Brazilian XP-E siblings carrying a novel DDB2 variant developed early-onset melanoma: a case report.

BACKGROUND: Xeroderma pigmentosum group E (XP-E) is one of the least common forms of XP, a rare syndrome where patients are prone to develop skin cancer in exposed sunlight areas. XP-E patients are generally not diagnosed until they are adults due to the mild phenotype. CASE PRESENTATION: two XP-E siblings, female, 23 years, and male, 25 years, from a Brazilian consanguineous family carrying the novel missense pathogenic variant in DDB2 gene, NM_000107.3:c.1027G > C, associated with skin cancer early-onset and severe phenotype, as nodular melanoma in the cornea and in the ear. CONCLUSION: The assessment of genomic variant pathogenicity was a challenge since this family belongs to an underrepresented population in genomic databases. Given the scarcity of literature documenting XP-E cases and the challenges encountered in achieving an early diagnosis, this report emphasizes the imperative of sun protection measures in XP-E patients. Additionally, it highlights the detrimental impact of the COVID-19 pandemic on cancer diagnosis, leading to the manifestation of a severe phenotype in affected individuals.

XPA deficiency affects the ubiquitin-proteasome system function.

Xeroderma pigmentosum complementation group A (XPA), is defective in xeroderma pigmentosum patients, causing pre-disposition to skin cancer and neurological abnormalities, which is not well understood. Here, we analyzed the XPA-deficient cells transcriptional profile under oxidative stress. The imbalance in of ubiquitin-proteasome system (UPS) gene expression was observed in XPA-deficient cells and the involvement of nuclear factor erythroid 2-related factor-2 (NFE2L2) was indicated. Co-immunoprecipitation assays showed the interaction between XPA, apurinic-apyrimidinic endonuclease 1 (APE1) and NFE2L2 proteins. Decreased NFE2L2 protein expression and proteasome activity was also observed in XPA-deficient cells. The data suggest the involvement of the growth arrest and DNA-damage-inducible beta (GADD45ß) in NFE2L2 functions. Similar results were obtained in xpa-1 (RNAi) Caenorhabditis elegans suggesting the conservation of XPA and NFE2L2 interactions. In conclusion, stress response activation occurs in XPA-deficient cells under oxidative stress; however, these cells fail to activate the UPS cytoprotective response, which may contribute to XPA patient's phenotypes.

Changes in redox and endoplasmic reticulum homeostasis are related to congenital generalized lipodystrophy type 2.

CGL type 2 is a rare autosomal recessive syndrome characterized by an almost complete lack of body fat. CGL is caused by loss-of-function mutations in both alleles of the BSCL2 gene that codifies to seipin. Subjects often show hyperglycemia, decreased HDL-c, and hypoadiponectinemia. These laboratory findings are important triggers for changes in redox and ER homeostasis. Therefore, our aim was to investigate whether these intracellular mechanisms are associated with this syndrome. We collected blood from people from Northeastern Brazil with 0, 1, and 2 mutant alleles for the rs786205071 in the BSCL2 gene. Through the qPCR technique, we evaluated the expression of genes responsible for triggering the antioxidant response, DNA repair, and ER stress in leukocytes. Colorimetric tests were applied to quantify lipid peroxidation and to evaluate the redox status of glutathione, as well as to access the panorama of energy metabolism. Long extension PCR was performed to observe leukocyte mitochondrial DNA lesions, and the immunoblot technique to investigate plasma adiponectin concentrations. Subjects with the rs786205071 in both BSCL2 alleles showed increased transcription of NFE2L2, APEX1, and OGG1 in leukocytes, as well as high concentrations of malondialdehyde and the GSSG:GSH ratio in plasma. We also observed increase of mitochondrial DNA lesions and XBP1 splicing, as well as a decrease in adiponectin and HDL-c. Our data suggest the presence of lipid lesions due to changes in redox homeostasis in that group, associated with increased levels of mitochondrial DNA damage and transcriptional activation of genes involved with antioxidant response and DNA repair.

A portrait of germline mutation in Brazilian at-risk for hereditary breast cancer.

PURPOSE: Knowledge about the germline mutational spectrum among Brazilian with hereditary breast and ovarian cancer (HBOC) is limited. Only five studies have performed comprehensive BRCA sequencing, corresponding to 1041 individuals among a Brazilian population of over 207 million people. Herein we aimed to determine the clinical and molecular characteristics of Brazilian patients who underwent oncogenetic counseling and genetic testing of a panel of high-risk and moderate-risk genes from 2009 to 2017. METHODS: Massively parallel sequencing was applied in 157 individuals (132 breast cancer-affected and 25 breast cancer-unaffected individuals) selected according NCCN criteria for hereditary breast cancer. Analysis of mutation segregation in family members was performed by capillary bidirectional sequencing, clinical response after treament and survival analysis was estimated by Kaplan-Meier. RESULTS: Nineteen germline variants were identified,15 pathogenic and 4 VUS (Variants of Uncertain Significance) in 27 individuals (27/157; 17% P < 0.0001) distributed among 7 genes. Sixty-eight percent of patients (13/19) harbor mutation in BRCA genes and 32% (6/19) in moderate risk genes. This is the first study reporting ATR deleterious germline mutation in association with hereditary breast cancer. Cancer-affected patients with moderate- risk mutation present a more aggressive phenotype, with bilateral cancer (25% vs. 13%, P = 0.0305), high-grade tumors (79.2% vs. 46.3%, P = 0.0001) and triple-negative (50% vs. 22.4%, P < 0.0001). However, no difference in the 5 years overall survival was observed between BRCA and moderate risk groups. CONCLUSIONS: This work highlights the benefits of large-scale sequencing for oncogenetic counseling and extends our understanding about the genetics of hereditary breast cancer in the multi-ethnic Brazilian population.

XPC deficiency is related to APE1 and OGG1 expression and function.

Oxidative DNA damage is considered to be a major cause of neurodegeneration and internal tumors observed in syndromes that result from nucleotide excision repair (NER) deficiencies, such as Xeroderma Pigmentosum (XP) and Cockayne Syndrome (CS). Recent evidence has shown that NER aids in removing oxidized DNA damage and may interact with base excision repair (BER) enzymes. Here, we investigated APE1 and OGG1 expression, localization and activity after oxidative stress in XPC-deficient cells. The endogenous APE1 and OGG1 mRNA levels were lower in XPC-deficient fibroblasts. However, XPC-deficient cells did not show hypersensitivity to oxidative stress compared with NER-proficient cells. To confirm the impact of an XPC deficiency in regulating APE1 and OGG1 expression and activity, we established an XPC-complemented cell line. Although the XPC complementation was only partial and transient, the transfected cells exhibited greater OGG1 expression and activity compared with XPC-deficient cells. However, the APE1 expression and activity did not significantly change. Furthermore, we observed a physical interaction between the XPC and APE1 proteins. Together, the results indicate that the responses of XPC-deficient cells under oxidative stress may not only be associated with NER deficiency per se but may also include new XPC functions in regulating BER proteins.