocrine Unit, Athens, Greece
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signaling pathways Important information about the genetic alterations in papillary thyroid carcinomas (PTCs) has been obtained from the study of the genetic landscape of a large series of PTCs. This information was published as the ‘Genetic Atlas of
Section of Endocrinology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
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reached). Genetic alterations in pNENs Targeted resequencing of the selected HaloPlex enrichment 20-gene panel (see Materials and methods) resulted in a total of 416,711,794 reads, passing quality filtering, across 38 tumor samples and three normal
Hormonal Biology Laboratory, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
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Department of Endocrinology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
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. Phosphodiesterases (PDE), involved in cAMP degradation, act as negative regulators of this pathway. (B) cAMP/PKA signaling pathway genetic alterations in PPNAD 1: PRKAR1A inactivation (germline mutation + somatic second-hit); 2: phosphodiesterases ( PDE11A or PD8
