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1.
N Engl J Med ; 384(5): 428-439, 2021 02 04.
Artículo en Inglés | MEDLINE | ID: mdl-33471991

RESUMEN

BACKGROUND: Genetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking. METHODS: We used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity. RESULTS: Protein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) were associated with a risk of breast cancer overall with a P value of less than 0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D, and TP53) were associated with a risk of breast cancer overall with a P value of less than 0.05 and a Bayesian false-discovery probability of less than 0.05. For protein-truncating variants in 19 of the remaining 25 genes, the upper limit of the 95% confidence interval of the odds ratio for breast cancer overall was less than 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios were higher for estrogen receptor (ER)-positive disease than for ER-negative disease; for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D, odds ratios were higher for ER-negative disease than for ER-positive disease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 were associated with a risk of breast cancer overall with a P value of less than 0.001. For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk of breast cancer overall, with the risk being similar to that of protein-truncating variants. CONCLUSIONS: The results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.).


Asunto(s)
Neoplasias de la Mama/genética , Predisposición Genética a la Enfermedad/genética , Variación Genética , Mutación Missense , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Modelos Logísticos , Persona de Mediana Edad , Oportunidad Relativa , Riesgo , Análisis de Secuencia de ADN , Adulto Joven
2.
BMC Cancer ; 23(1): 738, 2023 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-37563628

RESUMEN

BACKGROUND: Genetic screening for pathogenic variants (PVs) in cancer predisposition genes can affect treatment strategies, risk prediction and preventive measures for patients and families. For decades, hereditary breast and ovarian cancer (HBOC) has been attributed to PVs in the genes BRCA1 and BRCA2, and more recently other rare alleles have been firmly established as associated with a high or moderate increased risk of developing breast and/or ovarian cancer. Here, we assess the genetic variation and tumor characteristics in a large cohort of women with suspected HBOC in a clinical oncogenetic setting. METHODS: Women with suspected HBOC referred from all oncogenetic clinics in Sweden over a six-year inclusion period were screened for PVs in 13 clinically relevant genes. The genetic outcome was compared with tumor characteristics and other clinical data collected from national cancer registries and hospital records. RESULTS: In 4622 women with breast and/or ovarian cancer the overall diagnostic yield (the proportion of women carrying at least one PV) was 16.6%. BRCA1/2 PVs were found in 8.9% of women (BRCA1 5.95% and BRCA2 2.94%) and PVs in the other breast and ovarian cancer predisposition genes in 8.2%: ATM (1.58%), BARD1 (0.45%), BRIP1 (0.43%), CDH1 (0.11%), CHEK2 (3.46%), PALB2 (0.84%), PTEN (0.02%), RAD51C (0.54%), RAD51D (0.15%), STK11 (0) and TP53 (0.56%). Thus, inclusion of the 11 genes in addition to BRCA1/2 increased diagnostic yield by 7.7%. The yield was, as expected, significantly higher in certain subgroups such as younger patients, medullary breast cancer, higher Nottingham Histologic Grade, ER-negative breast cancer, triple-negative breast cancer and high grade serous ovarian cancer. Age and tumor subtype distributions differed substantially depending on genetic finding. CONCLUSIONS: This study contributes to understanding the clinical and genetic landscape of breast and ovarian cancer susceptibility. Extending clinical genetic screening from BRCA1 and BRCA2 to 13 established cancer predisposition genes almost doubles the diagnostic yield, which has implications for genetic counseling and clinical guidelines. The very low yield in the syndrome genes CDH1, PTEN and STK11 questions the usefulness of including these genes on routine gene panels.


Asunto(s)
Neoplasias de la Mama , Síndrome de Cáncer de Mama y Ovario Hereditario , Neoplasias Ováricas , Neoplasias de la Mama Triple Negativas , Humanos , Femenino , Proteína BRCA1/genética , Proteína BRCA2/genética , Predisposición Genética a la Enfermedad , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Pruebas Genéticas , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/genética , Proteínas Serina-Treonina Quinasas/genética , Neoplasias de la Mama Triple Negativas/genética , Síndrome de Cáncer de Mama y Ovario Hereditario/diagnóstico , Síndrome de Cáncer de Mama y Ovario Hereditario/genética , Mutación de Línea Germinal
3.
Hum Mutat ; 43(12): 1921-1944, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-35979650

RESUMEN

Skipping of BRCA2 exon 3 (∆E3) is a naturally occurring splicing event, complicating clinical classification of variants that may alter ∆E3 expression. This study used multiple evidence types to assess pathogenicity of 85 variants in/near BRCA2 exon 3. Bioinformatically predicted spliceogenic variants underwent mRNA splicing analysis using minigenes and/or patient samples. ∆E3 was measured using quantitative analysis. A mouse embryonic stem cell (mESC) based assay was used to determine the impact of 18 variants on mRNA splicing and protein function. For each variant, population frequency, bioinformatic predictions, clinical data, and existing mRNA splicing and functional results were collated. Variant class was assigned using a gene-specific adaptation of ACMG/AMP guidelines, following a recently proposed points-based system. mRNA and mESC analysis combined identified six variants with transcript and/or functional profiles interpreted as loss of function. Cryptic splice site use for acceptor site variants generated a transcript encoding a shorter protein that retains activity. Overall, 69/85 (81%) variants were classified using the points-based approach. Our analysis shows the value of applying gene-specific ACMG/AMP guidelines using a points-based approach and highlights the consideration of cryptic splice site usage to appropriately assign PVS1 code strength.


Asunto(s)
Genes BRCA2 , Sitios de Empalme de ARN , Animales , Humanos , Ratones , Empalme Alternativo , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Empalme del ARN , ARN Mensajero/genética , ARN Mensajero/metabolismo
4.
Blood ; 129(8): 950-958, 2017 02 23.
Artículo en Inglés | MEDLINE | ID: mdl-27899358

RESUMEN

Adhesion is a key component of hematopoietic stem cell regulation mediating homing and retention to the niche in the bone marrow. Here, using an RNA interference screen, we identify cytohesin 1 (CYTH1) as a critical mediator of adhesive properties in primary human cord blood-derived hematopoietic stem and progenitor cells (HSPCs). Knockdown of CYTH1 disrupted adhesion of HSPCs to primary human mesenchymal stroma cells. Attachment to fibronectin and ICAM1, 2 integrin ligands, was severely impaired, and CYTH1-deficient cells showed a reduced integrin ß1 activation response, suggesting that CYTH1 mediates integrin-dependent functions. Transplantation of CYTH1-knockdown cells to immunodeficient mice resulted in significantly lower long-term engraftment levels, associated with a reduced capacity of the transplanted cells to home to the bone marrow. Intravital microscopy showed that CYTH1 deficiency profoundly affects HSPC mobility and localization within the marrow space and thereby impairs proper lodgment into the niche. Thus, CYTH1 is a novel major regulator of adhesion and engraftment in human HSPCs through mechanisms that, at least in part, involve the activation of integrins.


Asunto(s)
Factores de Intercambio de Guanina Nucleótido/metabolismo , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/citología , Animales , Antígenos CD/metabolismo , Antígenos CD34/metabolismo , Adhesión Celular , Moléculas de Adhesión Celular/metabolismo , Movimiento Celular , Fibronectinas/metabolismo , Factores de Intercambio de Guanina Nucleótido/genética , Células Madre Hematopoyéticas/metabolismo , Humanos , Integrinas/metabolismo , Molécula 1 de Adhesión Intercelular/metabolismo , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Ratones Endogámicos , Interferencia de ARN
5.
Breast Cancer Res Treat ; 168(1): 117-126, 2018 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-29164420

RESUMEN

PURPOSE: To evaluate a simplified method of pre-test information and germline BRCA1/2 mutation testing. METHODS: In a prospective, single-arm study, comprehensive BRCA1/2 testing was offered to unselected patients with newly diagnosed breast cancer at three hospitals in south Sweden (BRCAsearch, ClinicalTrials.gov Identifier: NCT02557776). Pre-test information was provided by a standardized invitation letter, but the patients could contact a genetic counselor for telephone genetic counseling if they felt a need for that. Noncarriers were informed about the test result through a letter. Mutation carriers were contacted and offered an appointment for in-person post-test genetic counseling. RESULTS: During the period Feb 2, 2015-Aug 26, 2016, eight hundred and eighteen patients were invited to participate in the study. Through Jan 31, 2017, five hundred and forty-two (66.2%) of them consented to analysis of BRCA1 and BRCA2. Eleven pathogenic mutations were found (BRCA1, n = 2; BRCA2, n = 9), corresponding to a mutation prevalence of 2.0%. Six out of 11 fulfilled the Swedish BRCA testing criteria, and 9 out of 11 fulfilled the NCCN testing criteria. None of the BRCA-associated tumors were of the luminal A-like subtype. Very few patients contacted us for telephone genetic counseling or practical questions, suggesting that a majority felt that the written pre-test information was sufficient for them to make a decision on testing. CONCLUSIONS: Streamlining the process of pre-test information, genetic testing, and delivery of test results was feasible and was associated with an uptake of genetic testing in 2/3 of the breast cancer patients.


Asunto(s)
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de la Mama/genética , Predisposición Genética a la Enfermedad , Pruebas Genéticas/métodos , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/diagnóstico , Estudios de Factibilidad , Femenino , Asesoramiento Genético/métodos , Asesoramiento Genético/estadística & datos numéricos , Pruebas Genéticas/estadística & datos numéricos , Mutación de Línea Germinal , Humanos , Persona de Mediana Edad , Aceptación de la Atención de Salud/estadística & datos numéricos , Estudios Prospectivos , Suecia
6.
Genet Med ; 20(4): 452-457, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-28837162

RESUMEN

PurposeMonoallelic germ-line mutations in the BRCA1/FANCS, BRCA2/FANCD1 and PALB2/FANCN genes confer high risk of breast cancer. Biallelic mutations in these genes cause Fanconi anemia (FA), characterized by malformations, bone marrow failure, chromosome fragility, and cancer predisposition (BRCA2/FANCD1 and PALB2/FANCN), or an FA-like disease presenting a phenotype similar to FA but without bone marrow failure (BRCA1/FANCS). FANCM monoallelic mutations have been reported as moderate risk factors for breast cancer, but there are no reports of any clinical phenotype observed in carriers of biallelic mutations.MethodsBreast cancer probands were subjected to mutation analysis by sequencing gene panels or testing DNA damage response genes.ResultsFive cases homozygous for FANCM loss-of-function mutations were identified. They show a heterogeneous phenotype including cancer predisposition, toxicity to chemotherapy, early menopause, and possibly chromosome fragility. Phenotype severity might correlate with mutation position in the gene.ConclusionOur data indicate that biallelic FANCM mutations do not cause classical FA, providing proof that FANCM is not a canonical FA gene. Moreover, our observations support previous findings suggesting that FANCM is a breast cancer-predisposing gene. Mutation testing of FANCM might be considered for individuals with the above-described clinical features.


Asunto(s)
Alelos , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Fragilidad Cromosómica , ADN Helicasas/genética , Anemia de Fanconi/diagnóstico , Anemia de Fanconi/genética , Predisposición Genética a la Enfermedad , Mutación , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Consanguinidad , Resistencia a Antineoplásicos/genética , Femenino , Estudios de Asociación Genética , Genotipo , Mutación de Línea Germinal , Humanos , Masculino , Linaje , Fenotipo , Medición de Riesgo , Factores de Riesgo
7.
Proc Natl Acad Sci U S A ; 112(7): 2157-62, 2015 Feb 17.
Artículo en Inglés | MEDLINE | ID: mdl-25646469

RESUMEN

Breast cancer type 1 susceptibility protein (BRCA1) has a multitude of functions that contribute to genome integrity and tumor suppression. Its participation in the repair of DNA double-strand breaks (DSBs) during homologous recombination (HR) is well recognized, whereas its involvement in the second major DSB repair pathway, nonhomologous end-joining (NHEJ), remains controversial. Here we have studied the role of BRCA1 in the repair of DSBs in switch (S) regions during immunoglobulin class switch recombination, a physiological, deletion/recombination process that relies on the classical NHEJ machinery. A shift to the use of microhomology-based, alternative end-joining (A-EJ) and increased frequencies of intra-S region deletions as well as insertions of inverted S sequences were observed at the recombination junctions amplified from BRCA1-deficient human B cells. Furthermore, increased use of long microhomologies was found at recombination junctions derived from E3 ubiquitin-protein ligase RNF168-deficient, Fanconi anemia group J protein (FACJ, BRIP1)-deficient, or DNA endonuclease RBBP8 (CtIP)-compromised cells, whereas an increased frequency of S-region inversions was observed in breast cancer type 2 susceptibility protein (BRCA2)-deficient cells. Thus, BRCA1, together with its interaction partners, seems to play an important role in repairing DSBs generated during class switch recombination by promoting the classical NHEJ pathway. This may not only provide a general mechanism underlying BRCA1's function in maintaining genome stability and tumor suppression but may also point to a previously unrecognized role of BRCA1 in B-cell lymphomagenesis.


Asunto(s)
Linfocitos B/metabolismo , Proteína BRCA1/genética , Reparación del ADN , Cambio de Clase de Inmunoglobulina , Recombinación Genética , Humanos
8.
J Pathol ; 233(1): 39-50, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24399611

RESUMEN

Diversity between metastatic melanoma tumours in individual patients is known; however, the molecular and genetic differences remain unclear. To examine the molecular and genetic differences between metastatic tumours, we performed gene-expression profiling of 63 melanoma tumours obtained from 28 patients (two or three tumours/patient), followed by analysis of their mutational landscape, using targeted deep sequencing of 1697 cancer genes and DNA copy number analysis. Gene-expression signatures revealed discordant phenotypes between tumour lesions within a patient in 50% of the cases. In 18 of 22 patients (where matched normal tissue was available), we found that the multiple lesions within a patient were genetically divergent, with one or more melanoma tumours harbouring 'private' somatic mutations. In one case, the distant subcutaneous metastasis of one patient occurring 3 months after an earlier regional lymph node metastasis had acquired 37 new coding sequence mutations, including mutations in PTEN and CDH1. However, BRAF and NRAS mutations, when present in the first metastasis, were always preserved in subsequent metastases. The patterns of nucleotide substitutions found in this study indicate an influence of UV radiation but possibly also DNA alkylating agents. Our results clearly demonstrate that metastatic melanoma is a molecularly highly heterogeneous disease that continues to progress throughout its clinical course. The private aberrations observed on a background of shared aberrations within a patient provide evidence of continued evolution of individual tumours following divergence from a common parental clone, and might have implications for personalized medicine strategies in melanoma treatment.


Asunto(s)
Biomarcadores de Tumor/genética , Melanoma/genética , Melanoma/secundario , Mutación , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD , Cadherinas/genética , Cromosomas Humanos , Variaciones en el Número de Copia de ADN , Análisis Mutacional de ADN/métodos , Progresión de la Enfermedad , Femenino , GTP Fosfohidrolasas/genética , Dosificación de Gen , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Reordenamiento Génico , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Metástasis Linfática , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Fosfohidrolasa PTEN/genética , Fenotipo , Proteínas Proto-Oncogénicas B-raf/genética , Transcriptoma
9.
Breast Cancer Res ; 15(3): 402, 2013 Jun 21.
Artículo en Inglés | MEDLINE | ID: mdl-23809231

RESUMEN

Linkage analysis, positional cloning, candidate gene mutation scanning and genome-wide association study approaches have all contributed significantly to our understanding of the underlying genetic architecture of breast cancer. Taken together, these approaches have identified genetic variation that explains approximately 30% of the overall familial risk of breast cancer, implying that more, and likely rarer, genetic susceptibility alleles remain to be discovered.


Asunto(s)
Neoplasias de la Mama/genética , Predisposición Genética a la Enfermedad , Femenino , Ligamiento Genético , Estudio de Asociación del Genoma Completo , Humanos , Mutación
10.
Sci Rep ; 13(1): 8536, 2023 05 26.
Artículo en Inglés | MEDLINE | ID: mdl-37237042

RESUMEN

BOADICEA is a comprehensive risk prediction model for breast and/or ovarian cancer (BC/OC) and for carrying pathogenic variants (PVs) in cancer susceptibility genes. In addition to BRCA1 and BRCA2, BOADICEA version 6 includes PALB2, CHEK2, ATM, BARD1, RAD51C and RAD51D. To validate its predictions for these genes, we conducted a retrospective study including 2033 individuals counselled at clinical genetics departments in Denmark. All counselees underwent comprehensive genetic testing by next generation sequencing on suspicion of hereditary susceptibility to BC/OC. Likelihoods of PVs were predicted from information about diagnosis, family history and tumour pathology. Calibration was examined using the observed-to-expected ratio (O/E) and discrimination using the area under the receiver operating characteristics curve (AUC). The O/E was 1.11 (95% CI 0.97-1.26) for all genes combined. At sub-categories of predicted likelihood, the model performed well with limited misestimation at the extremes of predicted likelihood. Discrimination was acceptable with an AUC of 0.70 (95% CI 0.66-0.74), although discrimination was better for BRCA1 and BRCA2 than for the other genes in the model. This suggests that BOADICEA remains a valid decision-making aid for determining which individuals to offer comprehensive genetic testing for hereditary susceptibility to BC/OC despite suboptimal calibration for individual genes in this population.


Asunto(s)
Neoplasias de la Mama , Neoplasias Ováricas , Humanos , Femenino , Estudios Retrospectivos , Pruebas Genéticas , Genes BRCA2 , Predisposición Genética a la Enfermedad , Neoplasias de la Mama/diagnóstico , Neoplasias Ováricas/genética , Neoplasias Ováricas/epidemiología
11.
Mol Genet Metab ; 102(1): 82-90, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-20947401

RESUMEN

High testosterone levels have been associated with breast cancer. BRCA1 may function as an androgen receptor (AR) co-regulator. We aimed to examine AR haplotype-tagging single-nucleotide polymorphisms (AR htSNPs) and diplotypes in relation to in vivo androgen levels, combined OC use, CAG and GGC genotypes, and BRCA1/2/X family status in 269 young healthy women from breast cancer high-risk families and 56 additional BRCA1/2 mutation carriers. Testosterone, androstenedione, dehydroepiandrosterone sulfate, and body constitution were measured on cycle days 18-23. Six AR htSNPs and CAG and GGC repeat lengths were genotyped. Most OC users had lower androgen levels than non-users (all Ps<0.0001). Rare variant diplotypes were associated with higher testosterone levels in OC users than in non-users (P(interaction)=0.011). The interaction remained after adjustment for family clustering. Neither individual AR htSNPs nor other diplotypes were significantly associated with androgen levels and did not tag for CAG or GGC genotypes. In the first included woman from each family, the odds of having the most common diplotype was lower in BRCA1 families compared to other families OR 0.41 (95% CI 0.22-0.78). In conclusion, we found few associations between AR htSNPs or diplotypes and androgen levels in women. Diplotypes cannot replace genotyping of microsatellites CAG or GGC. Since testosterone levels are not affected the same way by combined OC use among all women, young women who have higher testosterone levels during combined OC use may belong to the subgroup of women who will not be helped by combined OCs for treatment of androgen-dependent conditions and may be at higher risk for early-onset breast cancer. Whether these women can be identified with AR genotyping needs to be confirmed in an independent cohort.


Asunto(s)
Andrógenos/sangre , Neoplasias de la Mama/genética , Anticonceptivos Orales Combinados , Haplotipos , Polimorfismo de Nucleótido Simple , Receptores Androgénicos/genética , Adulto , Secuencia de Bases , Neoplasias de la Mama/epidemiología , Femenino , Genes BRCA1 , Genes BRCA2 , Marcadores Genéticos , Humanos , Repeticiones de Microsatélite , Factores de Riesgo , Adulto Joven
12.
Cancers (Basel) ; 13(20)2021 Oct 19.
Artículo en Inglés | MEDLINE | ID: mdl-34680387

RESUMEN

BACKGROUND: We examined whether molecular characterization of high-grade epithelial ovarian cancer can inform the diagnosis and/or identify potential actionable targets. METHODS: All of the consecutively sequenced high-grade ovarian tumours with consent between 2014 until 2019 were included. A total of 274 tumours underwent next generation sequencing using a targeted panel. RESULTS: Patients with high-grade ovarian epithelial cancer were consented to prospective molecular characterization. Clinical information was extracted from their medical record. Tumour DNA was subjected to sequencing, and selected patients received PARP inhibitor therapy. CONCLUSIONS: Tumours from 274 women were sequenced, including high-grade serous carcinoma (n = 252), clear cell carcinoma (n = 4), carcinosarcoma (n = 9), endometrioid carcinoma (n = 3), undifferentiated carcinoma (n = 1), and mixed tumours (n = 5). Genomic profiling did not influence histologic diagnosis. Mutations were identified in TP53, BRCA1, BRCA2, as well as additional homologous recombination repair pathway genes BARD1, ATR, CHEK2, PALB2, RAD51D, RAD50, SLX4, FANCA, RAD51C, and RAD54L. In addition, mutations in PTEN and CDKN2A were identified. Several somatic mutations with implications for germline testing were identified, including RMI1, STK11, and CDH1. Germline testing identified 16 previously unknown BRCA1/2 carriers. Finally, 20 patients were treated with the PARP inhibitor olaparib based on the sequencing results.

13.
Hum Mutat ; 31(3): E1200-40, 2010 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-20104584

RESUMEN

BRCA1 and BRCA2 screening in women at high-risk of breast cancer results in the identification of both unambiguously defined deleterious mutations and sequence variants of unknown clinical significance (VUS). We examined a population-based sample of young women with contralateral breast cancer (CBC, n=705) or unilateral breast cancer (UBC, n=1398). We identified 470 unique sequence variants, of which 113 were deleterious mutations. The remaining 357 VUS comprised 185 unique missense changes, 60% were observed only once, while 3% occurred with a frequency of >10%. Deleterious mutations occurred three times more often in women with CBC (15.3%) than in women with UBC (5.2%), whereas combined, VUS were observed in similar frequencies in women with CBC and UBC. A protein alignment algorithm defined 16 rare VUS, occurring at highly conserved residues and/or conferring a considerable biochemical difference, the majority located in the BRCA2 DNA-binding domain. We confirm a multiplicity of BRCA1 and BRCA2 VUS that occur at a wide range of allele frequencies. Although some VUS inflict chemical differences at conserved residues, suggesting a deleterious effect, the majority are not associated with an increased risk of CBC.


Asunto(s)
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de la Mama/genética , Mutación , Adulto , Alelos , Proteínas Reguladoras de la Apoptosis , Análisis Mutacional de ADN , Femenino , Eliminación de Gen , Frecuencia de los Genes , Variación Genética , Humanos , Persona de Mediana Edad , Mutación Missense , Unión Proteica
14.
Breast Cancer Res Treat ; 120(1): 175-83, 2010 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19597986

RESUMEN

The potential effects of oral contraceptive (OC) and postmenopausal hormone (PMH) use are not well understood among BRCA1 or BRCA2 (BRCA1/2) deleterious mutation carriers with a history of breast cancer. We investigated the association between OC and PMH use and risk of contralateral breast cancer (CBC) in the WECARE (Women's Environment, Cancer, and Radiation Epidemiology) Study. The WECARE Study is a population-based case-control study of 705 women with asynchronous CBC and 1,398 women with unilateral breast cancer, including 181 BRCA1/2 mutation carriers. Risk-factor information was assessed by telephone interview. Mutation status was measured using denaturing high-performance liquid chromatography followed by direct sequencing in all participants. Outcomes, treatment, and tumor characteristics were abstracted from medical records. Ever use of OCs was not associated with risk among noncarriers (RR = 0.87; 95% CI = 0.66-1.15) or BRCA2 carriers (RR = 0.82; 95% CI = 0.21-3.13). BRCA1 carriers who used OCs had a nonsignificant greater risk than nonusers (RR = 2.38; 95% CI = 0.72-7.83). Total duration of OC use and at least 5 years of use before age 30 were associated with a nonsignificant increased risk among mutation carriers but not among noncarriers. Few women had ever used PMH and we found no significant associations between lifetime use and CBC risk among carriers and noncarriers. In conclusion, the association between OC/PMH use and risk of CBC does not differ significantly between carriers and noncarriers; however, because carriers have a higher baseline risk of second primaries, even a potential small increase in risk as a result of OC use may be clinically relevant.


Asunto(s)
Neoplasias de la Mama/inducido químicamente , Neoplasias de la Mama/genética , Anticonceptivos Orales/efectos adversos , Terapia de Reemplazo de Estrógeno/efectos adversos , Neoplasias Primarias Secundarias/inducido químicamente , Neoplasias Primarias Secundarias/genética , Adulto , Estudios de Casos y Controles , Cromatografía Líquida de Alta Presión , Femenino , Genes BRCA1 , Genes BRCA2 , Predisposición Genética a la Enfermedad , Heterocigoto , Humanos , Persona de Mediana Edad , Mutación , Factores de Riesgo , Adulto Joven
15.
Breast Cancer Res Treat ; 123(2): 491-8, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20135344

RESUMEN

Given the greatly elevated risks of contralateral breast cancer (CBC) observed in breast cancer patients who carry mutations in BRCA1 and BRCA2, it is critical to determine the effectiveness of standard adjuvant therapies in preventing CBC in mutation carriers. The WECARE study is a matched, case-control study of 708 women with CBC as cases and 1,399 women with unilateral breast cancer (UBC) as controls, including 181 BRCA1/BRCA2 mutation carriers. Interviews and medical record reviews provided detailed information on risk factors and breast cancer therapy. All study participants were screened for BRCA1 and BRCA2 mutations using denaturing high-performance liquid chromatography (DHPLC) to detect genetic variants in the coding and flanking regions of the genes. Conditional logistic regression was used to compare the risk of CBC associated with chemotherapy and tamoxifen in BRCA1/BRCA2 mutation carriers and non-carriers. Chemotherapy was associated with lower CBC risk both in non-carriers (RR = 0.6 [95% CI: 0.5-0.7]) and carriers (RR = 0.5 [95% CI: 0.2-1.0]; P value = 0.04). Tamoxifen was associated with a reduced CBC risk in non-carriers (RR = 0.7 [95% CI: 0.6-1.0]; P value = 0.03). We observed a similar but non-significant reduction associated with tamoxifen in mutation carriers (RR = 0.7 [95% CI: 0.3-1.8]). The tests of heterogeneity comparing carriers to non-carriers did not provide evidence for a difference in the associations with chemotherapy (P value = 0.51) nor with tamoxifen (P value = 0.15). Overall, we did not observe a difference in the relative risk reduction associated with adjuvant treatment between BRCA1/BRCA2 mutation carriers and non-carriers. However, given the higher absolute CBC risk in mutation carriers, the potentially greater impact of adjuvant therapy in reducing CBC risk among mutation carriers should be considered when developing treatment plans for these patients.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de la Mama/tratamiento farmacológico , Mutación , Recurrencia Local de Neoplasia/prevención & control , Adulto , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Estudios de Casos y Controles , Quimioterapia Adyuvante , Análisis Mutacional de ADN , Dinamarca , Femenino , Humanos , Funciones de Verosimilitud , Modelos Logísticos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Sistema de Registros , Medición de Riesgo , Factores de Riesgo , Programa de VERF , Tamoxifeno/administración & dosificación , Resultado del Tratamiento , Estados Unidos , Adulto Joven
16.
Cancer Causes Control ; 21(6): 839-46, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20130978

RESUMEN

OBJECTIVE: Reproductive factors, such as early age at menarche, late age at menopause, and nulliparity are known risk factors for breast cancer. Previously, we reported these factors to be associated with risk of developing contralateral breast cancer (CBC). In this study, we evaluated the association between these factors and CBC risk among BRCA1 and BRCA2 (BRCA1/2) mutation carriers and non-carriers. METHODS: The WECARE Study is a population-based multi-center case-control study of 705 women with CBC (cases) and 1,397 women with unilateral breast cancer (controls). All participants were screened for BRCA1/2 mutations and 181 carriers were identified. Conditional logistic regression models were used to evaluate associations between reproductive factors and CBC for mutation carriers and non-carriers. RESULTS: None of the associations between reproductive factors and CBC risk differed between mutation carriers and non-carriers. The increase in risk with younger age at menarche and decrease in risk in women with more than two full-term pregnancies seen in non-carriers were not significantly different in carriers (adjusted RRs = 1.31, 95% CI 0.65-2.65 and 0.53, 95% CI 0.19-1.51, respectively). No significant associations between the other reproductive factors and CBC risk were observed in mutation carriers or non-carriers. CONCLUSION: For two reproductive factors previously shown to be associated with CBC risk, we observed similar associations for BRCA1/2 carriers. This suggests that reproductive variables that affect CBC risk may have similar effects in mutation carriers and non-carriers.


Asunto(s)
Proteína BRCA2/genética , Neoplasias de la Mama/genética , Genes BRCA2 , Mutación , Historia Reproductiva , Neoplasias de la Mama/inducido químicamente , Estudios de Casos y Controles , Femenino , Humanos , Modelos Logísticos , Menarquia/genética , Menopausia/genética , Neoplasias/inducido químicamente , Neoplasias/genética , Paridad/genética , Embarazo , Riesgo , Factores de Riesgo
18.
Hum Mutat ; 29(4): 555-64, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18330910

RESUMEN

Disease-predisposing germline mutations in cancer susceptibility genes may consist of large genomic rearrangements that are challenging to detect and characterize using standard PCR-based mutation screening methods. Here, we describe a custom-made zoom-in microarray comparative genomic hybridization (CGH) platform of 60mer oligonucleotides. The 4 x 44 K array format provides high-resolution coverage (200-300 bp) of 400-700 kb genomic regions surrounding six cancer susceptibility genes. We evaluate its performance to accurately detect and precisely map earlier described or novel large germline deletions or duplications occurring in BRCA1 (n=11), BRCA2 (n=2), MSH2 (n=7), or MLH1 (n=9). Additionally, we demonstrate its applicability for uncovering complex somatic rearrangements, exemplified by zoom-in analysis of the PTEN and CDKN2A loci in breast cancer cells. The sizes of rearrangements ranged from several 100 kb, including large flanking regions, to <500-bp deletions, including parts of single exons that would be missed by standard multiplex ligation-dependent probe amplification (MLPA) methods. Zoom-in CGH arrays accurately defined the borders of rearrangements, allowing convenient design of primers for sequence determination of the breakpoints. The array platform can be streamlined for a particular application, e.g., focusing on breast cancer susceptibility genes, with increased capacity using multiformat design, and represents a valuable new tool and complement for genetic screening in clinical diagnostics.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Genes BRCA1 , Genes BRCA2 , Mutación de Línea Germinal , Proteína 2 Homóloga a MutS/genética , Proteínas Nucleares/genética , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Mapeo Cromosómico/métodos , Femenino , Reordenamiento Génico , Asesoramiento Genético , Pruebas Genéticas , Genómica , Humanos , Masculino , Homólogo 1 de la Proteína MutL , Hibridación de Ácido Nucleico , Eliminación de Secuencia
20.
Fam Cancer ; 16(2): 195-203, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-27696107

RESUMEN

Hereditary syndromes causing colorectal cancer include both polyposis and non-polyposis syndromes. Overlapping phenotypes between the syndromes have been recognized and this make targeted molecular testing for single genes less favorable, instead there is a gaining interest for multi-gene panel-based approaches detecting both SNVs, indels and CNVs in the same assay. We applied a panel including 19 CRC susceptibility genes to 91 individuals of six phenotypic subgroups. Targeted NGS-based sequencing of the whole gene regions including introns of the 19 genes was used. The individuals had a family history of CRC or had a phenotype consistent with a known CRC syndrome. The purpose of the study was to demonstrate the diagnostic difficulties linked to genotype-phenotype diversity and the benefits of using a gene panel. Pathogenicity classification was carried out on 46 detected variants. In total we detected sixteen pathogenic or likely pathogenic variants and 30 variants of unknown clinical significance. Four of the pathogenic or likely pathogenic variants were found in BMPR1A in patients with unexplained familial adenomatous polyposis or atypical adenomatous polyposis, which extends the genotype-phenotype spectrum for this gene. Nine patients had more than one variant remaining after the filtration, including three with truncating mutations in BMPR1A, PMS2 and AXIN2. CNVs were found in three patients, in upstream regions of SMAD4, MSH3 and CTNNB1, and one additional individual harbored a 24.2 kb duplication in CDH1 intron1.


Asunto(s)
Poliposis Adenomatosa del Colon/genética , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Variaciones en el Número de Copia de ADN/genética , Pruebas Genéticas/métodos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD , Proteína Axina/genética , Cadherinas/genética , Proteínas de Unión al ADN/genética , Femenino , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Intrones , Masculino , Persona de Mediana Edad , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/genética , Proteína 3 Homóloga de MutS , Mutación , Fenotipo , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADN , Proteína Smad4/genética , Adulto Joven , beta Catenina/genética
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