Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 87
Filtrar
1.
Nat Commun ; 11(1): 6383, 2020 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-33318493

RESUMO

Polygenic risk scores (PRS) for breast cancer have potential to improve risk prediction, but there is limited information on their utility in various clinical situations. Here we show that among 122,978 women in the FinnGen study with 8401 breast cancer cases, the PRS modifies the breast cancer risk of two high-impact frameshift risk variants. Similarly, we show that after the breast cancer diagnosis, individuals with elevated PRS have an elevated risk of developing contralateral breast cancer, and that the PRS can considerably improve risk assessment among their female first-degree relatives. In more detail, women with the c.1592delT variant in PALB2 (242-fold enrichment in Finland, 336 carriers) and an average PRS (10-90th percentile) have a lifetime risk of breast cancer at 55% (95% CI 49-61%), which increases to 84% (71-97%) with a high PRS ( > 90th percentile), and decreases to 49% (30-68%) with a low PRS ( < 10th percentile). Similarly, for c.1100delC in CHEK2 (3.7-fold enrichment; 1648 carriers), the respective lifetime risks are 29% (27-32%), 59% (52-66%), and 9% (5-14%). The PRS also refines the risk assessment of women with first-degree relatives diagnosed with breast cancer, particularly among women with positive family history of early-onset breast cancer. Here we demonstrate the opportunities for a comprehensive way of assessing genetic risk in the general population, in breast cancer patients, and in unaffected family members.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Herança Multifatorial , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Quinase do Ponto de Checagem 2/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Feminino , Finlândia , Genótipo , Mapeamento Geográfico , Heterozigoto , Humanos , Pessoa de Meia-Idade , Mutação , Medição de Risco , Fatores de Risco , Adulto Jovem
2.
PLoS One ; 15(9): e0239686, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32997692

RESUMO

INTRODUCTION: A significant proportion of patients with metastatic castration-resistant prostate cancer (mCRPC) harbor mutations in homologous recombination (HR) repair genes, with some of these mutations associating with increased tumor susceptibility to poly(ADP-ribose) polymerase (PARP) inhibitors and platinum-based chemotherapy. While mutations in some HR repair genes (e.g., BRCA1/2) have been associated with a more aggressive clinical course, prior studies correlating HR mutational status with treatment response to androgen receptor (AR) signaling inhibitors (ARSIs) or taxane-based chemotherapy have yielded conflicting results. METHODS: We conducted a single-center retrospective analysis to assess clinical outcomes to conventional, regulatory-approved therapies in mCRPC patients with somatic (monoallelic and biallelic) and/or germline HR repair mutations compared to patients without alterations as determined by clinical-grade next-generation sequencing assays. The primary endpoint was PSA30/PSA50 response, defined as ≥30%/≥50% prostate-specific antigen (PSA) reduction from baseline. Secondary endpoints of PSA progression-free survival (pPFS) and clinical/radiographic progression-free survival (crPFS) were estimated using Kaplan-Meier methods. RESULTS: A total of 90 consecutively selected patients were included in this analysis, of which 33 (37%) were identified to have HR repair gene mutations. Age, race, Gleason score, prior surgery, and receipt of prior radiation therapy were comparable between carriers and non-carriers. There was no evidence that PSA30/PSA50 differed by HR gene mutational status. Median pPFS and crPFS ranged 3-14 months across treatment modalities, but there was no evidence either differed by HR gene mutational status (all p>0.05). There was also no difference in outcomes between those with BRCA2 or PALB2 mutations (n = 17) compared to those without HR repair mutations. CONCLUSION: HR gene mutational status was associated with comparable clinical outcomes following treatment with ARSIs or taxane-based chemotherapy. Additional prospective studies are needed to confirm these findings.


Assuntos
Mutação , Neoplasias de Próstata Resistentes à Castração/genética , Reparo de DNA por Recombinação/genética , Idoso , Antineoplásicos/uso terapêutico , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteína BRCA2/genética , Quinases Ciclina-Dependentes/genética , Resistencia a Medicamentos Antineoplásicos , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Humanos , Proteína Homóloga a MRE11/genética , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Intervalo Livre de Progressão , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Inibidores da Síntese de Esteroides/uso terapêutico
3.
Breast Cancer Res Treat ; 181(2): 465-473, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32318955

RESUMO

PURPOSE: Limited studies have been conducted to evaluate pathogenetic mutations in breast cancer predisposition genes among Chinese women. To fully characterize germline mutations of these genes in this population, we used the whole-exome sequencing data in a population-based case-control study conducted in Shanghai, China. METHODS: We evaluated exonic, splicing, and copy number variants in 11 established and 14 candidate breast cancer predisposition genes in 831 invasive breast cancer cases and 839 controls. We identified 55 pathogenic variants, including 15 newly identified in this study. RESULTS: Approximately 8% of the cases and 0.6% of the cancer-free controls carried these pathogenetic variants (P = 3.05 × 10-15). Among cases, 3.7% had a BRCA2 pathogenic variant and 1.6% had a BRCA1 pathogenic variant, while 2.5% had a pathogenic variant in other genes including ATM, CHEK2, NBN, NF1, CDH1, PALB2, PTEN, TP53 as well as BARD1, BRIP, and RAD51D. Patients with BRCA1/2 pathogenic variants were more likely to have a family history of breast cancer and hormone receptor negative tumors compared with patients without pathogenic variants. CONCLUSIONS: This study highlighted the importance of hereditary breast cancer genes in the breast cancer etiology in this understudied population. Together with previous studies in East Asian women, this study suggested a relatively more prominent role of BRCA2 compared to BRCA1. This study also provides additional evidence to design cost-efficient genetic testing among Chinese women for risk assessment and early detection of breast cancer.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Adulto , Idoso , Neoplasias da Mama/genética , Estudos de Casos e Controles , Quinase do Ponto de Checagem 2/genética , China/epidemiologia , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Feminino , Seguimentos , Testes Genéticos , Humanos , Pessoa de Meia-Idade , Prognóstico , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo
4.
Gynecol Oncol ; 157(2): 514-520, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32199636

RESUMO

OBJECTIVES: Risk-reducing salpingo-oophorectomy (RRSO) is recommended for women at increased risk of ovarian, fallopian tube (FT), and peritoneal carcinoma (collectively OC). We describe rates of occult neoplasia in the largest single-institution prospective cohort of women undergoing RRSO, including those with mutations in non-BRCA homologous repair (HRR) genes. METHODS: Participants undergoing RRSO enrolled in a prospective tissue bank between 1999 and 2017. Ovaries and FTs were serially sectioned in all cases. Participants had OC susceptibility gene mutations or a family history suggesting OC risk. Analyses were completed in Stata IC 15.1. RESULTS: Of 644 women, 194 (30.1%) had mutations in BRCA1, 177 (27.5%) BRCA2, 27 (4.2%) other HRR genes, and 15 (2.3%) Lynch Syndrome-associated genes. Seventeen (2.6%) had occult neoplasms at RRSO, 15/17 (88.2%) in the FT. Of BRCA1 carriers, 14/194 (7.2%) had occult neoplasia, 8/194 (4.1%) invasive. One PALB2 and two BRCA2 carriers had intraepithelial FT neoplasms. Occult neoplasm occurred more frequently in BRCA1/2 carriers ≥45 years of age (6.5% vs 2.2%, chi square, p = .04), and 211/371 (56.9%) BRCA1/2 carriers had surgery after guideline-recommended ages. Four in 8 (50%) invasive and 2/9 (22%) intraepithelial neoplasms had positive pelvic washings. None with intraepithelial neoplasms developed recurrence or peritoneal carcinoma. CONCLUSIONS: BRCA1 carriers have the highest risk of occult neoplasia at RRSO, and the frequency increased with age. Women with BRCA1/2 mutations often have RRSO beyond recommended ages. One PALB2 carrier had FT intraepithelial neoplasia, a novel finding. Serial sectioning is critical to identifying occult neoplasia and should be performed for all risk-reducing surgeries.


Assuntos
Neoplasias das Tubas Uterinas/prevenção & controle , Tubas Uterinas/cirurgia , Neoplasias Ovarianas/prevenção & controle , Ovário/cirurgia , Adulto , Idoso , Proteína BRCA2/genética , Estudos de Coortes , Neoplasias das Tubas Uterinas/genética , Neoplasias das Tubas Uterinas/patologia , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Feminino , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Mutação , Neoplasias Primárias Desconhecidas/diagnóstico , Neoplasias Primárias Desconhecidas/patologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Linhagem , Estudos Prospectivos , Salpingo-Ooforectomia , Ubiquitina-Proteína Ligases/genética
5.
Nat Commun ; 11(1): 819, 2020 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-32041954

RESUMO

Loss of functional BRCA1 protein leads to defects in DNA double-strand break (DSB) repair by homologous recombination (HR) and renders cells hypersensitive to poly (ADP-ribose) polymerase (PARP) inhibitors used to treat BRCA1/2-deficient cancers. However, upon chronic treatment of BRCA1-mutant cells with PARP inhibitors, resistant clones can arise via several mechanisms, including loss of 53BP1 or its downstream co-factors. Defects in the 53BP1 axis partially restore the ability of a BRCA1-deficient cell to form RAD51 filaments at resected DSBs in a PALB2- and BRCA2-dependent manner, and thereby repair DSBs by HR. Here we show that depleting 53BP1 in BRCA1-null cells restores PALB2 accrual at resected DSBs. Moreover, we demonstrate that PALB2 DSB recruitment in BRCA1/53BP1-deficient cells is mediated by an interaction between PALB2's chromatin associated motif (ChAM) and the nucleosome acidic patch region, which in 53BP1-expressing cells is bound by 53BP1's ubiquitin-directed recruitment (UDR) domain.


Assuntos
Proteína BRCA1/deficiência , Cromatina/metabolismo , Proteína do Grupo de Complementação N da Anemia de Fanconi/metabolismo , Recombinação Homóloga , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/deficiência , Motivos de Aminoácidos , Proteína BRCA2/deficiência , Linhagem Celular , Quebras de DNA de Cadeia Dupla , Reparo do DNA/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/química , Proteína do Grupo de Complementação N da Anemia de Fanconi/deficiência , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Humanos , Nucleossomos/metabolismo
6.
J Hum Genet ; 65(2): 199-205, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31619740

RESUMO

Partner and localiser of BRCA2 forms part of a macromolecular complex with BRCA1 and BRCA2, which is critical for the repair of double-strand DNA breaks by homologous DNA recombination. Germline loss-of-function variants in the PALB2 gene may confer an increased lifetime risk of breast, pancreatic, ovarian and other cancers. However, the complete spectrum of predicted pathogenic PALB2 variants associated with each tissue type of cancer remains unknown. A systematic review is performed with the aim of cataloguing predicted pathogenic PALB2 variants in breast, ovary and pancreas cancers. All catalogued predicted pathogenic variants are analysed to assess for overlap and mutational "hotspots" within gene exons. Our results showed that 911 (92.5%) cases were described in breast cancer patients, 49 (5.0%) cases were described in ovarian cancer patients, and 24 (2.4%) cases were described in pancreatic cancer patients. The top five most frequently reported predicted pathogenic PALB2 variants were c.509_510delGA, c.3113G > A, c.1592delT, c.172_175delTTGT, and c.1240C > T, accounting for 57.3% of all cases. Breast and pancreatic cancers share five variants while breast and ovarian cancers share 12 variants. Breast, ovarian and pancreatic cancers share eight common variants. Exons with the highest mutation rates were exons 2 (6.7%), 1 (6.3%) and 3 (5.8%). This systematic review provides a quantitative catalogue of predicted pathogenic PALB2 variants described in cancers. This comprehensive analysis of the PALB2 mutational spectrum represents a useful resource for clinicians overseeing PALB2-related cancer surveillance and provides a valuable resource for future PALB2-specific research.


Assuntos
Neoplasias da Mama/genética , Carcinoma Epitelial do Ovário/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Neoplasias Ovarianas/genética , Neoplasias Pancreáticas/genética , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/patologia , Carcinoma Epitelial do Ovário/patologia , Éxons/genética , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Neoplasias Ovarianas/patologia , Neoplasias Pancreáticas/patologia
7.
Cancer ; 126(3): 549-558, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31682005

RESUMO

BACKGROUND: Although management guidelines exist for several genes associated with a 2-fold to 5-fold increase in the relative risk for certain cancers, the value of testing for them remains controversial. METHODS: De-identified personal and family history data for 654 individuals with pathogenic variants (PVs) in PALB2, ATM, CHEK2, NBN, BRIP1, RAD51C, and/or RAD51D were analyzed for pretest and post-test candidacy for guideline-recommended management of cancer risk. These individuals were invited to complete a survey about provider recommendations and their adherence. RESULTS: Twenty-four percent of CHEK2, ATM, PALB2, or NBN PV carriers were appropriate for consideration of annual breast magnetic resonance imaging screening before genetic testing, with the remaining 76% appropriate only after testing. No BRIP1, RAD51C, or RAD51D PV carriers were appropriate for consideration of risk-reducing salpingo-oophorectomy before genetic testing; 100% were appropriate only after testing. Seventeen percent of CHEK2 PV carriers were appropriate for earlier and more frequent colonoscopy before genetic testing, with the remaining 83% appropriate only after testing. Provider recommendations for annual breast magnetic resonance imaging, consideration of risk-reducing salpingo-oophorectomy, and earlier and more frequent colonoscopy were reported by 42%, 26%, and 66% of breast, ovarian, and colorectal cancer risk PV carriers, respectively, before genetic testing, versus 82%, 79%, and 81%, respectively, after testing. Nearly all respondents had planned or undertaken provider-recommended management. CONCLUSIONS: Testing for PALB2, ATM, CHEK2, NBN, BRIP1, RAD51C, and RAD51D changed management for those carrying PVs. Provider recommendations were aligned with guidelines, and patients adhered to recommendations, both of which are critical for reducing both long-term cancer morbidity and mortality.


Assuntos
Neoplasias da Mama/diagnóstico , Predisposição Genética para Doença , Testes Genéticos , Síndrome Hereditária de Câncer de Mama e Ovário/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas Mutadas de Ataxia Telangiectasia/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proteínas de Ciclo Celular/genética , Quinase do Ponto de Checagem 2/genética , Proteínas de Ligação a DNA/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Feminino , Pessoal de Saúde , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Síndrome Hereditária de Câncer de Mama e Ovário/patologia , Humanos , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Proteínas Nucleares/genética , RNA Helicases/genética , Fatores de Risco , Adulto Jovem
8.
Ann Lab Med ; 40(2): 148-154, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31650731

RESUMO

BACKGROUND: Hereditary breast and ovarian cancer syndrome (HBOC) is caused by pathogenic variants in BRCA and other cancer-related genes. We analyzed variants in BRCA gene and other cancer-related genes in HBOC patients to evaluate the clinical validity of next-generation sequencing (NGS) multi-gene panel testing. METHODS: The BRCA1/2 NGS testing was conducted for 262 HBOC patients. Multiplex ligation-dependent probe amplification and direct Sanger sequencing were performed for confirmation. Multi-gene panel testing was conducted for 120 patients who did not possess BRCA1/2 pathogenic variants but met the National Comprehensive Cancer Network criteria. RESULTS: Pathogenic variants in BRCA1/2 were detected in 30 HBOC patients (11.5%). Additionally, four out of the 120 patients possessed pathogenic variants by multi-gene panel testing (3.3%): MSH2 (c.256G>T, p.Glu86*), PMS2 (c.1687C>T, p.Arg563*), CHEK2 (c.546C>A, p.Tyr182*), and PALB2 (c.3351-1G>C). All the four patients had a family history of cancer. CONCLUSIONS: Multi-gene panel testing could be a significant screening tool for HBOC patients, especially for those with a family history of cancer.


Assuntos
Síndrome Hereditária de Câncer de Mama e Ovário/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína BRCA1/genética , Proteína BRCA2/genética , Quinase do Ponto de Checagem 2/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Feminino , Variação Genética , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Humanos , Pessoa de Meia-Idade , Linhagem , Análise de Sequência de DNA , Adulto Jovem
9.
Br J Cancer ; 122(3): 333-339, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31787751

RESUMO

BACKGROUND: Retrospective studies suggest a survival benefit when platinum-based chemotherapy is administered to patients with pancreatic cancer harbouring a germline mutation in BRCA1, BRCA2 or PALB2 (mut-positive PDAC). However, the objective response rate (ORR) and real-world progression free survival (rwPFS) achieved with such treatment remain ill-defined. METHODS: Twenty-six patients with advanced-stage mut-positive PDAC who had been treated with platinum-based therapy were matched by age, race and sex to 52 platinum-treated control PDAC patients. Responses to therapy were determined by RECIST v1.1, performed by blinded radiology review. Measured outcomes included ORR and rwPFS. RESULTS: The ORR in mut-positive patients was 58% compared to 21% in the control group (p = 0.0022). There was no significant difference in ORR between platinum regimens in mut-positive patients (p = 0.814), whereas in control patients, the only observed responses were to FOLFIRINOX. rwPFS was 10.1 mo. for mut-positive patients and 6.9 mo. for controls (HR 0.43; 95% CI 0.25-0.74; 0.0068). CONCLUSION: Mut-positive PDAC has a high ORR and prolonged rwPFS to platinum-based chemotherapy. These findings may have implications particularly in the neoadjuvant setting, and for future clinical trial design, and highlight the importance of early germline testing in patients with PDAC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuminas/administração & dosagem , Proteína BRCA1/genética , Proteína BRCA2/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Estudos de Casos e Controles , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Feminino , Fluoruracila/uso terapêutico , Mutação em Linhagem Germinativa , Humanos , Irinotecano/uso terapêutico , Leucovorina/uso terapêutico , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/secundário , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/uso terapêutico , Oxaliplatina/uso terapêutico , Paclitaxel/administração & dosagem , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Prognóstico , Intervalo Livre de Progressão , Estudos Retrospectivos
10.
Breast Cancer Res Treat ; 179(3): 605-614, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31768816

RESUMO

PURPOSE: To investigate the prevalence and clinical relevance of PALB2 germline mutations in BRCA1/2-negative breast cancer patients. METHODS: The exons and intron-exon boundaries of the PALB2 gene were sequenced by multigene panel testing in a cohort of 7657 Chinese BRCA1/2-negative breast cancer patients. RESULTS: Of the 7657 patients, 54 (0.71%) carried pathogenic PALB2 germline mutations, all of which were nonsense or frameshift mutations leading to a truncated protein. The 54 patients carried 42 distinct pathogenic mutations, of which 17 (40.5%) were novel and 8 were recurrent mutations. Compared with non-carriers, PALB2 pathogenic mutation carriers developed breast cancer at a younger age (47.52 years vs. 51.35 years, p = 0.016) and were more likely to have triple-negative (24.1% vs. 13.4%, p = 0.022) or HER2 negative (87.0% vs. 74.2%, p = 0.031) breast cancer and large breast tumors (> 2 cm) at diagnosis (72.2% vs. 57.0%, p = 0.024). PALB2 mutation carriers were also more likely to have family histories of breast and/or ovarian cancer (27.8% vs. 8.4%, p < 0.001) and any types of cancer (57.4% vs. 31.6%, p < 0.001) when compared with non-carriers. CONCLUSIONS: PALB2 germline mutations are present at 0.71% in Chinese BRCA1/2-negative breast cancer patients and are more frequent in patients with triple-negative breast cancer and family histories of breast and/or ovarian cancer.


Assuntos
Biomarcadores Tumorais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Mutação em Linhagem Germinativa , Proteína BRCA1/genética , Proteína BRCA2/genética , Análise Mutacional de DNA , Éxons , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Heterozigoto , Humanos , Íntrons , Anamnese , Taxa de Mutação , Gradação de Tumores , Estadiamento de Neoplasias , Linhagem
11.
PLoS One ; 14(12): e0226714, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31877165

RESUMO

Alterations of the PALB2 tumor suppressor gene have been identified in familial breast, ovarian and pancreatic cancer cases. PALB2 cooperates with BRCA1/2 proteins through physical interaction in initiation of homologous recombination, in maintenance of genome integrity following DNA double-strand breaks. To determine if the role of PALB2 as a linker between BRCA1 and BRCA2 is critical for BRCA1/2-mediated tumor suppression, we generated Palb2 mouse pancreatic cancer models and compared tumor latencies, phenotypes and drug responses with previously generated Brca1/2 pancreatic cancer models. For development of Palb2 pancreatic cancer, we crossed conditional Palb2 null mouse with mice carrying the KrasG12D; p53R270H; Pdx1-Cre (KPC) constructs, and these animals were observed for pancreatic tumor development. Individual deletion of Palb2, Brca1 or Brca2 genes in pancreas per se using Pdx1-Cre was insufficient to cause tumors, but it reduced pancreata size. Concurrent expression of mutant KrasG12D and p53R270H, with tumor suppressor inactivated strains in Palb2-KPC, Brca1-KPC or Brca2-KPC, accelerated pancreatic ductal adenocarcinoma (PDAC) development. Moreover, most Brca1-KPC and some Palb2-KPC animals developed mucinous cystic neoplasms with PDAC, while Brca2-KPC and KPC animals did not. 26% of Palb2-KPC mice developed MCNs in pancreata, which resemble closely the Brca1 deficient tumors. However, the remaining 74% of Palb2-KPC animals developed PDACs without any cysts like Brca2 deficient tumors. In addition, the number of ADM lesions and immune cells infiltrations (CD3+ and F/480+) were significantly increased in Brca1-KPC tumors, but not in Brca2-KPC tumors. Interestingly, the level of ADM lesions and infiltration of CD3+ or F/480+ cells in Palb2-KPC tumors were intermediate between Brca1-KPC and Brca2-KPC tumors. As expected, disruption of Palb2 and Brca1/2 sensitized tumor cells to DNA damaging agents in vitro and in vivo. Altogether, Palb2-KPC PDAC exhibited features observed in both Brca1-KPC and Brca2-KPC tumors, which could be due to its role, as a linker between Brca1 and Brca2.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Carcinoma/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Neoplasias Pancreáticas/genética , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/patologia , Carcinoma/tratamento farmacológico , Carcinoma/patologia , Modelos Animais de Doenças , Deleção de Genes , Regulação Neoplásica da Expressão Gênica , Camundongos , Camundongos Nus , Mutação , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia
12.
Klin Onkol ; 32(6): 456-462, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31842565

RESUMO

BACKGROUND: Oncological diseases have, in most cases, a multifactorial etiology, composed of a combination of external and internal environmental factors. Hereditary tumorous syndromes are mostly autosomal dominant diseases with incomplete but very high penetrance. OBSERVATION: The patient, an 18-year-old virgin female, consulted a gynecologist in June 2018 because of metrorrhagia. Magnetic resonance imaging revealed a cervical tumor with the dimensions 80 × 90 × 80 mm. Histological analysis confirmed the presence of a very rare hypercalcemic type of small-cell carcinoma of the cervix. Further investigation of the germinal exom of the patient showed pathological variations in genes PALB2 and BRCA2, presented with recommendation of detailed examination by medical genetics. CONCLUSION: Clinical experience with this type of tumor is very limited, but it still comes with some useful outcome. Small cell carcinomas of the gynecologic tract are very rare, aggressive diseases, with very poor prognosis, affecting mainly young women. Their origin is most often the ovaries, based on most clinical data, but these tumor also localize to the endometrium, cervix, vagina and vulva. It is an extremely rare type of cancer, for which clinical data is scant due to the extremely low number of reported cases. In this patient, the carcinoma had an unusual genetical mutation burden, which she inherited from her parents. In the light of these findings, we recommend that patients suspected of having a small-cell of the gynecologic tract provide a detailed family history, and that genetic testing be considered in similar cases. This work was supported by MH CR grant 16-33209A and research program of Charles University Progress Q40/06. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 10. 6. 2019 Accepted: 9. 9. 2019.


Assuntos
Proteína BRCA2/genética , Carcinoma de Células Pequenas/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Hipercalcemia/genética , Neoplasias do Colo do Útero/genética , Adolescente , Carcinoma de Células Pequenas/diagnóstico por imagem , Carcinoma de Células Pequenas/patologia , Feminino , Humanos , Hipercalcemia/diagnóstico por imagem , Hipercalcemia/patologia , Imagem por Ressonância Magnética , Mutação , Neoplasias do Colo do Útero/diagnóstico por imagem , Neoplasias do Colo do Útero/patologia
13.
Presse Med ; 48(10): 1092-1100, 2019 Oct.
Artigo em Francês | MEDLINE | ID: mdl-31706893

RESUMO

In France, breast cancer is the most common cancer among women and the leading cause of cancer deaths. Identifying women with a "high" or "very high" breast cancer risk, according the terminology of the Haute Autorité de Santé 2014 guidelines, is essential to offer them special cares in term of screening and prevention. Women genetically predisposed have a very high risk of breast cancer. During the oncogenetic specialist consultation, familial and personal history of cancer is taken into account to evaluate the risk of hereditary Breast/Ovarian syndrome and thus the need of a genetic screening. In 2017, a list of 13 genes involved in hereditary ovarian or breast cancer has been established in France (Genetic and Cancer Group - Unicancer). Women carrying a BRCA1, BRCA2, PALB2, TP53, CDH1, PTEN mutation have a higher risk of breast cancer and are considered as "high risk". Therefore, medical breast surveillance similar to carriers of BRCA1/BRCA2 mutation is recommended for these patients (INCa guidelines 2017). However a mutation in one of those genes is only identified in approximatively 10 % of the screened families. The oncogenetic specialist's assessment distinguishes families in which women remain at a "high" risk of breast cancer (HAS 2014 for screening) from those where women have a "very high" risk (INCa guidelines 2017 for screening and prevention).


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença , Mutação , Fatores Etários , Antígenos CD/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/terapia , Neoplasias da Mama Masculina/genética , Caderinas/genética , Saúde da Família , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Feminino , França , Genes BRCA1 , Genes BRCA2 , Genes p53 , Testes Genéticos , Síndrome do Hamartoma Múltiplo/genética , Humanos , Síndrome de Li-Fraumeni/genética , Masculino , Neoplasias Ovarianas/genética , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Gravidez , Mastectomia Profilática , Fatores de Risco , Nanomedicina Teranóstica , Neoplasias de Mama Triplo Negativas/genética
14.
Nat Commun ; 10(1): 5296, 2019 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-31757951

RESUMO

Heterozygous carriers of germ-line loss-of-function variants in the DNA repair gene PALB2 are at a highly increased lifetime risk for developing breast cancer. While truncating variants in PALB2 are known to increase cancer risk, the interpretation of missense variants of uncertain significance (VUS) is in its infancy. Here we describe the development of a relatively fast and easy cDNA-based system for the semi high-throughput functional analysis of 48 VUS in human PALB2. By assessing the ability of PALB2 VUS to rescue the DNA repair and checkpoint defects in Palb2 knockout mouse embryonic stem (mES) cells, we identify various VUS in PALB2 that impair its function. Three VUS in the coiled-coil domain of PALB2 abrogate the interaction with BRCA1, whereas several VUS in the WD40 domain dramatically reduce protein stability. Thus, our functional assays identify damaging VUS in PALB2 that may increase cancer risk.


Assuntos
Neoplasias da Mama/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Técnicas Genéticas , Células-Tronco Embrionárias Murinas/metabolismo , Proteínas Mutantes/metabolismo , Mutação de Sentido Incorreto , Animais , DNA Complementar , Proteína do Grupo de Complementação N da Anemia de Fanconi/metabolismo , Citometria de Fluxo , Predisposição Genética para Doença , Instabilidade Genômica , Humanos , Camundongos , Camundongos Knockout
15.
Nucleic Acids Res ; 47(20): 10662-10677, 2019 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-31586400

RESUMO

While biallelic mutations in the PALB2 tumor suppressor cause Fanconi anemia subtype FA-N, monoallelic mutations predispose to breast and familial pancreatic cancer. Although hundreds of missense variants in PALB2 have been identified in patients to date, only a few have clear functional and clinical relevance. Herein, we investigate the effects of 44 PALB2 variants of uncertain significance found in breast cancer patients and provide detailed analysis by systematic functional assays. Our comprehensive functional analysis reveals two hotspots for potentially deleterious variations within PALB2, one at each terminus. PALB2 N-terminus variants p.P8L [c.23C>T], p.Y28C [c.83A>G], and p.R37H [c.110G>A] compromised PALB2-mediated homologous recombination. At the C-terminus, PALB2 variants p.L947F [c.2841G>T], p.L947S [c.2840T>C], and most strikingly p.T1030I [c.3089C>T] and p.W1140G [c.3418T>C], stood out with pronounced PARP inhibitor sensitivity and cytoplasmic accumulation in addition to marked defects in recruitment to DNA damage sites, interaction with BRCA2 and homologous recombination. Altogether, our findings show that a combination of functional assays is necessary to assess the impact of germline missense variants on PALB2 function, in order to guide proper classification of their deleteriousness.


Assuntos
Neoplasias da Mama/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Mutação de Sentido Incorreto/genética , Linhagem Celular Tumoral , Simulação por Computador , Dano ao DNA , Feminino , Loci Gênicos , Recombinação Homóloga/genética , Humanos , Cinética , Rad51 Recombinase/metabolismo , Reprodutibilidade dos Testes
16.
Lung Cancer ; 137: 48-51, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31542568

RESUMO

OBJECTIVES: Identifying new predictive biomarkers in lung cancer that will prolong survival for additional subgroups of patients is of utmost importance. We report response to treatment and survival among homologous recombination deficient (HRD) lung cancer patients mostly BRCA mutation carriers to better define the predictive value of HRD status among non-small cell lung cancer (NSCLC). METHODS: We retrospectively evaluated our genetic and pathology database and identified 14 carriers of germline mutation in BRCA1 (n = 5), BRCA2 (n = 8), or PALB2 (n = 1) and a patient with a somatic BRCA2 mutation. Platinum compounds were part of the initial or follow-on treatment protocols in 9/11 with metastatic disease. Overall survival (OS) and response to platinum were analyzed in these patients. RESULTS: Median OS for the 11 patients was 30 months. The 2- and 3-year survival rates in our cohort were 62.5% and 28.6%, respectively, and 7/10 patients with metastatic lung cancer survived for more than 1 year which compares favorably with the literature. Of eight patients who were treated with platinum compounds, seven responded; however, in two the response endured for <6 months. The Foundation Medicine LOH/HRD genomic score was calculated in three patients and the level was high in 2/3 (66%), including 1/2 tumors in germline BRCA mutation carriers and tumor in the patient with a somatic BRCA2 mutation. In both complete response to platinum was recorded. CONCLUSION: Response rate to platinum compounds and survival in these patients do suggest that platinum-based therapies should still be incorporated in our treatment regimen for the patients with HRD lung cancer, and that BRCA and other HRR associated gene testing may be important in lung cancer patients.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Mutação em Linhagem Germinativa , Recombinação Homóloga , Neoplasias Pulmonares/patologia , Mutação , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Idoso , Proteína BRCA1/genética , Proteína BRCA2/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Platina/uso terapêutico , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
17.
Breast Cancer Res Treat ; 178(3): 629-636, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31446535

RESUMO

PURPOSE: Each year, 17,000 new breast cancer cases are diagnosed in Argentina, and 5400 women die of breast cancer. The contribution of cancer-related mutations to the incidence of breast cancer in Argentina has not yet been explored. METHODS: We sequenced the entire coding regions of BRCA1, BRCA2, PALB2 and RAD51C in 112 unselected Argentinian breast cancer patients. RESULTS: A pathogenic genetic variant was found in 12 of 112 (10.7%) patients; two in BRCA1 (1.8%), five in BRCA2 (4.5%), four in PALB2 (3.6%) and one in RAD51C (0.9%). Three of four (75%) PALB2 mutation carriers carried the same variant (c.1653T > A). CONCLUSIONS: A founder mutation in PALB2 accounts for up to 4% of breast cancer patients in Argentina. BRCA1, BRCA2, PALB2 and RAD51C should be included in the genetic testing panel of breast cancer patients in Argentina.


Assuntos
Neoplasias da Mama/genética , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Predisposição Genética para Doença/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Argentina/epidemiologia , Proteína BRCA1/genética , Proteína BRCA2/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama/sangue , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Proteínas de Ligação a DNA/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Feminino , Estudos de Associação Genética , Mutação em Linhagem Germinativa , Humanos , Pessoa de Meia-Idade , Linhagem
18.
Cancer Prev Res (Phila) ; 12(11): 763-770, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31451522

RESUMO

Because the contribution of genetic factors to the burden of breast cancer is not well investigated in Iran, we aimed to examine the prevalence of mutations in breast cancer susceptibility genes, BRCA1/2 and PALB2, and to investigate the predictive potential of hereditary breast cancer risk criteria for genetic testing in Iranian population. Next-generation sequencing was conducted on a population consisting of 299 and 125 patients with breast cancer, with and without hereditary cancer risk criteria for genetic testing, respectively. The pathogenic mutation frequency rate was 10.7% in patients with hereditary cancer criteria versus 1.6% in no criteria group (P = 0.0017). None of the 107 tested patients with only young age at onset (<40) criterion had a pathogenic mutation. Patients who had only a single heritable risk criterion [OR, 6.15; 95% confidence interval (CI), 1.26-58.59; P = 0.009] and patients with multiple heritable risk criteria (OR, 22.5; 95% CI, 5.19-201.31; P < 0.0001) had higher probabilities of carrying a mutation compared with no criteria group. Our results showed that young age at onset alone is not an indicator of hereditary breast cancer at least in the Iranian population. This is while women with multiple hereditary breast cancer risk criteria were enriched for BRCA1/2 mutations. Given such high risk of identification of a disease-causing mutation, multiple hereditary criteria should be regarded as a strong predictor for a hereditary breast cancer syndrome. These findings are important concerning the optimization of genetic counseling and furthermore establishing criteria for BRCA1/2 testing of the Iranian population.


Assuntos
Neoplasias da Mama/diagnóstico , Carcinoma Ductal de Mama/diagnóstico , Carcinoma Lobular/diagnóstico , Predisposição Genética para Doença , Testes Genéticos/métodos , Mutação em Linhagem Germinativa , Síndromes Neoplásicas Hereditárias/diagnóstico , Adulto , Idade de Início , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Carcinoma Ductal de Mama/epidemiologia , Carcinoma Ductal de Mama/genética , Carcinoma Lobular/epidemiologia , Carcinoma Lobular/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Feminino , Seguimentos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Irã (Geográfico)/epidemiologia , Pessoa de Meia-Idade , Taxa de Mutação , Síndromes Neoplásicas Hereditárias/epidemiologia , Síndromes Neoplásicas Hereditárias/genética , Prognóstico , Adulto Jovem
20.
Int J Oncol ; 55(3): 597-616, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31322208

RESUMO

Several ongoing international prostate cancer (PC) clinical trials are exploring therapies that target the DNA damage response (DDR) pathway. This systematic review summarizes the prevalence of DDR mutation carriers in the unselected (general) PC and familial PC populations. A total of 11 electronic databases, 10 conference proceedings, and grey literature sources were searched from their inception to December 2017. Studies reporting the prevalence of somatic and/or germline DDR mutations were summarized. Metastatic PC (mPC), castration­resistant PC (CRPC) and metastatic CRPC (mCRPC) subgroups were included. A total of 11,648 records were retrieved, and 80 studies (103 records) across all PC populations were included; 59 records were of unselected PC and 13 records of familial PC. Most data were available for DDR panels (n=12 studies), ataxia telangiectasia mutated (ATM; n=13), breast cancer susceptibility gene (BRCA)1 (n=14) and BRCA2 (n=20). ATM, BRCA2 and partner and localizer of BRCA2 (PALB2) had the highest mutation rates (≥4%). Median prevalence rates for DDR germline mutations were 18.6% in PC (range, 17.2­19%; three studies, n=1,712), 11.6% in mPC (range, 11.4­11.8%; two studies, n=1,261) and 8.3% in mCRPC (range, 7.5­9.1%; two studies, n=738). Median prevalence rates for DDR somatic mutations were 10.7% in PC (range, 4.9­22%; three studies, n=680), 13.2% in mPC (range, 10­16.4%; two studies, n=105) and not reported (NR) in mCRPC. The prevalence of DDR germline and/or somatic mutations was 27% in PC (one study, n=221), 22.67% in mCRPC (one study, n=150) and NR in mPC. In familial PC, median mutation prevalence was 12.1% (range, 7.3­16.9%) for germline DDR (two studies, n=315) and 3.7% (range, 1.3­7.9%) for BRCA2 (six studies, n=945). In total, 88% of studies were at a high risk of bias. The prevalence of DDR gene mutations in PC varied widely within somatic subgroups depending on study size, genetic screening techniques, DDR mutation definition and PC diagnosis; somatic and/or germline DDR mutation prevalence was in the range of 23­27% in PC. These findings support DDR mutation testing for all patients with PC (including those with mCRPC). With the advent of the latest clinical practice PC guidelines highlighting the importance of DDR mutation screening, and ongoing mCRPC clinical trials evaluating DDR mutation­targeted drugs, future larger epidemiological studies are warranted to further quantify the international burden of DDR mutations in PC.


Assuntos
Reparo do DNA , Redes Reguladoras de Genes , Mutação , Neoplasias da Próstata/genética , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteína BRCA1/genética , Proteína BRCA2/genética , Dano ao DNA , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Mutação em Linhagem Germinativa , Humanos , Masculino , Taxa de Mutação , Prevalência
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...