Hypoxia-inducible factor 1 alpha expression is an indicator of invasiveness in uterine cervical tumors

Background: Hypoxia is a common feature of cancers. Hypoxia-inducible factor 1A (HIF1A) is a causative agent that changes the transcriptional response of tumors under hypoxia. Some alterations lead to an increase in HIF1A activity and this supports other critical pathways leading to angiogenesis, metabolic adaptation and tumor progression. This retrospective study was designed to evaluate the differences of tissue expressions of HIF1A in a spectrum of cervical neoplasms.Methods: Tissue expression of HIF1A was studied in a total of 107 formalin-fixed, paraffin-embedded uterine cervical tumors specimens and its association with different clinicopathologic parameters was evaluated.Results: In this series, there were 30 low and 29 high grade cervical intraepithelial neoplasms (CINs), 27 squamous cell carcinomas, 15 adenosquamous carcinomas and 6 adenocarcinomas. Strong and diffuse nuclear staining was evaluated as positive HIF1A expression. Positive HIF-1 alpha expression was detected in 7 (25.9%) of squamous cell carcinomas, 1 of adenocarcinomas (16.7%) and only 1 of HGSILs (3.4%). Statistically it was determined that the positivity rate of strong nuclear HIF1A expression was significantly higher in invasive carcinomas when compared with in non-invasive squamous cell carcinomas (p=0.07). Contrary, there was no statistically significant difference according to the subtypes of carcinomas due to scarce number of cases with adenocarcinoma (p=0.188).Conclusions: Our findings were demonstrated to link of nuclear HIF1A expression and the invasive characters of uterine neoplasms. As a result, HIF-1 alpha expression may be important in foreseeing of the invasion and tumor progression.

Una nueva variante del gen COL4A4 (c.1856G> A). De un caso de glomeruloesclerosis focal y segmentaria a una familia con síndrome de Alport / A novel COL4A4 gene variant (c.1856G>A): from a focal segmental glomerulosclerosis case to a family with Alport syndrome

El síndrome de Alport (SA), también conocido como nefritis hereditaria, es una forma progresiva hereditaria de enfermedad glomerular que a menudo se asocia con pérdida auditiva neurosensorial y anomalías oculares. Es causada por mutaciones en los genes que codifican varios miembros de las proteínas de colágeno del tipo IV, que se hallan en las membranas basales principalmente. Los análisis genéticos de las familias afectadas han identificado cuatro modos diferentes de transmisión en pacientes con síndrome de Alport. La forma del síndrome ligada al X surge a partir de mutaciones de COL4A5 y COL4A6 en el cromosoma X, mientras que las formas autosómicas resutan de defectos genéticos tanto en el gen COL4A3 como en el COL4A4, en el cromosoma 2q35-37. Las formas digénicas incluyen pacientes con mutaciones coexistentes en COL4A3, COL4A4 y COL4A5. El resultado clínico a largo plazo en pacientes con SA con mutaciones heterocigotas de COL4A3/A4es generalmente impredecible. La glomeruloesclerosis focal y segmentaria suele desarrollarse en el SA clásico en etapas posteriores y se presenta predominantemente con proteinuria asociada con hematuria. En el caso índice presentado en este informe, a un hombre de 26 años se le realizó una biopsia de riñón debido a una proteinuria nefrótica y una hematuria microscópica acompañada de una función renal alterada. Se le diagnosticó glomeruloesclerosis focal y segmentaria. Debido a que tenía una pérdida auditiva progresiva desde el inicio del estudio, se le realizó un estudio genético de mutaciones en los genes COL4A3 y COL4A4. Se detectó una nueva mutación en el gen COL4A4 (c.1804-7T> C).Debido a que sus padres tenían un matrimonio consanguíneo, el resto de la familia fue sometida a estudio para la misma variante. Sus padres y su hermana fueron heterocigotos y homocigota para la misma variante, respectivamente. En este estudio, se demostró la existencia de una familia con síndrome de Alport con una nueva mutación en el gen COL4A4 (c.1856G> A) que, según sabemos, es el primer caso reportado.

Alport syndrome, also known as hereditary nephritis, is an inherited progressive form of glomerular disease that is often associated with sensorineural hearing loss and ocular abnormalities. It is caused by mutations in genes encoding several members of type IV colagen proteins primarily found in basement membranes. Genetic analyses of affected families have identified four different modes of transmission in patients with Alport syndrome. X-linked form of the syndrome arises from mutations of COL4A5 and COL4A6 on chromosome X, whereas autosomal forms result from genetic defects in either the COL4A3 or COL4A4 genes at chromosome 2q35-37. Digenic forms include patients with coexisting mutations in COL4A3, COL4A4, and COL4A5. The long-term clinical outcome in AS patients with heterozygous COL4A3/A4 mutations is generally unpredictable. Focal segmental glomerulosclerosis usually develops in classical AS at later stages and presents predominantly with proteinuria associated with hematuria. The index case presented in this report, a 26-year-old man, had kidney biopsy because of nephrotic proteinuria and microscopic hematuria accompanied by impaired renal function. He diagnosed focal segmental glomerulosclerosis. As he had progressive hearing loss since chidhood we conducted a genetic study for mutations in COL4A3 and COL4A4 genes. A novel mutation in COL4A4 gene (c.1804-7T>C) was detected. As his parents had consanguineous marriage we investigated the rest of the family for the same variant. His parents, and his sister were found to be heterozygote, and homozygote for the same variant, respectively. In this report we demonstrated an Alport syndrome family with a novel mutation in COL4A4 gene (c.1856G>A) that has been first reported to our best knowledge.

The evaluation of the caveolin‑1 and AT‑rich interactive domain 1 alpha expressions in uterine smooth muscle tumors.

Objectives: This retrospective study was designed to evaluate the importance of tissue expressions of caveolin‑1 (Cav‑1) and AT‑rich interactive domain 1 alpha (ARID‑1A) which are known as signal regulator and tumor suppressor in differential diagnosis of uterine smooth muscle tumors (SMTs). Materials and Methods: Thirty patients recently diagnosed as uterine SMTs at the Tepecik Training and Research Hospital were identified using pathology databases. Immunohistochemical stains for Cav‑1 and ARID‑1A were performed. Results: In this series, there were 10 leiomyosarcomas (LMSs), 10 uterine smooth muscle tumors of uncertain malignant potentials (STUMPs), and 10 leiomyomas (LMs). Cav‑1 expression located cytoplasmic or perivascular area. Cytoplasmic Cav‑1 expression was determined in 5 LMSs and 2 STUMPs while perivascular Cav‑1 expression was determined in 9 LMSs and 2 STUMPs. Statistically, it was determined that if the tumor becomes malignant and more invasive, it gains the perivascular Cav‑1 expression (P = 0.029). On the other hand, the mean nuclear staining rate for ARID‑1A in LMSs (63 ± 23.4%) was higher than both STUMPs (60 ± 18.5%) and LMs (34.5 ± 16.5%). Statistically, it was determined that the expression of ARID‑1A was significantly downregulated in LMs when compared with STUMPs and LMSs (P = 0.004). Conclusions: Our findings were demonstrated that perivascular Cav‑1 expression was seen to be a marker for malignancy of uterine SMTs. Similarly, we found to link of ARID‑1A expression and the aggressiveness of SMTs. Therefore, it may be suggested that Cav‑1 and ARID‑1A may act as predictive biomarkers in uterine SMTs.