Association of germline variation with the survival of women with BRCA1/2 pathogenic variants and breast cancer

Muranen, Taru; Khan, Sofia; Fagerholm, Rainer; Aittomäki, Kristiina; Cunningham, Julie M.; Dennis, Joe; Leslie, Goska; McGuffog, Lesley; Parsons, Michael T.; Simard, Jacques; Slager, Susan L.; Soucy, Penny; Easton, Douglas F.; Tischkowitz, Marc; Spurdle, Amanda B.; Investigators, kConFab; Schmutzler, Rita K.; Wappenschmidt, Barbara; Hahnen, Eric; Hooning, Maartje J.; Investigators, Hebon; Singer, Christian F.; Wagner, Gabriel; Thomassen, Mads; Pedersen, Inge Søkilde; Domchek, Susan M.; Nathanson, Katherine L.; Lázaro, Conxi; Rossing, Caroline Maria; Andrulis, Irene L.; Teixeira, Manuel R.; James, Paul; Garber, Judy E.; Weitzel, Jeffrey N.; Investigators, Swe-Brca; Jakubowska, Anna; Yannoukakos, Drakoulis; John, Esther M.; Southey, Melissa C.; Schmidt, Marjanka K.; Antoniou, Antonis C.; Chenevix-Trench, Georgia; Blomqvist, Carl; Nevanlinna, Heli

doi:10.1038/s41523-020-00185-6

Cited by 5 publications

(7 citation statements)

References 82 publications

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“…(2018) publicaron un estudio que incluyó 338 mujeres con CM y VP en BRCA1/2 cuya edad de diagnóstico fue de 35 y 37 años respectivamente (6) ; similar observación informan Muraren y col (2020) (22) . Por otra parte, otros autores, estudiaron mujeres con CM y CO con VP en BRCA1/2 y no observaron diferencias en la edad de diagnóstico entre los grupos de estudio (7,9,23) .…”

Section: Discussionunclassified

“…Diferentes autores (8,23,24) mencionan en artículos de los últimos años, resultados similares en donde se destaca la presencia de tumores TN entre los casos con VP en BRCA1 en el 30-35%, y en BRCA2 en el 20%; observando que nuestro trabajo es concordante con la mayor frecuencia de CM triple negativo entre los casos con VP en BRCA1/2. Respecto a las VP halladas en la muestra, observamos que corresponden al 25% y el porcentaje de variantes noveles fue del 10,0%; estos resultados son consistentes con lo publicado por otros autores (16)(17)(22)(23)(24)26) . De las variantes nóveles, tres fueron en BRCA1 y sólo una fue en BRCA2.…”

Section: Discussionunclassified

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Características clínicas de pacientes con Cáncer de Mama y / o Cáncer de Ovario con mutaciones en los genes BRCA1 y BRCA2 en Córdoba, Argentina

Martin

Villasmil

Sembaj

et al. 2022

Rev Fac Cien Med Univ Nac Cordoba

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Introducción: Los síndromes de predisposición hereditaria al cáncer representan un 5-10% de los casos de cáncer, el más estudiado es HBOC producido por mutaciones en los genes BRCA1/2. Objetivos: Describir características clínicas, histopatológicas y VP en pacientes con HBOC en Córdoba, Argentina y compararla con aquellas sin mutaciones en BRCA1/2. Métodos: Análisis transversal, correlacional y observacional de pacientes de Córdoba. Se utilizó la prueba ANOVA, t de Student, tablas de contingencia y prueba exacta de Fisher, el nivel de significancia fue α=0,05. Resultados: Se estudiaron 155 mujeres con CM, CO y CM/CO. Se identificaron 40 mutaciones en BRCA1/2. No se encontraron diferencias en edad de diagnóstico entre pacientes con y sin mutaciones en BRCA1/2. Se encontró asociación significativa entre VP en BRCA1/2 y el tipo de cáncer (p=0,003); todos los casos con CM/CO presentaron mutaciones en BRCA1/2. No se encontró asociación significativa entre mutados/no mutados y AP, AF, RE-RP-HER2. El 23.1% y 38.1% de los casos de CM fueron TN en individuos con VP en BRCA 1 y 2 respectivamente. La prevalencia de mutaciones fue 25,8% y la prevalencia de VP noveles del 10,0%. Conclusiones: Las pacientes con CM-VP BRCA1/2 están asociadas con histología ductal, y menor edad de presentación con VP BRCA1. No encontramos diferencias significativas en edad de diagnóstico del CM entre pacientes con mutaciones BRCA1 y BRCA2, se observa una mayor proporción CM TN que en la población en general. En nuestra muestra, la prevalencia de mutaciones en BRCA1/2 entre los pacientes que reúnen criterios para HBOC es del 25,8%, con 10% de VP noveles.

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Section: Discussionunclassified

Características clínicas de pacientes con Cáncer de Mama y / o Cáncer de Ovario con mutaciones en los genes BRCA1 y BRCA2 en Córdoba, Argentina

Martin

Villasmil

Sembaj

et al. 2022

Rev Fac Cien Med Univ Nac Cordoba

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“…Then, RNA is isolated for reverse transcription, and the chimeric transcripts generated from both wild-type and mutant constructs are compared by PCR and sequencing to determine splicing changes. Several studies have shown that the impacts of variants on splicing patterns and protein functions are not always equivalent; they can vary depending on the proportions of truncated and functional isoforms (37)(38)(39)(40).…”

Section: Vus and Synonymous Variants Reported In Databasesmentioning

confidence: 99%

Characterization of Synonymous BRCA1:c.132C>T as a Pathogenic Variant

Wang

Zhang

et al. 2022

Front. Oncol.

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Breast cancer gene 1 (BRCA1) and BRCA2 are tumor suppressors involved in DNA damage response and repair. Carriers of germline pathogenic or likely pathogenic variants in BRCA1 or BRCA2 have significantly increased lifetime risks of breast cancer, ovarian cancer, and other cancer types; this phenomenon is known as hereditary breast and ovarian cancer (HBOC) syndrome. Accurate interpretation of BRCA1 and BRCA2 variants is important not only for disease management in patients, but also for determining preventative measures for their families. BRCA1:c.132C>T (p.Cys44=) is a synonymous variant recorded in the ClinVar database with “conflicting interpretations of its pathogenicity”. Here, we report our clinical tests in which we identified this variant in two unrelated patients, both of whom developed breast cancer at an early age with ovarian presentation a few years later and had a family history of relevant cancers. Minigene assay showed that this change caused a four-nucleotide loss at the end of exon 3, resulting in a truncated p.Cys44Tyrfs*5 protein. Reverse transcription-polymerase chain reaction identified two fragments (123 and 119 bp) using RNA isolated from patient blood samples, in consistency with the results of the minigene assay. Collectively, we classified BRCA1:c.132C>T (p.Cys44=) as a pathogenic variant, as evidenced by functional studies, RNA analysis, and the patients’ family histories. By analyzing variants recorded in the BRCA Exchange database, we found synonymous changes at the ends of exons could potentially influence splicing; meanwhile, current in silico tools could not predict splicing changes efficiently if the variants were in the middle of an exon, or in the deep intron region. Future studies should attempt to identify variants that influence gene expression and post-transcription modifications to improve our understanding of BRCA1 and BRCA2, as well as their related cancers.

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“…Systemic injustices, like disparities in healthcare access, explain a substantial proportion of breast cancer outcome disparities (14)(15)(16)(17). Recent studies additionally suggest that germline genetic variation is associated with breast cancer outcomes, and these associations vary across ancestry groups (18)(19)(20)(21). In The Cancer Genome Atlas (TCGA), BW had substantially higher polygenic risk scores for the more aggressive ER-negative subtype than WW, suggesting differential genetic contributions for susceptibility for breast cancer, especially ER-negative breast cancer (21).…”

Section: Introductionmentioning

confidence: 99%

Gene-Level Germline Contributions to Clinical Risk of Recurrence Scores in Black and White Patients with Breast Cancer

et al. 2021

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Continuous risk of recurrence scores (CRS) based on tumor gene expression are vital prognostic tools for breast cancer. Studies have shown that Black women (BW) have higher CRS than White women (WW). Although systemic injustices contribute substantially to breast cancer disparities, evidence of biological and germline contributions is emerging. In this study, we investigated germline genetic associations with CRS and CRS disparity using approaches modeled after transcriptome-wide association studies (TWAS). In the Carolina Breast Cancer Study, using race-specific predictive models of tumor expression from germline genetics, we performed race-stratified (N = 1,043 WW, 1,083 BW) linear regressions of three CRS (ROR-S: PAM50 subtype score; proliferation score; ROR-P: ROR-S plus proliferation score) on imputed tumor genetically regulated tumor expression (GReX). Bayesian multivariate regression and adaptive shrinkage tested GReX-prioritized genes for associations with tumor PAM50 expression and subtype to elucidate patterns of germline regulation underlying GReX-CRS associations. At FDR-adjusted P < 0.10, 7 and 1 GReX prioritized genes among WW and BW, respectively. Among WW, CRS were positively associated with MCM10, FAM64A, CCNB2, and MMP1 GReX and negatively associated with VAV3, PCSK6, and GNG11 GReX. Among BW, higher MMP1 GReX predicted lower proliferation score and ROR-P. GReX-prioritized gene and PAM50 tumor expression associations highlighted potential mechanisms for GReX-prioritized gene to CRS associations. Among patients with breast cancer, differential germline associations with CRS were found by race, underscoring the need for larger, diverse datasets in molecular studies of breast cancer. These findings also suggest possible germline trans-regulation of PAM50 tumor expression, with potential implications for CRS interpretation in clinical settings. Significance: This study identifies race-specific genetic associations with breast cancer risk of recurrence scores and suggests mediation of these associations by PAM50 subtype and expression, with implications for clinical interpretation of these scores.

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Association of germline variation with the survival of women with BRCA1/2 pathogenic variants and breast cancer

Cited by 5 publications

References 82 publications

Características clínicas de pacientes con Cáncer de Mama y / o Cáncer de Ovario con mutaciones en los genes BRCA1 y BRCA2 en Córdoba, Argentina

Características clínicas de pacientes con Cáncer de Mama y / o Cáncer de Ovario con mutaciones en los genes BRCA1 y BRCA2 en Córdoba, Argentina

Characterization of Synonymous BRCA1:c.132C>T as a Pathogenic Variant

Gene-Level Germline Contributions to Clinical Risk of Recurrence Scores in Black and White Patients with Breast Cancer

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