Hotspot mutation profiles of AKT1 in Asian women with breast and endometrial cancers.

BACKGROUND: The V-Akt murine thymoma viral oncogene (AKT) 1 (E17K) is a subfamily of serine/threonine protein kinases that affects the survival, proliferation, and invasion of cancer cells. The clinicopathological features and frequencies in Asian populations with AKT1 mutations in breast and endometrial cancers are unclear. Hence, we aimed to determine the frequencies and relationships between clinicopathological features and AKT1 mutations in Asian women with cancer. METHODS: We extracted DNA from 311 and 143 samples derived from patients with breast and endometrial cancers to detect the AKT1 point mutation (hotspot), E17K. We examined correlations between clinicopathological features and AKT1 mutation status. RESULTS: The frequency of AKT1 mutations in breast cancer was 7.4%, and they were found more frequently in human epidermal growth factor receptor 2 (HER2)-negative breast cancer subtypes, although this was not statistically significant (P = 0.08). The frequency of AKT1 mutations in endometrial cancer was 4.1%, and the mutations were histologically detected only in endometrioid types. However, AKT1 mutations did not correlate with relapse-free or overall survival of patients with breast or endometrial cancer. CONCLUSIONS: AKT1 mutations are associated with HER2-negative subtype in breast cancer and in endometrial cancer with endometrioid histology. The frequencies of AKT1 mutations in breast and endometrial cancers were similar between Asian and other regional women. The frequency of mutations is too low in both tumor types to talk about predictive significance.

Loss of SMARCB1/INI1 Immunoexpression in Chordoid Meningiomas.

BACKGROUND: Chordoid meningiomas have an aggressive clinical course characterized by frequent recurrences. Recent whole-genome sequencing studies demonstrated Chr22 loss in chordoid meningiomas not accounted for by NF2 mutations. SMARCB1/INI1 is a candidate gene on Chr22, which has not been analyzed extensively in meningiomas. AKT1 mutation has been recently identified to be a driver of meningiomagenesis. MATERIALS AND METHODS: Cases of chordoid meningioma were retrieved along with meningiomas of other subtypes for comparison. INI1 immunohistochemistry was performed. SMARCB1 and AKT1 were analyzed by sequencing. RESULTS: Sixteen chordoid meningiomas were identified (1.1% of all meningiomas). Six cases (37.5%) showed loss of INI1 immunoexpression. All other meningioma subtypes (n = 16) retained INI1 immunoexpression. AKT1 E17K mutation was identified in one case (16.7%). Notably, SMARCB1 mutations were not identified in any of the chordoid meningiomas analyzed, including those showing INI1 loss immunohistochemically. CONCLUSION: This is the first study to demonstrate loss of SMARCB1/INI1 immunoexpression in chordoid meningiomas, adding to the tumors with INI1 loss. However, in absence of INI1 mutation, mechanisms for INI1 loss require further evaluation. Identification of AKT1 mutation opens up new avenues for targeted therapy in patients with such aggressive tumors.

Severe gynaecological involvement in Proteus Syndrome.

Proteus Syndrome is a rare complex overgrowth syndrome. We report a young female patient with Proteus Syndrome due to AKT1 mutation c.49G > A (p.Glu17Lys), presenting with a severe gynaecological involvement which necessitated a complete hysterectomy and a left adnexectomy. Cases of gynecological involvements in Proteus Syndrome are rare, not well known by physicians while they can be potentially severe.

Characterization of the hepatosplenic and portal venous findings in patients with Proteus syndrome.

Proteus syndrome (PS) is a rare disorder caused by a mosaic AKT1 variant that comprises patchy overgrowth of tissues derived from all three germinal layers affecting multiple viscera. We sought to delineate the extent of hepatoportal manifestations in patients with PS. We identified patients with PS who had abdominal imaging from 1989 to 2015 in a natural history study. Imaging was characterized for evidence of focal findings in the liver, spleen, and portal vasculature and for organomegaly. Relevant clinical and laboratory data were compared among those with or without organomegaly. Abdominal imaging was available on 38 patients including 20 who had serial studies. Nine patients had focal hepatic lesions including vascular malformations (VMs). Focal splenic abnormalities were noted in seven patients. Patients without cutaneous VMs did not have visceral VMs. Nine patients had splenomegaly, 12 had portal vein dilation, and 4 had hepatomegaly. There was a weak correlation of portal vein dilation to spleen height ratio (r2 = 0.18, p < .05). On laboratory evaluation, hepatic function was normal but there was thrombocytopenia in those with splenomegaly; platelet counts were 179 ± 87K/µL compared to those with normal spleen size at 253 ± 57K/µL (p < .05). Overall, focal hepatosplenic abnormalities occurred in 11 of 38 (29%) patients with PS. Splenomegaly and portal venous dilation were both found in 8 of 38 (21%) patients; however, other than relative thrombocytopenia, there was no evidence of portal hypertension. Although the AKT1-E17K somatic variant is a suspected oncogene, there were no malignant lesions identified in this study.

Clinical significance of plasma cell-free DNA mutations in PIK3CA, AKT1, and ESR1 gene according to treatment lines in ER-positive breast cancer.

The somatic activation of PI3K/AKT pathway mutations, PIK3CA and AKT1, and ESR1 mutations in plasma cell-free DNA (cfDNA) has been studied as a non-invasive procedure to quickly assess and monitor disease progression or therapeutic effect in breast cancer (BC) patients, but the clinical significance of these mutations in late treatment lines (TLs) remains unclear. The subjects of this study were a total of 251 plasma samples from 128 estrogen receptor-positive (ER+) BC patients. Of these plasma samples, 133 were from 73 primary BC (PBC) patients, and 118 plasma samples were from 68 metastatic BC (MBC) patients. We developed droplet digital PCR (ddPCR) assays to verify the clinical significance of PIK3CA, AKT1, and ESR1 mutations in these patients. cfDNA PIK3CA mutations were observed in 15.1% of the PBC patients, while a cfDNA AKT1 mutation was observed in 1.4% of patients, and cfDNA ESR1 mutations were observed in 2.7% of patients. Patients with detectable cfDNA PIK3CA mutations were not associated with clinical outcomes. According to the TL, the prevalence of the PIK3CA and ESR1 mutations in cfDNA were lower in early TLs compared with late TLs. In the early TL group, patients with cfDNA PIK3CA mutations had a shorter time to treatment failure (TTF) than patients without mutations (P = 0.035). However, there was no statistically significant difference between patients with or without cfDNA ESR1 mutations. However, in the late TL group, patients with cfDNA ESR1 mutations had a shorter TTF than patients without mutations (P = 0.048). However, there was no statistically significant difference between patients with or without cfDNA PIK3CA mutations. Since the prevalence of cfDNA AKT1 mutation is low in both PBC and MBC patients, the impact of AKT1 mutations on the prognosis remains unclear. We have demonstrated the difference in the clinical significance of the hotspot PIK3CA, AKT1, and ESR1 mutations in cfDNA for each TL in ER+ BC patients.

Whole-exome sequencing identifies recurrent AKT1 mutations in sclerosing hemangioma of lung.

Pulmonary sclerosing hemangioma (PSH) is a benign tumor with two cell populations (epithelial and stromal cells), for which genomic profiles remain unknown. We conducted exome sequencing of 44 PSHs and identified recurrent somatic mutations of AKT1 (43.2%) and ß-catenin (4.5%). We used a second subset of 24 PSHs to confirm the high frequency of AKT1 mutations (overall 31/68, 45.6%; p.E17K, 33.8%) and recurrent ß-catenin mutations (overall 3 of 68, 4.4%). Of the PSHs without AKT1 mutations, two exhibited AKT1 copy gain. AKT1 mutations existed in both epithelial and stromal cells. In two separate PSHs from one patient, we observed two different AKT1 mutations, indicating they were not disseminated but independent arising tumors. Because the AKT1 mutations were not found to co-occur with ß-catenin mutations (or any other known driver alterations) in any of the PSHs studied, we speculate that this may be the single-most common driver alteration to develop PSHs. Our study revealed genomic differences between PSHs and lung adenocarcinomas, including a high rate of AKT1 mutation in PSHs. These genomic features of PSH identified in the present study provide clues to understanding the biology of PSH and for differential genomic diagnosis of lung tumors.

A five year-old child with clear cell petro-clival meningioma: case report with clinical and histopathological long-term follow-up.

BACKGROUND: Only a few cases have been previously published about clear cell meningiomas in children, the majority of them in the location of the spine. We describe an unusual case of clear cell meningioma occurring at the petro-clival region in a 5-year-old child. We further seek to determine the impact of several growth factors as well as the AKT1 mutation on the tumor growth pattern. CASE PRESENTATION: A five-year-old girl was presented with a one-week history of cephalgia, ataxia, and left sided torticollis. Magnetic resonance imaging (MRI) revealed a dumbbell-shaped homogeneously petro-clival gadolinium-enhancing mass. A staged operative approach was chosen, and a complete removal of the tumor was achieved. Due to recurrent tumor progression, the child underwent several tumor surgeries and two cranial radiations. None of the treatments were able to stop tumor progression. Consequently, the child died at the age of 14 after further extensive intracranial and extracranial tumor progression. The initial histological examination revealed a clear cell meningioma WHO grade II with an MIB-1 labeling index of <1%, which gradually increased with every recurrence up to 10% by the last progression at the age of 13 years. Analogically, an increasing overexpression of epidermal growth factor receptor (EGFR), the platelet-derived growth factor receptor (PDGFR), and the vascular endothelial growth factor receptor (VEGFR) was observed with each recurrence. The AKT1 (E17K) mutation in the tumor was not detectable in all investigated specimens. CONCLUSION: Pediatric clear cell meningiomas WHO grade II are very rare. Our data demonstrate the progressive overexpression of EGF-, PDGF-, and VEGF-receptors in each recurrence, providing one of these receptors as targeted therapy in such cases. Further evaluation of these growth factors in clear cell meningioma is required to establish the optimal treatment of these aggressive tumors.

Proteus syndrome review: molecular, clinical, and pathologic features.

Proteus syndrome is caused by an activating AKT1 mutation (c.49G>A, p.Glu17Lys). Many variable features are possible in this mosaic disorder, including: (i) disproportionate, asymmetric, and distorting overgrowth; (ii) bone abnormalities different from those observed in other disorders; (iii) a characteristic cerebriform connective tissue nevus made up of highly collagenized connective tissue; (iv) epidermal nevi in early life, consisting of acanthosis and hyperkeratosis; (v) vascular malformations of the capillary, venous, or lymphatic types; (vi) dysregulated adipose tissue including lipomas, lipohypoplasia, fatty overgrowth, and localized fat deposits; (vii) other unusual features, including bullous lung alterations; specific neoplasms; a facial phenotype associated with intellectual disability and/or seizures, and/or brain malformations; and (viii) deep vein thrombosis, resulting in premature death. Concluding remarks address diagnostic criteria, natural history, management, psychosocial issues, and differential diagnosis.