Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 449
Filtrar
1.
Pathologica ; 116(1): 62-68, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38482676

RESUMO

Male breast cancer (MBC) accounts for approximately 1% of all breast cancers and among these infiltrating lobular carcinomas (ILC) represents only 1-2% of all MBC cases. Pleomorphic invasive lobular carcinoma (PILC) is an aggressive variant of ILC with only eight cases reported until now in males. Up to 10% of MBC cases have a germline pathogenic variant in a predisposing gene such as BRCA1 and BRCA2 genes. Mutations in PALB2 (partner and localizer of BRCA2) have been reported in men with breast cancer, with a frequency that ranges from 0.8 to 6.4%, but it has never been reported in male ILC. Here, we report a rare and interesting case of an invasive pleomorphic/solid lobular carcinoma, which carries a pathogenic variant in PALB2 gene, and a family history of breast cancer without other well defined risk factors for developing this type of neoplasia. In addition, we review the current literature.


Assuntos
Neoplasias da Mama Masculina , Neoplasias da Mama , Carcinoma Lobular , Masculino , Humanos , Carcinoma Lobular/genética , Carcinoma Lobular/patologia , Mutação em Linhagem Germinativa , Neoplasias da Mama/genética , Neoplasias da Mama Masculina/genética , Neoplasias da Mama Masculina/patologia , Mutação , Predisposição Genética para Doença , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética
2.
Curr Treat Options Oncol ; 25(3): 346-363, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38311708

RESUMO

OPINION STATEMENT: An important subgroup of pancreatic ductal adenocarcinomas (PDACs) harbor pathogenic variants in BRCA1, BRCA2, or PALB2. These tumors are exquisitely sensitive to platinum-based chemotherapy and patients may experience deep and durable responses to this treatment. PARP inhibitors offer potential respite from the cumulative toxicities of chemotherapy as they significantly extend progression-free survival compared to a chemotherapy holiday. Given the lack of proven survival benefit, the decision to use a maintenance PARP inhibitor rather than continue chemotherapy should be individualized. Interestingly, in both published clinical trials of maintenance PARP inhibitors, there is a striking range of interpatient benefit: Even in the platinum-sensitive setting, roughly 25% of tumors appear to be PARP inhibitor refractory (progressive disease within 2 months of starting treatment), 50% sustain moderate benefit (up to 2 years), and 25% are hyper-responsive (more than 2 years of benefit). This finding highlights the need to refine our understanding of which patients will respond to maintenance PARP inhibitors, both by being able to identify biallelic loss and by deepening our knowledge of resistance mechanisms and who develops them. Recent data supports that reversion mutations are common in PARP inhibitor refractory patients, but we have little understanding of the mechanisms that drive delayed resistance and long-term responses. Identifying which patients are more prone to certain mechanisms of resistance and tackling them with specific treatment strategies are areas of active investigation. Additionally, given that PARP inhibitors have limited overall efficacy for most patients, upfront combination strategies are an important future strategy.


Assuntos
Antineoplásicos , Neoplasias Ovarianas , Neoplasias Pancreáticas , Humanos , Feminino , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Antineoplásicos/uso terapêutico , Mutação , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Proteína BRCA2/genética , Proteína BRCA1/genética , Poli(ADP-Ribose) Polimerases/genética , Neoplasias Ovarianas/tratamento farmacológico , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética
3.
Curr Oncol ; 31(1): 350-365, 2024 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-38248108

RESUMO

Female BRCA1/2 and PALB2 germline pathogenic variant carriers have an increased lifetime risk of breast cancer and may wish to consider risk-reducing mastectomy (RRM) for surgical prevention. Quantifying the residual lifetime risk and absolute benefit from RRM requires careful consideration of a patient's age, pathogenic variant, and their personal history of breast or ovarian cancer. Historically, patients have been counselled that RRM does not necessarily prolong survival relative to high-risk surveillance, although recent studies suggest a possible survival benefit of RRM in BRCA1 carriers. The uptake of RRM has increased dramatically over the last several decades yet varies according to sociodemographic factors and geographic region. The increased adoption of nipple-sparing mastectomy techniques, ability to avoid axillary staging, and availability of reconstructive options for most germline pathogenic variant carriers has helped to minimize the morbidity of RRM. Preoperative discussions should include evidence regarding postmastectomy sensation, the potential for supplemental surgery, pregnancy-related chest wall changes, and the need for continued clinical surveillance. Approaches that include sensation preservation and robotic nipple-sparing mastectomy are an area of evolving research that may be more widely adopted in the future.


Assuntos
Neoplasias da Mama , Mastectomia , Gravidez , Humanos , Feminino , Neoplasias da Mama/genética , Neoplasias da Mama/cirurgia , Proteína BRCA1/genética , Proteína BRCA2/genética , Aconselhamento , Células Germinativas , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética
4.
Breast Cancer Res Treat ; 203(2): 307-315, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37851290

RESUMO

BACKGROUND: Mountain areas of the North Caucasus host several large ethnic communities that have preserved their national identity over the centuries. METHODS: This study involved high-grade serous ovarian cancer (HGSOC) and breast cancer (BC) patients from Dagestan (HGSOC: 37; BC: 198), Kabardino-Balkaria (HGSOC: 68; BC: 155), North Ossetia (HGSOC: 51; BC: 104), Chechnya (HGSOC: 68; BC: 79), Ingushetia (HGSOC: 19; BC: 103), Karachay-Cherkessia (HGSOC: 13; BC: 47), and several Armenian settlements (HGSOC: 16; BC: 101). The group of BC patients was enriched by young-onset and/or family history-positive and/or bilateral and/or receptor triple-negative cases. The entire coding region of BRCA1, BRCA2, PALB2, and ATM genes was analyzed by next-generation sequencing. RESULTS: A significant contribution of BRCA1/2 pathogenic variants (PVs) to HGSOC and BC development was observed across all North Caucasus regions (HGSOC: 19-39%; BC: 6-13%). Founder alleles were identified in all ethnic groups studied, e.g., BRCA1 c.3629_3630delAG in Chechens, BRCA2 c.6341delC in North Ossetians, BRCA2 c.5351dupA in Ingush, and BRCA1 c.2907_2910delTAAA in Karachays. Some BRCA1/2 alleles, particularly BRCA2 c.9895C > T, were shared by several nationalities. ATM PVs were detected in 14 patients, with c.1673delG and c.8876_8879delACTG alleles occurring twice each. PALB2 heterozygosity was observed in 5 subjects, with one variant seen in 2 unrelated women. CONCLUSION: This study adds to the evidence for the global-wide contribution of BRCA1/2 genes to HGSOC and BC morbidity, although the spectrum of their PVs is a subject of ethnicity-specific variations. The data on founder BRCA1/2 alleles may be considered when adjusting the BRCA1/2 testing procedure to the ethnic origin of patients.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia , Neoplasias da Mama , População do Leste Europeu , Neoplasias Ovarianas , Humanos , Feminino , Proteína BRCA1/genética , Proteína BRCA2/genética , Etnicidade , Alelos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Predisposição Genética para Doença , Neoplasias Ovarianas/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética
5.
Clin Chim Acta ; 552: 117695, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-38061684

RESUMO

BACKGROUND AND AIMS: Cancer predisposition goes beyond BRCA and DNA Mismatch Repair (MMR) genes since multi-gene panel testing has become the routine diagnostic tool for hereditary cancer suspicion (HCS) cases. CHEK2 and PALB2 are some of the foremost-mutated non-BRCA/MMR actionable genes in families with a significant familial aggregation. Therefore, the purpose of this work is to unravel which tumours other than breast, ovary or colorectal display the patients. MATERIALS AND METHODS: We have analysed 528 probands that meet the inclusion criteria for Hereditary Breast and Ovarian Cancer and Lynch Syndrome established by our Hereditary Cancer Regional Program with a customized 35 genes-panel by using Ion Torrent™ Technology. RESULTS: We have identified pathogenic variants (PVs) in 61 families (1.55%), of which more than half (31 probands) harboured PVs in CHEK2 and PALB2 genes. Ours results reveal that not only were PVs CHEK2 and PALB2 carriers more likely to have family history of cancer not limited to breast, ovarian or colorectal cancers, but also they are prone to other extracolonic cancers, noteworthy endometrial and gastric cancers. CONCLUSIONS: Multigene panel testing improves the chance of finding PVs in actionable genes in families with HCS. In addition, the coexistence of variants should be recorded to implement a polygenic risk algorithm that might explain the missing heritability in the aforementioned families.


Assuntos
Neoplasias da Mama , Neoplasias Colorretais , Neoplasias Ovarianas , Feminino , Humanos , Mutação em Linhagem Germinativa/genética , Predisposição Genética para Doença , Neoplasias Ovarianas/genética , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Neoplasias da Mama/genética , Testes Genéticos/métodos , Quinase do Ponto de Checagem 2/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética
6.
J Med Genet ; 61(4): 385-391, 2024 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-38123987

RESUMO

BACKGROUND: The identification of germline pathogenic gene variants (PGVs) in triple negative breast cancer (TNBC) is important to inform further primary cancer risk reduction and TNBC treatment strategies. We therefore investigated the contribution of breast cancer associated PGVs to familial and isolated invasive TNBC. METHODS: Outcomes of germline BRCA1, BRCA2 and CHEK2_c.1100delC testing were recorded in 1514 women (743-isolated, 771-familial), and for PALB2 in 846 women (541-isolated, 305-familial), with TNBC and smaller numbers for additional genes. Breast cancer free controls were identified from Predicting Risk Of Cancer At Screening and BRIDGES (Breast cancer RIsk after Diagnostic GEne Sequencing) studies. RESULTS: BRCA1_PGVs were detected in 52 isolated (7.0%) and 195 (25.3%) familial cases (isolated-OR=58.9, 95% CI: 16.6 to 247.0), BRCA2_PGVs in 21 (2.8%) isolated and 67 (8.7%) familial cases (isolated-OR=5.0, 95% CI: 2.3 to 11.2), PALB2_PGVs in 9 (1.7%) isolated and 12 (3.9%) familial cases (isolated-OR=8.8, 95% CI: 2.5 to 30.4) and CHEK2_c.1100delC in 0 isolated and 3 (0.45%) familial cases (isolated-OR=0.0, 95% CI: 0.00 to 2.11). BRCA1_PGV detection rate was >10% for all familial TNBC age groups and significantly higher for younger diagnoses (familial: <50 years, n=165/538 (30.7%); ≥50 years, n=30/233 (12.9%); p<0.0001). Women with a G3_TNBC were more likely to have a BRCA1_PGV as compared with a BRCA2 or PALB2_PGV (p<0.0001). 0/743 isolated TNBC had the CHEK2_c.1100delC PGV and 0/305 any ATM_PGV, but 2/240 (0.83%) had a RAD51D_PGV. CONCLUSION: PGVs in BRCA1 are associated with G3_TNBCs. Familial TNBCs and isolated TNBCs <30 years have a >10% likelihood of a PGV in BRCA1. BRCA1_PGVs are associated with younger age of familial TNBC. There was no evidence for any increased risk of TNBC with CHEK2 or ATM PGVs.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia , Proteína BRCA2 , Neoplasias da Mama , Proteína do Grupo de Complementação N da Anemia de Fanconi , Neoplasias de Mama Triplo Negativas , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias da Mama/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Predisposição Genética para Doença , Genes BRCA2 , Genes BRCA1 , Células Germinativas/patologia , Mutação em Linhagem Germinativa/genética , Quinase do Ponto de Checagem 2/genética , Proteínas de Ligação a DNA/genética , Proteína BRCA1/genética
7.
Breast Cancer Res ; 25(1): 152, 2023 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-38098088

RESUMO

BACKGROUND: The homologous recombination (HR) repair pathway for DNA damage, particularly the BRCA1 and BRCA2 genes, has become a target for cancer therapy, with poly ADP-ribose polymerase (PARP) inhibitors showing significant outcomes in treating germline BRCA1/2 (gBRCA1/2) mutated breast cancer. Recent studies suggest that some patients with somatic BRCA1/2 (sBRCA1/2) mutation or mutations in HR-related genes other than BRCA1/2 may benefit from PARP inhibitors as well, particularly those with PALB2 mutations. The current analysis aims to evaluate the prevalence of genetic alterations specific to BRCA1, BRCA2, and PALB2 in a large cohort of Taiwanese breast cancer patients through tumor-targeted sequencing. METHODS: A total of 924 consecutive assays from 879 Taiwanese breast cancer patients underwent tumor-targeted sequencing (Thermo Fisher Oncomine Comprehensive Assay v3). We evaluated BRCA1, BRCA2, and PALB2 mutational profiles, with variants annotated and curated by the ClinVAR, the Oncomine™ Knowledgebase Reporter, and the OncoKB™. We also conducted reflex germline testing using either whole exome sequencing (WES) or whole genome sequencing (WGS), which is ongoing. RESULTS: Among the 879 patients analyzed (924 assays), 130 had positive mutations in BRCA1 (3.1%), BRCA2 (8.6%), and PALB2 (5.2%), with a total of 14.8% having genetic alterations. Co-occurrence was noted between BRCA1/BRCA2, BRCA1/PALB2, and BRCA2/PALB2 mutations. In BRCA1-mutated samples, only p.K654fs was observed in three patients, while other variants were observed no more than twice. For BRCA2, p.N372H was the most common (26 patients), followed by p.S2186fs, p.V2466A, and p.X159_splice (5 times each). For PALB2, p.I887fs was the most common mutation (30 patients). This study identified 176 amino acid changes; 60.2% (106) were not documented in either ClinVAR or the Oncomine™ Knowledgebase Reporter. Using the OncoKB™ for annotation, 171 (97.2%) were found to have clinical implications. For the result of reflex germline testing, three variants (BRCA1 c.1969_1970del, BRCA1 c.3629_3630del, BRCA2 c.8755-1G > C) were annotated as Pathogenic/Likely pathogenic (P/LP) variants by ClinVar and as likely loss-of-function or likely oncogenic by OncoKB; while one variant (PALB2 c.448C > T) was not found in ClinVar but was annotated as likely loss-of-function or likely oncogenic by OncoKB. CONCLUSION: Our study depicted the mutational patterns of BRCA1, BRCA2, and PALB2 in Taiwanese breast cancer patients through tumor-only sequencing. This highlights the growing importance of BRCA1/2 and PALB2 alterations in breast cancer susceptibility risk and the treatment of index patients. We also emphasized the need to meticulously annotate variants in cancer-driver genes as well as actionable mutations across multiple databases.


Assuntos
Proteína BRCA1 , Neoplasias da Mama , Humanos , Feminino , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Genes BRCA2 , Prevalência , Mutação em Linhagem Germinativa , Predisposição Genética para Doença , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Genômica
8.
JCO Precis Oncol ; 7: e2300091, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37992259

RESUMO

PURPOSE: Poly ADP-ribose polymerase inhibitors (PARPi) are approved for patients with human epidermal growth factor receptor 2-negative metastatic breast cancer (mBC) and germline pathogenic/likely pathogenic variant (hereafter mutation) in the BRCA1/2 genes (gBRCA); however, clinical benefit has also been demonstrated in mBC with somatic BRCA1/2 mutations (sBRCA) or germline PALB2 mutations (gPALB2). This study aims to describe the genomic landscape of homologous recombination repair (HRR) gene alterations in mBC and assess PARPi treatment outcomes for patients with gBRCA compared with other HRR genes and by status of a novel homologous recombination deficiency signature (HRDsig). METHODS: A real-world (RW) clinico-genomic database (CGDB) of comprehensive genomic profiling (CGP) linked to deidentified, electronic health record-derived clinical data was used. CGP was analyzed for HRR genes and HRDsig. The CGDB enabled cohort characterization and outcomes analyses of 177 patients exposed to PARPi. RW progression-free survival (rwPFS) and RW overall survival (rwOS) were compared. RESULTS: Of 28,920 patients with mBC, gBRCA was detected in 3.4%, whereas the population with any BRCA alteration or gPALB2 increased to 9.5%. HRDsig+ represented 21% of patients with mBC. BRCA and gPALB2 had higher levels of biallelic loss and HRDsig+ than other HRR alterations. Outcomes on PARPi were assessed for 177 patients, and gBRCA and sBRCA/gPALB2 cohorts were similar: gBRCA versus sBRCA/gPALB2 rwPFS was 6.3 versus 5.4 months (hazard ratio [HR], 1.37 [0.77-2.43]); rwOS was 16.2 versus 21.2 months (HR, 1.45 [0.74-2.86]). Additionally, patients with HRDsig+ versus HRDsig- had longer rwPFS (6.3 v 2.8 months; HR, 0.62 [0.42-0.92]) and numerically longer rwOS (17.8 v 13.0 months; HR, 0.72 [0.46-1.14]). CONCLUSION: Patients with sBRCA and gPALB2 derive similar benefit from PARPi as those with gBRCA alterations. In combination, HRDsig+, sBRCA, and gPALB2 represent an additional 19% of mBC that can potentially benefit from PARPi. Randomized trials exploring a more inclusive biomarker such as HRDsig are warranted.


Assuntos
Neoplasias da Mama , Recombinação Homóloga , Inibidores de Poli(ADP-Ribose) Polimerases , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Genes BRCA1 , Genes BRCA2 , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Mutação em Linhagem Germinativa , Masculino , Adulto , Pessoa de Meia-Idade , Idoso
9.
Genes (Basel) ; 14(8)2023 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-37628606

RESUMO

It has been shown that the loss of function of the BRCA1, BRCA2, and PALB2 genes due to a number of hereditary mutations or chromosomal aberrations can affect the effectiveness of chemotherapy treatment and disease prognosis in patients with various types of cancer, and in particular in breast cancer. Thus, the aim of the work was to evaluate the predictive and prognostic potential of DNA copy number aberrations and mutations in the BRCA1, BRCA2, and PALB2 genes in breast tumors. MATERIALS AND METHODS: The study included 66 patients with breast cancer. DNA copy number aberrations (CNA) were assessed by high-density CytoScanHD™ Array micro matrix analysis. Gene mutations were assessed by sequencing on the MiSeq™ Sequencing System using the Accel-Amplicon BRCA1, BRCA2, and PALB2 Panel. RESULTS: It has been established that the presence of a normal copy number of PALB2 is associated with a lack of response to chemotherapy in Taxotere-containing treatment regimens (p = 0.05). In addition, the presence of a PALB2 deletion is associated with 100% metastatic survival rates (log-rank test p = 0.04). As a result of sequencing, 25 mutations were found in the BRCA1 gene, 42 mutations in BRCA2, and 27 mutations in the PALB2 gene. The effect of mutations on the effectiveness of treatment is controversial, but an effect on the survival of patients with breast cancer has been shown. So, in the presence of pathogenic mutations in the BRCA2 gene, 100% metastatic survival is observed (log-rank test p = 0.05), as well as in the elimination of PALB2 mutations during treatment (log-rank test p = 0.07). CONCLUSION: Currently, there is little data on the effect of chromosomal aberrations and mutations in the BRCA1/2 and PALB2 genes on the effectiveness of treatment and prognosis of the disease. At the same time, the study of these genes has great potential for testing focused on a personalized approach to the treatment of patients with breast cancer.


Assuntos
Neoplasias da Mama , Genes BRCA2 , Humanos , Feminino , Proteína BRCA2/genética , Proteína BRCA1/genética , Terapia Neoadjuvante , Prognóstico , Mutação , Aberrações Cromossômicas , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética
10.
Int J Mol Sci ; 24(14)2023 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-37511102

RESUMO

PALB2 (Partner and localizer of BRCA2) is crucial for repairing DNA double-stranded breaks (DSBs) through homologous recombination (HR). Germline pathogenic variation in PALB2 disrupts DNA damage repair and increases the risk of Fanconi Anemia, breast cancer, and ovarian cancer. Determination of the evolutionary origin of human PALB2 variants will promote a deeper understanding of the biological basis of PALB2 germline variation and its roles in human diseases. We tested the evolution origin for 1444 human PALB2 germline variants, including 484 pathogenic and 960 benign variants. We performed a phylogenic analysis by tracing the variants in 100 vertebrates. However, we found no evidence to show that cross-species conservation was the origin of PALB2 germline pathogenic variants, but it is indeed a rich source for PALB2 germline benign variants. We performed a paleoanthropological analysis by tracing the variants in over 5000 ancient humans. We identified 50 pathogenic in 71 ancient humans dated from 32,895 to 689 before the present, of which 90.1% were dated within the recent 10,000 years. PALB2 benign variants were also highly shared with ancient humans. Data from our study reveal that human PALB2 pathogenic variants mostly arose in recent human history.


Assuntos
Neoplasias da Mama , Proteína do Grupo de Complementação N da Anemia de Fanconi , Anemia de Fanconi , Mutação em Linhagem Germinativa , Neoplasias Ovarianas , Animais , Feminino , Humanos , Proteína BRCA2/genética , Neoplasias da Mama/patologia , Reparo do DNA , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Predisposição Genética para Doença , Células Germinativas/metabolismo , Neoplasias Ovarianas/genética , Anemia de Fanconi/genética , Evolução Molecular
11.
Genet Med ; 25(11): 100945, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37515473

RESUMO

PURPOSE: Following disclosure of pathogenic or likely pathogenic variants in hereditary cancer genes, patients face cancer risk management decisions. Through this mixed-methods study, we investigated cancer risk management decisions among females with pathogenic or likely pathogenic variants in PALB2, CHEK2, and ATM to understand why some patients follow National Comprehensive Cancer Network guidelines, whereas others do not. METHODS: Survey and interview data were cross-analyzed using a 3-stage approach. Identified factors were used to conduct coincidence analysis and differentiate between combinations of factors that result in following or not following guidelines. RESULTS: Of the 13 participants who underwent guideline inconsistent prophylactic surgery, 12 fit 1 of 3 unique patterns: (1) cancer-related anxiety in the absence of trust in care, (2) provider recommending surgery inconsistent with National Comprehensive Cancer Network guidelines, or (3) surgery occurring before genetic testing. Two unique patterns were found among 18 of 20 participants who followed guidelines: (1) anxiety along with trust in care or (2) lack of anxiety and no prophylactic surgery before testing. CONCLUSION: Health care provider recommendations and trust in care may influence whether individuals receive care that is congruent with risk levels conferred by specific genes. Interventions are needed to improve provider knowledge, patient trust in non-surgical care, and patient anxiety.


Assuntos
Predisposição Genética para Doença , Neoplasias , Humanos , Feminino , Testes Genéticos/métodos , Risco , Neoplasias/genética , Gestão de Riscos , Quinase do Ponto de Checagem 2/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Proteínas Mutadas de Ataxia Telangiectasia/genética
12.
Clin Cancer Res ; 29(24): 5207-5216, 2023 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-37486343

RESUMO

PURPOSE: PARP inhibitors (PARPi) provide an effective maintenance option for patients with BRCA- or PALB2-mutated pancreatic cancer. However, mechanisms of PARPi resistance and optimal post-PARPi therapeutic strategies are poorly characterized. EXPERIMENTAL DESIGN: We collected paired cell-free DNA samples and post-PARPi clinical data on 42 patients with advanced, platinum-sensitive pancreatic cancer who were treated with maintenance rucaparib on NCT03140670, of whom 32 developed progressive disease. RESULTS: Peripherally detected, acquired BRCA or PALB2 reversion variants were uncommon (5/30; 16.6%) in patients who progressed on rucaparib. Reversions were significantly associated with rapid resistance to PARPi treatment (median PFS, 3.7 vs. 12.5 months; P = 0.001) and poor overall survival (median OS, 6.2 vs. 23.0 months; P < 0.0001). All patients with reversions received rechallenge with platinum-based chemotherapy following PARPi progression and experienced faster progression on this therapy than those without reversion variants (real-world time-to-treatment discontinuation, 2.4 vs. 5.8 months; P = 0.004). Of the patients who progressed on PARPi and received further chemotherapy, the OS from initiation of second-line therapy was significantly lower in those with reversion variants than in those without (5.5 vs. 12.0 months, P = 0.002). Finally, high levels of tumor shedding were independently associated with poor outcomes in patients who received rucaparib. CONCLUSIONS: Acquired reversion variants were uncommon but detrimental in a population of patients with advanced BRCA- or PALB2-related pancreatic ductal adenocarcinoma who received maintenance rucaparib. Reversion variants led to rapid progression on PARPi, rapid failure of subsequent platinum-based treatment, and poor OS of patients. The identification of such variants in the blood may have both predictive and prognostic value. See related commentary by Tsang and Gallinger, p. 5005.


Assuntos
Neoplasias Ovarianas , Neoplasias Pancreáticas , Feminino , Humanos , Neoplasias Ovarianas/patologia , Proteína BRCA2/genética , Prognóstico , Indóis , Inibidores de Poli(ADP-Ribose) Polimerases , Platina/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Proteína BRCA1/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética
13.
Sci Rep ; 13(1): 7666, 2023 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-37169825

RESUMO

The PALB2 gene is a breast cancer (BC) and ovarian cancer (OC) predisposition gene involved in the homologous recombination repair pathway. However, the prevalence and clinicopathological association of PALB2 pathogenic/likely pathogenic (PV/LPV) variants in Middle East is still not fully explored. Total 918 BC/OC patients from Saudi Arabia were selected for PALB2 mutations screening using capture sequencing technology. Five heterozygous PVs or LPVs were identified in six cases, accounting for 0.65% (6/918) of entire cohort. Two cases (33.3%) harbored PVs and four cases (66.7%) carried LPVs. Four PVs/LPVs (80%) were frameshift along with one novel splicing LPV (c.2835-2_2835-1delinsTT). One recurrent LPV (c.3425delT: p.L1142fs) was identified in two cases. All six affected carriers have breast cancer diagnosis with median age of 39.5 years (range 34-49 years). Only two cases (33%) have documented family history of cancer. Breast cancer phenotype was invasive ductal unilateral cancer in all cases with 66.7% of hormone receptor positive and 16% of triple negative tumors. Germline PVs/LPVs in the PALB2 gene were observed in low frequency of 0.65% in Saudi BC and/or OC. Our study confirms one recurrent LPV and one novel LPV in Saudi breast cancer patients.


Assuntos
Neoplasias da Mama , Proteína do Grupo de Complementação N da Anemia de Fanconi , Neoplasias Ovarianas , Feminino , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Heterozigoto , Oriente Médio , Neoplasias Ovarianas/genética , Arábia Saudita , População do Oriente Médio/genética
14.
Clin Breast Cancer ; 23(4): e259-e266, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36997402

RESUMO

BACKGROUND: PALB2 plays a crucial role in genome stability and the DNA repair process, and its mutation is associated with a moderate to high risk of breast cancer. However, the status and prognostic role of PALB2 expression in breast cancer are still unclear. MATERIALS AND METHODS: The expression level of PALB2 mRNA was evaluated by using quantitative real-time polymerase chain reaction in core biopsy samples from 563 primary breast cancer tissues. RESULTS: In the entire cohort, low expression of PALB2 mRNA was significantly associated with poor survival (low vs. intermediate: DFS, adjusted HR = 1.79, 95% CI = 1.21-2.65, P = .003; DDFS, adjusted HR = 2.07, 95% CI = 1.34-3.20, P = .001; DSS, adjusted HR = 2.59, 95% CI = 1.45-4.64, P = .001; OS, adjusted HR = 2.77, 95% CI = 1.56-4.92, P = .001; low vs. high: DFS, adjusted HR = 1.57, 95% CI = 1.06-2.35, P = .026; DDFS, adjusted HR = 1.66, 95% CI = 1.08-2.55, P = .020; DSS, adjusted HR = 1.74, 95% CI = 1.00-3.03, P = .048; OS, adjusted HR = 1.59, 95% CI = 0.95-2.67, P = .08). Notably, among hormone receptor (HR)-positive/HER2-negative subtype, patients with low PALB2 expression also had significantly worse outcomes (low vs. intermediate: DFS, adjusted HR = 2.33, 95% CI = 1.32-4.13, P = .004; DDFS, adjusted HR = 2.78, 95% CI = 1.47-5.27, P < .001; DSS, adjusted HR = 3.08, 95% CI = 1.27-7.43, P = .013; OS, adjusted HR = 3.15, 95% CI = 1.32-7.50, P = .010; low vs. high: DFS, adjusted HR = 1.84, 95% CI = 1.04-3.28, P = .04; DDFS, adjusted HR = 1.82, 95% CI = 0.99-3.36, P = .05; DSS, adjusted HR = 2.06, 95% CI = 0.87-4.86, P = .10; OS, adjusted HR = 1.54, 95% CI = 0.71-3.33, P = .28). CONCLUSION: Breast cancer patients with low expression of mRNA have a poor survival, suggesting that patients with PALB2 low expression may be the potential beneficiaries for PARP inhibitors therapy.


Assuntos
Neoplasias da Mama , Proteína do Grupo de Complementação N da Anemia de Fanconi , Feminino , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Intervalo Livre de Doença , População do Leste Asiático , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real
15.
Clin Breast Cancer ; 23(4): e194-e199, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36966080

RESUMO

BACKGROUND: This study aims to capture clinical and surgical practice patterns of patients with deleterious mutations in partner and localizer of BRCA2 (PALB2), checkpoint kinase 2 (CHEK2) and ataxia telangiesctasia mutated (ATM) genes. MATERIALS AND METHODS: This study is a retrospective chart review of patients with PALB2, CHEK2 or ATM mutations. Patient demographics, testing indications, management decisions, and surveillance strategies were recorded. RESULTS: Sixty-two patients were found to have deleterious mutations: 14 (23%) with a PALB2 mutation, 30 (48%) with a CHEK2 mutation, and 18 (29%) patients with an ATM mutation. Thirty-one (50%) patients have a history of breast cancer. Twenty-three patients were diagnosed and treated prior to genetic testing while 8 patients learned of their mutation status and breast cancer diagnosis simultaneously. Of these 8 patients, 4 sought treatment at our institution, 3 underwent bilateral mastectomy, and 1 patient opted for lumpectomy and surveillance. Thirty-one patients had no history of breast cancer. After genetic diagnosis, 3 of the 9 patients who continued clinical follow-up proceeded with bilateral prophylactic mastectomy within 2 years. Clinical surveillance continued for 23 months on average. CONCLUSION: Most patients who learned of their genetic and breast cancer diagnoses simultaneously underwent bilateral mastectomy, whereas only a third of patients without cancer opted for bilateral prophylactic mastectomy.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Neoplasias da Mama/cirurgia , Quinase do Ponto de Checagem 2/genética , Estudos Retrospectivos , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Predisposição Genética para Doença , Mastectomia , Mutação , Ataxia , Proteínas Mutadas de Ataxia Telangiectasia/genética
16.
Breast Cancer ; 30(4): 577-583, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36897545

RESUMO

BACKGROUND: In Japan, with the introduction of multigene panel testing, there is an urgent need to build a new medical system for hereditary breast cancer patients that covers pathogenic variants other than BRCA1/2. The aim of this study was to reveal the current status of breast MRI surveillance for high-risk breast cancer susceptibility genes other than BRCA1/2 and the characteristics of detected breast cancer. METHODS: We retrospectively examined 42 breast MRI surveillance with contrast performed on patients with hereditary tumors other than BRCA1/2 pathogenic variants at our hospital from 2017 to 2021. MRI exams were evaluated independently by two radiologists. Final histopathological diagnosis for malignant lesions were obtained from surgical specimen. RESULTS: A total of 16 patients included TP53, CDH1, PALB2, ATM pathogenic variants and 3 variant of unknown significance. 2 patients with TP53 pathogenic variants were detected breast cancer by annual MRI surveillance. The rate of cancer detection was 12.5% (2/16). One patient was detected synchronous bilateral breast cancer and unilateral multiple breast cancers (3 lesions in 1 patient), so there were 4 malignant lesions in total. Surgical pathology of 4 lesions were 2 ductal carcinoma in situ, 1 invasive lobular carcinoma, and 1 invasive ductal carcinoma. MRI findings of 4 malignant lesions were detected as 2 non mass enhancement, 1 focus and 1 small mass. All of 2 patients with PALB2 pathogenic variants had previously developed breast cancer. CONCLUSIONS: Germline TP53 and PALB2 were strongly associated with breast cancer, suggesting that MRI surveillance is essential for breast cancer-related hereditary predisposition.


Assuntos
Neoplasias da Mama , Detecção Precoce de Câncer , Genes Neoplásicos , Predisposição Genética para Doença , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Imageamento por Ressonância Magnética , Risco , Japão , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Antígenos CD/genética , Caderinas/genética , Proteína Supressora de Tumor p53/genética , Detecção Precoce de Câncer/métodos , Estadiamento de Neoplasias , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Idoso
17.
Cancer Epidemiol ; 83: 102333, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36758349

RESUMO

OBJECTIVE: Gastric carcinoma (GC) has received extensive attention due to its complex pathogenesis. Studies have shown that the expression of Trefoil factor 1 (TFF1) and Partner and localiser of BRCA2 (PALB2) genes promotes the occurrence of GC. Therefore, we investigated whether TFF1 and PALB2 gene polymorphisms are associated with GC risk in the Chinese Han population. METHODS: A total of 509 GC cases and 505 controls were recruited, and single nucleotide polymorphisms (SNPs) of TFF1 and PALB2 in these subjects were genotyped. The association between each candidate polymorphism and GC risk was assessed by calculating odds ratios (ORs) and 95% confidence intervals (CIs). The visualization of gene-gene interactions and functional enrichment analysis were then performed using Cytoscape software and the R package "cluster profile". RESULTS: The TFF1 rs2156310 polymorphism significantly reduced the predisposition to GC in people under 60 years of age (AA vs. AG - GG, OR = 0.58, 95% CI = 0.35-0.97, p = 0.036). The gender-stratified analysis found that PALB2 rs513313 was significantly associated with the risk of GC in males (CT vs. TT, OR = 1.51, 95% CI = 1.06-2.15, p = 0.022). Besides, PALB2 rs249954 significantly reduced the susceptibility to GC in females (AA vs GG, OR = 0.42, 95% CI = 0.19-0.94, p = 0.034). CONCLUSION: Our results revealed that TFF1 and PALB2 gene polymorphisms were correlated with the genetic susceptibility to GC, providing certain data support for researchers to further study the mechanism of GC.


Assuntos
Carcinoma , Neoplasias Gástricas , Masculino , Feminino , Humanos , Fator Trefoil-1/genética , População do Leste Asiático , Predisposição Genética para Doença , Genótipo , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , China , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética
18.
J Clin Oncol ; 41(9): 1703-1713, 2023 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-36623243

RESUMO

PURPOSE: To estimate the risk of contralateral breast cancer (CBC) among women with germline pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2. METHODS: The study population included 15,104 prospectively followed women within the CARRIERS study treated with ipsilateral surgery for invasive breast cancer. The risk of CBC was estimated for PV carriers in each gene compared with women without PVs in a multivariate proportional hazard regression analysis accounting for the competing risk of death and adjusting for patient and tumor characteristics. The primary analyses focused on the overall cohort and on women from the general population. Secondary analyses examined associations by race/ethnicity, age at primary breast cancer diagnosis, menopausal status, and tumor estrogen receptor (ER) status. RESULTS: Germline BRCA1, BRCA2, and CHEK2 PV carriers with breast cancer were at significantly elevated risk (hazard ratio > 1.9) of CBC, whereas only the PALB2 PV carriers with ER-negative breast cancer had elevated risks (hazard ratio, 2.9). By contrast, ATM PV carriers did not have significantly increased CBC risks. African American PV carriers had similarly elevated risks of CBC as non-Hispanic White PV carriers. Among premenopausal women, the 10-year cumulative incidence of CBC was estimated to be 33% for BRCA1, 27% for BRCA2, and 13% for CHEK2 PV carriers with breast cancer and 35% for PALB2 PV carriers with ER-negative breast cancer. The 10-year cumulative incidence of CBC among postmenopausal PV carriers was 12% for BRCA1, 9% for BRCA2, and 4% for CHEK2. CONCLUSION: Women diagnosed with breast cancer and known to carry germline PVs in BRCA1, BRCA2, CHEK2, or PALB2 are at substantially increased risk of CBC and may benefit from enhanced surveillance and risk reduction strategies.


Assuntos
Neoplasias da Mama , Predisposição Genética para Doença , Feminino , Humanos , Proteínas Mutadas de Ataxia Telangiectasia/genética , Negro ou Afro-Americano/genética , Negro ou Afro-Americano/estatística & dados numéricos , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etnologia , Neoplasias da Mama/genética , Neoplasias da Mama/cirurgia , Quinase do Ponto de Checagem 2/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Genes BRCA2 , Predisposição Genética para Doença/genética , Mutação em Linhagem Germinativa , Heterozigoto , Brancos/genética , Brancos/estatística & dados numéricos
19.
J Clin Pathol ; 76(2): 73-75, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36600573

RESUMO

The partner and localiser of BRCA2 (PALB2) gene, located on chromosome 16, functions as a tumour suppressor that plays a critical role in homologous recombination repair after DNA double-strand breaks. It encodes proteins involved in the BRCA2 and BRCA1, and RAD51 pathways. Heterozygous germline mutations in PALB2 have been implicated in the development of breast, pancreatic and ovarian cancers. Whereas biallelic mutations of PALB2 have been associated with Fanconi anaaemia. Currently, 604 distinct PALB2 variants have been discovered. However, only 140 variants are thought to be pathogenic and approximately 400 are variants of unknown significance. Further studies are needed before the presence of PLAB2 mutations can be implemented as a routine clinical biomarker.


Assuntos
Neoplasias da Mama , Proteínas Supressoras de Tumor , Feminino , Humanos , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Proteínas Nucleares/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/metabolismo , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Proteína BRCA1/genética , Reparo do DNA , Mutação , Neoplasias da Mama/genética , Predisposição Genética para Doença
20.
J Med Genet ; 60(2): 112-118, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-35396271

RESUMO

BACKGROUND: PALB2 is the most important contributor to familial breast cancer after BRCA1 and BRCA2. Large genomic rearrangements (LGRs) in BRCA1 and BRCA2 are routinely assessed in clinical testing and are a significant contributor to the yield of actionable findings. In contrast, the contribution of LGRs in PALB2 has not been systematically studied. METHODS: We performed targeted sequencing and real-time qPCR validation to identify LGRs in PALB2 in 5770 unrelated patients with familial breast cancer and 5741 cancer-free control women from the same Australian population. RESULTS: Seven large deletions ranging in size from 0.96 kbp to 18.07 kbp involving PALB2 were identified in seven cases, while no LGRs were identified in any of the controls. Six LGRs were considered pathogenic as they included one or more exons of PALB2 and disrupted the WD40 domain at the C terminal end of the PALB2 protein while one LGR only involved a partial region of intron 10 and was considered a variant of unknown significance. Altogether, pathogenic LGRs identified in this study accounted for 10.3% (6 of 58) of the pathogenic PALB2 variants detected among the 5770 families with familial breast cancer. CONCLUSIONS: Our data show that a clinically important proportion of PALB2 pathogenic mutations in Australian patients with familial breast cancer are LGRs. Such observations have provided strong support for inclusion of PALB2 LGRs in routine clinical genetic testing.


Assuntos
Neoplasias da Mama , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Genes BRCA1 , Genes BRCA2 , Neoplasias Ovarianas/genética , Austrália/epidemiologia , Testes Genéticos , Proteína BRCA1/genética , Proteína BRCA2/genética , Genômica , Predisposição Genética para Doença , Mutação em Linhagem Germinativa
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...