Compelling evidence broadens our understanding of tumors as highly heterogeneous populations derived from one common progenitor. In this review we portray various stages of tumorigenesis, tumor progression, self-seeding and metastasis in analogy to the superorganisms of insect societies to exemplify the highly complex architecture of a neoplasm as a system of functional "castes."Accordingly, we propose a model in which clonal expansion and cumulative acquisition of genetic alterations produce tumor compartments each equipped with distinct traits and thus distinct functions that cooperate to establish clinically apparent tumors. This functional compartment model also suggests mechanisms for the self-construction of tumor stem cell niches. Thus, thinking of a tumor as a superorganism will provide systemic insight into its functional compartmentalization and may even have clinical implications.
known to cause FMTC and multiple endocrine neoplasia type 2a/b. The clinical significance of other novel missense variants within this hotspot region of exon 14 is not delineated. Case Description: A three-generation pedigree of FMTC is presented with the co-occurrence of two missense variants within exon 14 of the RET gene, the known variant p.Val804Met and the novel variant p.Val826Met. The female index patient developed medullary thyroid cancer at the age of 42 years and was heterozygous for both missense variants.Her younger sister was also tested to be compound hetero-
Key Words
What Is Known about This Topic?• The pathogenic effect of the p.Val804Met missense mutation of the RET proto-oncogene is well described in familial medullary thyroid cancer. In contrast, the clinical significance of the novel missense variant p.Tyr826Ser in exon 14 is unclear and no scientific publications on this genotype have been published so far.
What Does This Case Report Add?• In the absence of functional studies, the plausibility of pathologic significance of a detected endocrine genetic variant can be estimated by in silico methods such as computational analysis of protein structure and biophysical differences or a comparative database search for evolutionary conservation. This family report supports a functional role of p.Tyr826Ser as predisposing RET variant. Patients with a compound heterozygosity of an established pathogenic RET mutation in combination with this novel variant seem to be at a higher risk of developing FMTC. The malignant risk of patients carrying only the heterozygous novel variant p.Tyr826Ser seems to be low with careful clinical surveillance. For individualized and patient-related decision making, our data emphasize the importance of combined clinical and genetic assessment of novel RET variants in patients with familial medullary thyroid cancer and their relatives. zygous for both mutations, and five further relatives were heterozygous for only one of both sequence variants. Prophylactic thyroidectomy was recommended for the two carriers of the RET mutation p.Val804Met, revealing a C-cell hyperplasia for one of them at the age of 19 years. Medical surveillance of 6 heterozygous carriers including repeated neck ultrasound examination as well as basal and calcium (pentagastrin)-stimulated calcitonin levels were recommended. Conclusion: Our data emphasize the importance of an interdisciplinary approach to assess the functional and clinical significance of novel RET variants. In the absence of functional studies, the plausibility of the pathologic significance of a detected endocrine genetic variant can be estimated by in silico methods such as computational analysis of protein structure and biophysical differences or comparative database search for evolutionary conservation.
Zusammenfassung
Hirnfehlbildungen sind ein häufiger Befund bei Mikrozephalien, ihr Nachweis erhöht die Wahrscheinlichkeit einer genetisch bedingten Grunderkrankung. Werden weitere Zusatzsymptome wie Entwicklungsverzögerung oder Epilepsie beobachtet, sollte frühzeitig eine zerebrale Bildgebung möglichst mittels MRT und neuroradiologischer Beurteilung veranlasst werden. Insbesondere Hinweise auf eine Holoprosenzephalie oder neuronale Migrationsstörungen können die Einleitung zielführender genetischer Untersuchungen bahnen. In diesem Artikel sollen für häufigere Formen syndromaler und nicht-syndromaler Mikrozephalien mit wichtigen neuroradiologischen Leitbefunden wie periventrikulären Heterotopien, Lissenzephalie, Double Cortex, Holoprosenzephalie, pontozerebelläre Hypoplasien und Agenesie oder Hypoplasie des Corpus callosum differenzialdiagnostische Überlegungen und diagnostische Algorithmen vorgestellt werden.
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