Banca de DEFESA: Brunna Santana

Uma banca de DEFESA de MESTRADO foi cadastrada pelo programa.
STUDENT : Brunna Santana
DATE: 27/05/2024
TIME: 14:30
LOCAL: Auditório da Pós Graduação da Faculdade de Medicina
TITLE:

Integrative analysis of molecular alterations in SMYD methyltransferase family genes in solid tumors and leukemia.

KEY WORDS:

SMYD family; Carcinogenesis, Solid tumors; Epigenetics; Lysine methyltransferase / Leukemias; Acute lymphocytic leukemia; SMYD family; SMYD5; CRISPRCas9.

PAGES: 102
BIG AREA: Ciências Biológicas
AREA: Biologia Geral
SUMMARY:

: Capitulo 1: The SMYD family, which contains the conserved SET and MYND domains, comprises five members that have a lysine methyltransferase function. A growing number of evidences indicate the involvement of SMYD family genes in different types of cancer. Here, the aim was to investigate the most common genetic alterations of the SMYD family among the most frequent solid tumors and determine their potential use as biomarkers. A multiplatform integrative analysis was performed on the most common mutations, copy number alterations (CNA) and mRNA expression in SMYD family genes. Data from cohorts of invasive breast carcinoma (BRCA), prostate adenocarcinoma (PRAD), colorectal carcinoma (CRC), stomach adenocarcinoma (STAD), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), uterine corpus endometrial carcinoma (UCEC) and uterine carcinosarcoma (UCS) available on The Cancer Genome Atlas (TCGA) and cBioPortal were analyzed. SMYD genes were found to have a lower overall mutation frequency among the tumors examined. Most are missense mutations scattered between their domains. Different mutations were identified in SMYD1 (78), SMYD3 (44), SMYD5 (44), SMYD4 (39) and SMYD2 (33). It is interesting to note that mutations in all SMYD genes were found more frequently in UCECs. Therefore, no mutation was detected frequently in the same cohort and no specific mutation had sufficient stratification power to be used as a biomarker in the cancers examined. With regard to CNA, the low-level gain alteration was the most common among the genes, with the exception of SMYD4, which had heterozygous loss as the most frequent alteration in all the tumors analyzed. With regard to mRNA expression, each member of the SMYD family had a distinct expression pattern. SMYD1 was divided between downregulated expression and basal level, while SMYD2 and SMYD3 had alterations depending on the tumor analyzed, but most tended to upregulation; SMYD4 showed a great tendency to downregulation, suggesting tumor suppressor action; SMYD5 was both upregulated and downregulated, depending on the tumor evaluated. With regard to survival analysis, SMYD3 and SMYD4 in STAD, SMYD3 in BC and SMYD2 and SMYD4 in LUAD showed differences in survival time, depending on the level of expression. Therefore, the results show that SMYD family members have different functions depending on the tumor, and can act as oncogene and tumor suppressor, which makes it even more evident the importance of a better understanding of the involvement of these genes during carcinogenesis. Capitulo 2: Leukemias are a group of malignant diseases that affect blood cells, leading to a high proliferation rate of non-functional white blood cells and inhibiting normal hematopoietic development. They are characterized by the type of cell affected and its stage of maturation and are classified into four main subtypes: chronic myeloid leukaemia (CML), acute myeloid leukaemia (AML), chronic lymphocytic leukaemia (CLL) and acute lymphocytic leukaemia (ALL), the last of which is the subject of this study. ALL is generally characterized by the high proliferation of blasts, with the capacity to invade other regions of the body. It mostly affects children between the ages of 1 and 4. The SMYD family of methyltransferases has so far had few studies correlating them with ALL, but there are studies in the literature showing SMYD2 altered in samples from children with ALL, which is a possible prognostic indicator. SMYD5, on the other hand, was found to be upregulated in these same samples and, as a result of this finding, SMYD5 was chosen as the subject of this study. It was proposed to evaluate the number of altered copies (CNA) and mRNA expression levels of the SMYD family from cohorts obtained through cBioPortal and BloodSpot. In relation to CNA, there were differences in alterations between the SMYD family, with SMYD1 and SMYD5 showing heterozygous loss as the most frequent alteration, while the others showed a low-level gain as the most frequent alteration in ALL. In terms of mRNA expression, SMYD1 and SMYD2 were downregulated while SMYD5 was upregulated in ALL when compared to healthy bone marrow samples. The other members showed no statistically significant difference in expression. Therefore, despite the limited information, the SMYD family has been correlated not only with ALL but also with other blood malignancies. Previous studies have shown that SMYD5 has a function in hematopoiesis and that it was altered in ALL. It has also been reported that SMYD5 forms a repressor complex with NCoR and is responsible for H4K20me3, thus maintaining the repression of pro-inflammatory genes. In the literature, it has been described that its depletion can lead to chromosomal aberrations. Therefore, there is evidence that SMYD5 plays a role in leukemogenesis due to its involvement in the above-mentioned functions. It was then proposed to evaluate the effects caused by SMYD5 more precisely by starting stable models of ALL-B cell lines expressing Cas9, in order to perform a gene knockout using the CRISPR-Cas9 technique.

COMMITTEE MEMBERS:
Interna - 2088007 - CARLA NUNES DE ARAUJO
Presidente - 1643347 - FABIO PITTELLA SILVA
Externo ao Programa - 1912768 - FELIPE SALDANHA DE ARAUJO - nullExterna à Instituição - ROSÂNGELA VIEIRA DE ANDRADE - UCB