Clinical and genetic characterization of basal cell carcinoma and breast cancer in a single patient

Multiple environmental and genetic factors are involved with the development of basal cell\ud carcinomas (BCC), as well as with breast cancers. Tumor initiation and progression are often associated with genomic instability such as aneuploidies, and gains or losses of large chromosomal segments, known as copy number alterations (CNAs). CNAs have been successfully detected using the microarray comparative genomic hybridization technique (array-CGH) at high resolution. Data thus obtained are useful to identify specific genomic\ud aberrations, to classify tumor stages, and to stratify subgroups of patients with different prognosis and clinical behaviors. Clinical study of a 66-year-old white female identified two primary tumors, a ductal invasive grade-II carcinoma of the breast, and one nodular BCC. Germline and tumor genomic survey utilized the 180 K array-CGH analysis to investigate chromosomal alterations. Several chromosomal anomalies were detected in the breast tumor genome, including focal ~422 Kb 13q13.3 microdeletion. In the BCC, amplification of a chromosome 6 spanning the centromere region between the cytobands 6p23 and 6q12 was identified. Several 6p amplified genes correspond to families of histone and human leukocyte antigen genes, whereas some of the CNAs found in the breast tumor are uncommon. No germline CNA was detected in the normal skin of the patient at this technical resolution. CNAs found in the two different tumors of the patient constitute independent events arisen in the somatic lineage. Relevant genes to both carcinogenesis and progression are to be affected by these CNAs

Stability of XIST repression in relation to genomic imprinting following global genome demethylation in a human cell line

DNA methylation is essential in X chromosome inactivation and genomic imprinting, maintaining repression of XIST in the active X chromosome and monoallelic repression of imprinted genes. Disruption of the DNA methyltransferase genes DNMT1 and DNMT3B in the HCT116 cell line (DKO cells) leads to global DNA hypomethylation and biallelic expression of the imprinted gene IGF2 but does not lead to reactivation of XIST expression, suggesting that XIST repression is due to a more stable epigenetic mark than imprinting. To test this hypothesis, we induced acute hypomethylation in HCT116 cells by 5-aza-2′-deoxycytidine (5-aza-CdR) treatment (HCT116-5-aza-CdR) and compared that to DKO cells, evaluating DNA methylation by microarray and monitoring the expression of XIST and imprinted genes IGF2, H19, and PEG10. Whereas imprinted genes showed biallelic expression in HCT116-5-aza-CdR and DKO cells, the XIST locus was hypomethylated and weakly expressed only under acute hypomethylation conditions, indicating the importance of XIST repression in the active X to cell survival. Given that DNMT3A is the only active DNMT in DKO cells, it may be responsible for ensuring the repression of XIST in those cells. Taken together, our data suggest that XIST repression is more tightly controlled than genomic imprinting and, at least in part, is due to DNMT3A.FAPESP (#2008/07370-0

Genomic profile of a squamous cell carcinoma ex pleomorphic adenoma compared to a head and neck squamous cell carcinoma

FAPESPUniv Estadual Campinas UNICAMP, Dept Patol, Fac Ciencias Med, Campinas, SP, BrazilUniv Estadual Campinas UNICAMP, Fac Ciencias Med Cirurgia Cabeca & Pescoco, Campinas, SP, BrazilAC Camargo Canc Ctr, Dept Cirurgia Cabeca & Pescoco, Sao Paulo, SP, BrazilUniv Sao Paulo UNIFESP, Inst Biociencias, Dept Genet & Biol Evolucionaria, Sao Paulo, SP, BrazilUniv Sao Paulo UNIFESP, Inst Biociencias, Dept Genet & Biol Evolucionaria, Sao Paulo, SP, BrazilFAPESP: 2011/23204-5FAPESP: 2011/23366-5SciEL

An Inherited Small Microdeletion at 15q13.3 in a Patient\ud with Early- Onset Obsessive-Compulsive Disorder

Copy number variations (CNVs) have been previously associated with several different neurodevelopmental psychiatric\ud disorders, such as autism, schizophrenia, and attention deficit hyperactivity disorder (ADHD). The present study consisted of\ud a pilot genome-wide screen for CNVs in a cohort of 16 patients with early-onset obsessive-compulsive disorder (OCD) and\ud 12 mentally healthy individuals, using array-based comparative genomic hybridization (aCGH) on 44K arrays. A small rare\ud paternal inherited microdeletion (,64 kb) was identified in chromosome 15q13.3 of one male patient with very early onset\ud OCD. The father did not have OCD. The deletion encompassed part of the FMN1 gene, which is involved with the\ud glutamatergic system. This finding supports the hypothesis of a complex network of several genes expressed in the brain\ud contributing for the genetic risk of OCD, and also supports the glutamatergic involvement in OCD, which has been\ud previously reported in the literature.We wish to thank the patients and heathy controls who volunteered to participate in this study.This study was supported by grants to Dras Cappi and Brentani from the Foundation for Research Support of the State of São Paulo (FAPESP); grant number: 2008/11537-7, and from the Brazilian National Council for Scientific and Technological Development (CNPq; protocol number MCT/CNPq 14/2008). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Insights in Osteosarcoma by Proton Nuclear Magnetic Resonance Serum Metabonomics

Pediatric osteosarcoma outcomes have improved over the last decades; however, patients who do not achieve a full resection of the tumor, even after aggressive chemotherapy, have the worst prognosis. At a genetic level, osteosarcoma presents many alterations, but there is scarce information on alterations at metabolomic levels. Therefore, an untargeted nuclear magnetic resonance metabonomic approach was used to reveal blood serum alterations, when samples were taken from 21 patients with osteosarcoma aged from 12–20 (18, 86%) to 43 (3, 14%) years before any anticancer therapy were collected. The results showed that metabolites differed greatly between osteosarcoma and healthy control serum samples, especially in lipids, aromatic amino acids (phenylalanine and tyrosine), and histidine concentrations. Besides, most of the loading plots point to protons of the fatty acyls (-CH3 and -CH2-) from very-low- and low-density lipoproteins and cholesterol, as crucial metabolites for discrimination of the patients with osteosarcoma from the healthy samples. The relevance of blood lipids in osteosarcoma was highlighted when analyzed together with the somatic mutations disclosed in tumor samples from the same cohort of patients, where six genes linked to the cholesterol metabolism were found being altered too. The high consistency of the discrimination between osteosarcoma and healthy control blood serum suggests that nuclear magnetic resonance could be successfully applied for osteosarcoma diagnostic and prognostic purposes, which could ameliorate the clinical efficacy of therapy

Association of melanoma with intraepithelial neoplasia of the pancreas in three patients

Melanoma and pancreatic cancer are two low frequency types of cancer. In this study, three patients who developed both melanoma and intraepithelial neoplasia of the pancreas were tested for CDKN2A mutations and deletions, and investigated for rare germline copy number variations (CNVs). The three patients were negative for CDKN2A point mutations and intragenic deletions. One of these patients carried two large (> 300 kb) germline CNVs, both genomic duplications affecting coding sequences that are not copy number variable in the population. A second patient exhibited loss of the entire Y chromosome, an event probably coincidental related to his advanced age (79 years-old). Our data pinpoint that rare germline CNVs harboring genes can contribute to the cancer predisposition of melanoma and intraepithelial neoplasia of the pancreas.This work was supported by the National Institute of Science and Technology in Oncogenomics (Grant 08/57887-9) and FAPESP (Grants 2012/21932-6 and 2013/07480-8)

Li-Fraumeni-like syndrome associated with a large BRCA1 intragenic deletion

Background: Li-Fraumeni (LFS) and Li-Fraumeni-like (LFL) syndromes are associated to germline TP53 mutations, and are characterized by the development of central nervous system tumors, sarcomas, adrenocortical carcinomas, and other early-onset tumors. Due to the high frequency of breast cancer in LFS/LFL families, these syndromes clinically overlap with hereditary breast cancer (HBC). Germline point mutations in BRCA1, BRCA2, and TP53 genes are associated with high risk of breast cancer. Large rearrangements involving these genes are also implicated in the HBC phenotype. Methods: We have screened DNA copy number changes by MLPA on BRCA1, BRCA2, and TP53 genes in 23 breast cancer patients with a clinical diagnosis consistent with LFS/LFL; most of these families also met the clinical criteria for other HBC syndromes. Results: We found no DNA copy number alterations in the BRCA2 and TP53 genes, but we detected in one patient a 36.4 Kb BRCA1 microdeletion, confirmed and further mapped by array-CGH, encompassing exons 9-19. Breakpoints sequencing analysis suggests that this rearrangement was mediated by flanking Alu sequences. Conclusion: This is the first description of a germline intragenic BRCA1 deletion in a breast cancer patient with a family history consistent with both LFL and HBC syndromes. Our results show that large rearrangements in these known cancer predisposition genes occur, but are not a frequent cause of cancer susceptibility.Brazilian National Institute of Science and Technology in OncogenomicsBrazilian National Institute of Science and Technology in Oncogenomics [FAPESP 2008/57887-9, CNPq 573589/08-9]Fundo de Incentivo a Pesquisa (FIP)Fundo de Incentivo a Pesquisa (FIPE)Hospital de Clinicas de Porto Alegre [04-081, 09-115]Hospital de Clinicas de Porto AlegreFAPERGS (Brazil)FAPERGS, BrazilCAPES [Process: 2317/10-9]CAPE