Publications by authors named "Natalia Campacci"

13 Publications

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Clinicopathological and molecular characterization of Brazilian families at risk for Lynch syndrome.

Cancer Genet 2021 Jun 14;254-255:82-91. Epub 2021 Feb 14.

Molecular Diagnosis Laboratory, Barretos Cancer Hospital, Barretos, São Paulo, Brazil; Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil; Pele Pequeno Principe Research Institute, Curitiba, Brazil; Faculdades Pequeno Principe, Curitiba, Brazil. Electronic address:

Lynch syndrome (LS), is the most common hereditary colorectal cancer syndrome. However, it is poorly characterized in Brazil. Therefore, we aimed to determine the spectrum of pathogenic variants in Mismatch Repair (MMR) genes and investigate the MLH1 promotor methylation role as a second hit in LS tumors. Tumor screening through microsatellite instability and immunohistochemistry for MMR proteins was performed in 323 cases who met clinical criteria. BRAF-V600E and MLH1 promoter methylation were analyzed for all MLH1-deficient tumors. Patients with MMR deficient tumor proceeded to germline genetic testing. MMR deficient tumors were detected in 41% of patients recruited. About half of patients carried a pathogenic germline variant. Two recurrent variants in MLH1 and three novel pathogenic variants were identified. Furthermore, pathogenic germline variants with concomitant somatic MLH1 hypermethylation were found in 6% of cases. Predictive genetic testing was offered to 387 relatives. Overall, 127 tumors were diagnosed in 100 LS patients, from 62 unrelated families. Our molecular data provide new information about the spectrum of MMR mutations, which contributes to a better characterization of LS in Brazil. Furthermore, we call attention to the possibility of failure in the diagnosis of germline MLH1 mutation carriers when somatic MLH1 hypermethylation is used to rule out LS.
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http://dx.doi.org/10.1016/j.cancergen.2021.02.003DOI Listing
June 2021

Whole-exome sequencing of non-BRCA1/BRCA2 mutation carrier cases at high-risk for hereditary breast/ovarian cancer.

Hum Mutat 2021 Mar 28;42(3):290-299. Epub 2020 Dec 28.

Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil.

The current study aimed to identify new breast and/or ovarian cancer predisposition genes. For that, whole-exome sequencing (WES) was performed in the germline DNA of 52 non-BRCA1/BRCA2/TP53 mutation carrier women at high-risk for hereditary breast and ovarian cancer (HBOC). All variants were classified using information from population and disease specific databases, in silico prediction tools and the American College of Medical Genetics and Genomics (ACMG) criteria. Loss of heterozygosity (LOH) of tumor samples and segregation analyses were performed whenever possible. The variants identified were investigated in a second, independent cohort of 17 BC cases. Pathogenic/Likely Pathogenic variants were identified in known cancer genes such as CHEK2, MUTYH, PMS2, and RAD51C. Rare and potentially pathogenic variants were identified in DNA repair genes (FAN1, POLQ, and RAD54L) and other cancer-related genes such as DROSHA and SLC34A2. Interestingly, the variant c.149T>G in the FAN1 gene was identified in two unrelated families, and exhibited LOH in the tumor tissue of one of them. In conclusion, this is the largest Brazilian WES study involving families at high-risk for HBOC which has brought novel insights into the role of potentially new genetic risk factors for hereditary breast and ovarian cancer.
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http://dx.doi.org/10.1002/humu.24158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898723PMC
March 2021

Using Co-segregation and Loss of Heterozygosity Analysis to Define the Pathogenicity of Unclassified Variants in Hereditary Breast Cancer Patients.

Front Oncol 2020 2;10:571330. Epub 2020 Oct 2.

Molecular Oncology Research Center, Barretos Cancer Hospital, São Paulo, Brazil.

The use of gene panels introduces a new dilemma in the genetics field due to the high frequency of variants of uncertain significance (VUS). The objective of this study was to provide evidence that may help in the classification of these germline variants in terms of their clinical impact and association with the disease in question. A total of 52 unrelated women at-risk for HBOC and negative for pathogenic variants were evaluated through a gene panel comprising 14 breast and/or ovarian cancer susceptibility genes. Of the 453 germline variants identified, 15 variants (classes 3, 4, and 5) in the , and genes were evaluated via databases, co-segregation studies and loss of heterozygosity in the tumor. The co-segregation analysis allowed the establishment of an association with the presence of variants and the risk of cancer for variant c.316C>T in the gene. Four variants of uncertain significance showed loss of heterozygosity in the tumor ( c.4709T>C; c.1036C>T; c.1001A>G, and c.281T>C), which is an indication of pathogenicity. Thus, the present study provides novel evidence that favors the association of variants in moderate-risk genes with the development of hereditary breast cancer.
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http://dx.doi.org/10.3389/fonc.2020.571330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566163PMC
October 2020

Cancer-related worry and risk perception in Brazilian individuals seeking genetic counseling for hereditary breast cancer.

Genet Mol Biol 2020 22;43(2):e20190097. Epub 2020 Apr 22.

Universidade Federal do Rio Grande do Sul, Departamento de Genética, Porto Alegre, RS, Brazil.

In Brazil, the population in general has little knowledge about genetic risks, as well as regarding the role and importance of the Cancer Genetic Counseling (CGC). The goal of this study was to evaluate cancer-related worry and cancer risk perception during CGC sessions in Brazilian women at-risk for hereditary breast cancer. This study was performed in 264 individuals seeking CGC for hereditary breast cancer. Both cancer-affected and unaffected individuals were included. As results, individuals with and without cancer reported different motivations for seeking CGC and undergoing genetic testing. A correlation was observed between age at the first CGC session and age at which the closest relative was diagnosed with cancer. Multivariate analysis showed that educational level, cancer risk discussion within the family, and number of deaths by cancer among first-degree relatives influenced positively the cancer risk perception. In conclusion, the results of this study indicate that cancer-related worry and cancer risk perception are significant aspects of morbidity in individuals seeking CGC, whether they are cancer-affected or unaffected. CGC has an important role in health education and cancer prevention for its potential of promoting an accurate perception of the risk.
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http://dx.doi.org/10.1590/1678-4685-GMB-2019-0097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210979PMC
April 2020

Genetic cancer risk assessment: A screenshot of the psychosocial profile of women at risk for hereditary breast and ovarian cancer syndrome.

Psychooncology 2020 04 6;29(4):681-687. Epub 2020 Feb 6.

Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil.

Objective: There is a lack of information describing Brazilian women at risk of hereditary breast and ovarian cancer syndrome (HBOC) who undergo genetic cancer risk assessment (GCRA). This study aims to characterize the psychosocial profile of women at risk for HBOC at their first GCRA to obtain an overview of their families' profiles and the challenges of the oncogenetics setting.

Methods: This was a cross-sectional study in which interviews were conducted with 83 cancer-affected women at their first GRCA appointment after the pedigree draw. Tools to evaluate psychological outcomes were applied. The pedigree genogram and ecomap were constructed and analyzed with content analysis using the "life course perspective" theory.

Results: Individuals perceived their breast/ovarian cancer risk to be equal to that of the general population, although they were highly concerned about developing cancer. No evidence of anxiety or depressive symptoms was identified. Participants used the coping strategy of searching for religiosity. The genograms and ecomaps resulted in five major themes: support and social support; attitudes, feelings and emotions; cancer causes; communication; and relationships with relatives. Individuals between 20-29 years of age and those with no family history of cancer tended not to communicate with relatives, which may indicate future problems in the GCRA process regarding genetic testing.

Conclusions: This study demonstrated that knowing the families who undergo the GCRA process can help professionals provide more individualized and thorough attention during GCRA and genetic testing, which results in better follow-up and prevention strategies.
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http://dx.doi.org/10.1002/pon.5305DOI Listing
April 2020

The Brazilian TP53 mutation (R337H) and sarcomas.

PLoS One 2020 24;15(1):e0227260. Epub 2020 Jan 24.

Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil.

Sarcomas represent less than 1% of all solid neoplasms in adults and over 20% in children. Their etiology is unclear, but genetic susceptibility plays an important role in this scenario. Sarcoma is central in Li-Fraumeni Syndrome (LFS), a familial predisposition cancer syndrome. In Brazil, the high prevalence of p.Arg337His mutations in the TP53 gene brings about a unique condition: a cluster of LFS. In the present work, we studied 502 sarcoma patients not selected by age or family history in an attempt to assess the impact of the so-called "Brazilian germline TP53 mutation" (p.Arg337His) on this tumor type. We found that 8% of patients are carriers, with leiomyosarcoma being the main histologic type of sarcoma, corresponding to 52.5% of the patients with the mutated TP53 gene. These findings emphasize the importance of genetic counseling and can better guide the management of sarcoma patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227260PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980636PMC
May 2020

Genetic alterations detected by comparative genomic hybridization in BRCAX breast and ovarian cancers of Brazilian population.

Oncotarget 2018 Jun 8;9(44):27525-27534. Epub 2018 Jun 8.

Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP, Brazil.

Background: About 5-10% of breast/ovarian cancers are hereditary. However, for a large proportion of cases (around 50%), the genetic cause remains unknown. These cases are grouped in a separated BRCAX category. The aim of this study was to identify genomic alterations in wild-type tumor samples from women with family history strongly suggestive of hereditary breast/ovarian cancer.

Results: A cohort of 31 Brazilian women was included in the study. Using the GISTIC algorithm, we identified 20 regions with genomic gains and 31 with losses. The most frequent altered regions were 1q21.2, 6p22.1 and 8p23.3 in breast tumors and Xq26 and Xp22.32-22.31 among the ovarian cancer cases. An interesting association identified was the loss of 22q13.31-13.32 and the presence of ovarian cancer cases. Among the genes present in the frequently altered regions, we found , , , , , , and several genes of and family.

Conclusions: In conclusion, our results suggest that alterations on chromosomes 1, 6, 8 and X are common on BRCAX tumors and that the loss on 22q can be associated with the presence of ovarian cancer.

Methods: DNA copy number alterations were analyzed by 60K array comparative genomic hybridization in breast and ovarian FFPE tumors.
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http://dx.doi.org/10.18632/oncotarget.25537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6007956PMC
June 2018

The germline mutational landscape of BRCA1 and BRCA2 in Brazil.

Sci Rep 2018 06 15;8(1):9188. Epub 2018 Jun 15.

Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.

The detection of germline mutations in BRCA1 and BRCA2 is essential to the formulation of clinical management strategies, and in Brazil, there is limited access to these services, mainly due to the costs/availability of genetic testing. Aiming at the identification of recurrent mutations that could be included in a low-cost mutation panel, used as a first screening approach, we compiled the testing reports of 649 probands with pathogenic/likely pathogenic variants referred to 28 public and private health care centers distributed across 11 Brazilian States. Overall, 126 and 103 distinct mutations were identified in BRCA1 and BRCA2, respectively. Twenty-six novel variants were reported from both genes, and BRCA2 showed higher mutational heterogeneity. Some recurrent mutations were reported exclusively in certain geographic regions, suggesting a founder effect. Our findings confirm that there is significant molecular heterogeneity in these genes among Brazilian carriers, while also suggesting that this heterogeneity precludes the use of screening protocols that include recurrent mutation testing only. This is the first study to show that profiles of recurrent mutations may be unique to different Brazilian regions. These data should be explored in larger regional cohorts to determine if screening with a panel of recurrent mutations would be effective.
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http://dx.doi.org/10.1038/s41598-018-27315-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6003960PMC
June 2018

Identification of hereditary cancer in the general population: development and validation of a screening questionnaire for obtaining the family history of cancer.

Cancer Med 2017 Dec 21;6(12):3014-3024. Epub 2017 Oct 21.

Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil.

One of the challenges for Latin American countries is to include in their healthcare systems technologies that can be applied to hereditary cancer detection and management. The aim of the study is to create and validate a questionnaire to identify individuals with possible risk for hereditary cancer predisposition syndromes (HCPS), using different strategies in a Cancer Prevention Service in Brazil. The primary screening questionnaire (PSQ) was developed to identify families at-risk for HCPS. The PSQ was validated using discrimination measures, and the reproducibility was estimated through kappa coefficient. Patients with at least one affirmative answer had the pedigree drawn using three alternative interview approaches: in-person, by telephone, or letter. Validation of these approaches was done. Kappa and intraclass correlation coefficients were used to analyze data's reproducibility considering the presence of clinical criteria for HCPS. The PSQ was applied to a convenience sample of 20,000 women of which 3121 (15.6%) answered at least one affirmative question and 1938 had their pedigrees drawn. The PSQ showed sensitivity and specificity scores of 94.4% and 75%, respectively, and a kappa of 0.64. The strategies for pedigree drawing had reproducibility coefficients of 0.976 and 0.850 for the telephone and letter approaches, respectively. Pedigree analysis allowed us to identify 465 individuals (24.0%) fulfilling at least one clinical criterion for HCPS. The PSQ fulfills its function, allowing the identification of HCPS at-risk families. The use of alternative screening methods may reduce the number of excluded at-risk individuals/families who live in locations where oncogenetic services are not established.
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http://dx.doi.org/10.1002/cam4.1210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727305PMC
December 2017

Genetic and epigenetic characterization of the BRCA1 gene in Brazilian women at-risk for hereditary breast cancer.

Oncotarget 2017 Jan;8(2):2850-2862

Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP, Brazil.

This study aimed to characterize women at-risk for hereditary BC regarding their clinical and molecular characteristics (mutation and methylation in the BRCA1 gene) and correlate the gene expression levels with histopathological, clinical and family history information. BRCA1 real time qPCR was performed to evaluate methylation status and gene expression. The study included 88 women grouped according to the BRCA1 mutational status: 23 BRCA1 mutated, 22 with a Variant of Unknown Significance (VUS) in BRCA1 and 43 BRCA1 WT. Most BRCA1 mutated tumors were triple negative (69.6%) and had histologic grade III (61.0%). Patients with VUS/WT BRCA1 were predominantly of luminal B subtype with histological grades I and II. Regarding the methylation profile, BRCA1 hypermethylation was observed in only two patients (both WT) and none had association with pathogenic BRCA1 mutation. In one patient methylation was present in both, tumor and normal tissues. Hypermethylated tumors had ductal histology, negativity for ER and occurred in < 50 years patients. Gene expression profile showed in all groups lower BRCA1 mRNA levels in tumor tissue compared to the adjacent breast tissue, thereby indicating the loss/decrease of gene function. No association was found between the levels of BRCA1 gene expression and family history of cancer. In summary, our findings suggested that methylation at the BRCA1 gene is not the "second" event in the development of BC in patients with germline mutations in BRCA1 and, although rare, BRCA1 epimutations can constitute an explanation for a fraction of HBOC families.
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http://dx.doi.org/10.18632/oncotarget.13750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356847PMC
January 2017

The significance of augmented high-grade squamous intraepithelial lesion detection on pap test examination: partial results from the RODEO study team.

Acta Cytol 2013 7;57(5):489-94. Epub 2013 Sep 7.

Barretos Cancer Hospital, Pio XII Foundation, Barretos, Brazil.

Objective: This study sought to ascertain the significance of augmented high-grade squamous intraepithelial lesion (HSIL) detection by Pap test using both conventional smear and liquid-based cytology (LBC) in a high-risk population.

Study Design: We conducted a direct-to-vial study to compare the diagnostic performance of Pap smear versus LBC in a high-risk population of women referred for colposcopy at a gynecologic ambulatory clinic at the Barretos Cancer Hospital in Brazil during 2011.

Results: The detection of both low-grade squamous intraepithelial lesions (LSILs) and HSILs was significantly greater (p = 0.04 and p = 0.033, respectively) in the LBC arm [84 LSIL cases (5.7%) and 148 HSIL cases (10.1%)] than in the conventional smear arm [66 LSIL cases (4.1%) and 126 HSIL cases (7.9%)]; however, no differences were found for invasive squamous carcinoma or adenocarcinoma (p = 0.678). Of 3,071 women who were examined cytologically (1,604 conventional preparations and 1,467 LBC) and colposcopically, biopsies were available for 279 conventional preparations (17.6%) and 325 LBC preparations (22.2%). No significant differences were found between the methods with respect to diagnostic performance.

Conclusion: LBC was significantly superior to conventional smears for the detection of LSILs and HSILs, but these results did not influence biopsy confirmation. Both methods showed similar performances with high positive predictive values but very low sensitivities.
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http://dx.doi.org/10.1159/000351789DOI Listing
December 2013

Performance and reproducibility of gynecologic cytology interpretation using the FocalPoint system: results of the RODEO Study Team.

Am J Clin Pathol 2013 Oct;140(4):567-71

Laboratory of Medical Investigation (LIM) 14, Faculty of Medicine, University of São Paulo, 1246-903 São Paulo, Brazil; e-mail:

Objectives: To assess whether automated screening in the cytologic examination of Papanicolaou smear slides results in smaller margins of error than manual screening.

Methods: We compared cytotechnologists' performance and reproducibility of manual and automated screening of 10,165 consecutive cervical cytology slides examined at Barretos Cancer Hospital using the FocalPoint system.

Results: In total, 83% of atypical squamous cells of undetermined significance and greater were classified as quintiles 1 and 2; no high-grade squamous intraepithelial lesions and greater were observed in quintile 5. No statistically significant differences were found between manual and automated screening, using cervical biopsy specimens as the gold standard.

Conclusions: FocalPoint safely screened high-grade lesions, which can be valuable for high-workload routines.
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http://dx.doi.org/10.1309/AJCPWL36JXMRESFHDOI Listing
October 2013

Could alarmingly high rates of negative diagnoses in remote rural areas be minimized with liquid-based cytology? Preliminary results from the RODEO Study Team.

Acta Cytol 2013 6;57(1):69-74. Epub 2012 Dec 6.

Barretos Cancer Hospital, Pio XII Foundation, Barretos, Brazil.

Objective: It was the aim of this study to compare diagnostic performances of the BD SurePath™ liquid-based Papanicolaou test (LBC) and the conventional Papanicolaou test (CPT) in cervical samples of women from remote rural areas of Brazil.

Study Design: Specimens were collected by mobile units provided by Barretos Cancer Hospital. This report evaluates the manual screening arm of the RODEO study. Of 12,048 women seen between May and December 2010, 6,001 were examined using LBC and 6,047 using CPT.

Results: Comparative (LBC vs. CPT) outcomes were: all abnormal tests, 2.1 versus 1.0%; ASC-US (atypical squamous cells of unknown significance), 0.7 versus 0.1%; ASC-H (atypical squamous cells with possible high-grade squamous intraepithelial lesions) and AGC (atypical glandular cells), 0.4 versus 0.3%; LSIL (low-grade squamous intraepithelial lesions), 0.7 versus 0.3%; HSIL (high-grade squamous intraepithelial lesions), 0.4 versus 0.2%, and unsatisfactory, 0.03 versus 0.08%. The LBC arm detected significantly more lesions (ASC-US+) than CPT (p < 0.001); however, when we divided the diagnoses into two groups, ASC-H- (negative/ASC-US/LSIL) and ASC-H+ (ASC-H/AGC/HSIL), the difference was not statistically important (p = 0.213).

Conclusions: With inherent difficulties in patient recruitment and patient compliance with cancer screening, best test performance including human papillomavirus test capability are vitally necessary in Brazil's struggle to reduce cervical cancer.
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http://dx.doi.org/10.1159/000343046DOI Listing
March 2013