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Giannikou, Krinio

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Giannikou

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Krinio

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Giannikou, Krinio
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    Whole Exome Sequencing Identifies TSC1/TSC2 Biallelic Loss as the Primary and Sufficient Driver Event for Renal Angiomyolipoma Development
    (Public Library of Science, 2016) Giannikou, Krinio; Malinowska, Izabela A.; Pugh, Trevor J.; Yan, Rachel; Tseng, Yuen-Yi; Oh, Coyin; Kim, Jaegil; Tyburczy, Magdalena E.; Chekaluk, Yvonne; Liu, Yang; Alesi, Nicola; Finlay, Geraldine A.; Wu, Chin-Lee; Signoretti, Sabina; Meyerson, Matthew; Getz, Gad; Boehm, Jesse S.; Henske, Elizabeth; Kwiatkowski, David
    Renal angiomyolipoma is a kidney tumor in the perivascular epithelioid (PEComa) family that is common in patients with Tuberous Sclerosis Complex (TSC) and Lymphangioleiomyomatosis (LAM) but occurs rarely sporadically. Though histologically benign, renal angiomyolipoma can cause life-threatening hemorrhage and kidney failure. Both angiomyolipoma and LAM have mutations in TSC2 or TSC1. However, the frequency and contribution of other somatic events in tumor development is unknown. We performed whole exome sequencing in 32 resected tumor samples (n = 30 angiomyolipoma, n = 2 LAM) from 15 subjects, including three with TSC. Two germline and 22 somatic inactivating mutations in TSC2 were identified, and one germline TSC1 mutation. Twenty of 32 (62%) samples showed copy neutral LOH (CN-LOH) in TSC2 or TSC1 with at least 8 different LOH regions, and 30 of 32 (94%) had biallelic loss of either TSC2 or TSC1. Whole exome sequencing identified a median of 4 somatic non-synonymous coding region mutations (other than in TSC2/TSC1), a mutation rate lower than nearly all other cancer types. Three genes with mutations were known cancer associated genes (BAP1, ARHGAP35 and SPEN), but they were mutated in a single sample each, and were missense variants with uncertain functional effects. Analysis of sixteen angiomyolipomas from a TSC subject showed both second hit point mutations and CN-LOH in TSC2, many of which were distinct, indicating that they were of independent clonal origin. However, three tumors had two shared mutations in addition to private somatic mutations, suggesting a branching evolutionary pattern of tumor development following initiating loss of TSC2. Our results indicate that TSC2 and less commonly TSC1 alterations are the primary essential driver event in angiomyolipoma/LAM, whereas other somatic mutations are rare and likely do not contribute to tumor development.
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    Notch transactivates Rheb to maintain the multipotency of TSC-null cells
    (Nature Publishing Group UK, 2017) Cho, Jun-Hung; Patel, Bhaumik; Bonala, Santosh; Manne, Sasikanth; Zhou, Yan; Vadrevu, Surya K.; Patel, Jalpa; Peronaci, Marco; Ghouse, Shanawaz; Henske, Elizabeth; Roegiers, Fabrice; Giannikou, Krinio; Kwiatkowski, David; Mansouri, Hossein; Markiewski, Maciej M.; White, Brandon; Karbowniczek, Magdalena
    Differentiation abnormalities are a hallmark of tuberous sclerosis complex (TSC) manifestations; however, the genesis of these abnormalities remains unclear. Here we report on mechanisms controlling the multi-lineage, early neuronal progenitor and neural stem-like cell characteristics of lymphangioleiomyomatosis (LAM) and angiomyolipoma cells. These mechanisms include the activation of a previously unreported Rheb-Notch-Rheb regulatory loop, in which the cyclic binding of Notch1 to the Notch-responsive elements (NREs) on the Rheb promoter is a key event. This binding induces the transactivation of Rheb. The identified NRE2 and NRE3 on the Rheb promoter are important to Notch-dependent promoter activity. Notch cooperates with Rheb to block cell differentiation via similar mechanisms in mouse models of TSC. Cell-specific loss of Tsc1 within nestin-expressing cells in adult mice leads to the formation of kidney cysts, renal intraepithelial neoplasia, and invasive papillary renal carcinoma.
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    Subependymal giant cell astrocytomas in Tuberous Sclerosis Complex have consistent TSC1/TSC2 biallelic inactivation, and no BRAF mutations
    (Impact Journals LLC, 2017) Bongaarts, Anika; Giannikou, Krinio; Reinten, Roy J.; Anink, Jasper J.; Mills, James D.; Jansen, Floor E.; Spliet, G.M Wim; den Dunnen, Willfred F.A.; Coras, Roland; Blümcke, Ingmar; Paulus, Werner; Scholl, Theresa; Feucht, Martha; Kotulska, Katarzyna; Jozwiak, Sergiusz; Buccoliero, Anna Maria; Caporalini, Chiara; Giordano, Flavio; Genitori, Lorenzo; Söylemezoğlu, Figen; Pimentel, José; Nellist, Mark; Schouten-van Meeteren, Antoinette Y.N.; Nag, Anwesha; Mühlebner, Angelika; Kwiatkowski, David; Aronica, Eleonora
    Subependymal giant cell astrocytomas (SEGAs) are rare, low-grade glioneuronal brain tumors that occur almost exclusively in patients with tuberous sclerosis complex (TSC). Though histologically benign, SEGAs can lead to serious neurological complications, including hydrocephalus, intractable seizures and death. Previous studies in a limited number of SEGAs have provided evidence for a biallelic two-hit inactivation of either TSC1 or TSC2, resulting in constitutive activation of the mechanistic target of rapamycin complex 1 pathway. The activating BRAF V600E mutation is a common genetic alteration in low grade gliomas and glioneuronal tumors, and has been reported in SEGAs as well. In the present study, we assessed the prevalence of the BRAF V600E mutation in a large cohort of TSC related SEGAs (n=58 patients including 56 with clinical TSC) and found no evidence of either BRAF V600E or other mutations in BRAF. To confirm that these SEGAs fit the classic model of two hit TSC1 or TSC2 inactivation, we also performed massively parallel sequencing of these loci. Nineteen (19) of 34 (56%) samples had mutations in TSC2, 10 (29%) had mutations in TSC1, while 5 (15%) had no mutation identified in TSC1/TSC2. The majority of these samples had loss of heterozygosity in the same gene in which the mutation was identified. These results significantly extend previous studies, and in agreement with the Knudson two hit mechanism indicate that biallelic alterations in TSC2 and less commonly, TSC1 are consistently seen in SEGAs.