CHEK2 Pathogenic Variants in Greek Breast Cancer Patients: Evidence for Strong Associations with Estrogen Receptor Positivity, Overuse of Risk-Reducing Procedures and Population Founder Effects

Apostolou, Paraskevi; Dellatola, Vasiliki; Papadimitriou, Christos; Kalfakakou, Despoina; Fountzilas, Elena; Faliakou, Eleni C.; Fountzilas, George; Romanidou, Ourania; Konstantopoulou, Irene; Fostira, Florentia

doi:10.3390/cancers13092106

Cited by 5 publications

(1 citation statement)

References 34 publications

(54 reference statements)

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“…This discrepancy may be due to the fact that the CHEK2 c. 1100delC allele is rarely identified in breast cancer patients of Greek descent [ 47 ]. Pathogenic variants in CHEK2 are associated with an increased risk of estrogen receptor-positive breast cancer, although the risk decreases significantly with age, making these carriers more likely to develop the disease prior to menopause [ 48 , 49 ]. Notably, the I157T low-risk allele that was identified in two of our patients is associated with moderate risk and a more favorable prognosis [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Multi-Gene Mutation Profiling by Targeted Next-Generation Sequencing in Premenopausal Breast Cancer

Zografos

Andrikopoulou

Papatheodoridi

et al. 2022

Genes

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Breast cancer has distinct etiology, prognoses, and clinical outcomes at premenopausal ages. Determination of the frequency of germline and somatic mutations will refine our understanding of the genetic contribution to premenopausal breast cancer susceptibility. We applied a comprehensive next generation sequencing-based approach to analyze blood and/or tissue samples of 54 premenopausal breast cancer patients treated in our clinic. Genetic testing results were descriptively analyzed in correlation with clinicopathological data. In the present study, 42.5% of premenopausal breast cancer patients tested carried pathogenic mutations in cancer predisposition genes (CHEK2, BRCA1, TP53, and MUTYH). Germline variants of unknown/uncertain significance (VUSs) in eight different cancer susceptibility genes, namely BRCA1, BRCA2, CHEK2, RAD51C, RAD51D, ATM, BRIP1, and PMS2, were also identified in 14 premenopausal patients (35%). Of the breast tumors tested, 61.8% harbored pathogenic somatic variants in tumor suppressor genes (TP53, NF1, RB), genes involved in DNA repair (BRCA1, BRCA2, ATM, RAD50), cell proliferation (PTEN, PIK3C FGFR3, AKT1, ROS1, ERBB2, NOTCH1), and cell adhesion (CTNNB1). This descriptive study employs the powerful NGS technology to highlight the high frequency of premenopausal cases attributable to genetic predisposition. Mutation identification in a larger cohort may further ensure that these patients receive tailored treatment according to their menopausal status.

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Section: Discussionmentioning

confidence: 99%

Multi-Gene Mutation Profiling by Targeted Next-Generation Sequencing in Premenopausal Breast Cancer

Zografos

Andrikopoulou

Papatheodoridi

et al. 2022

Genes

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Systematic Minigene-Based Splicing Analysis and Tentative Clinical Classification of 52 CHEK2 Splice-Site Variants

Sanoguera-Miralles,

Valenzuela-Palomo,

Bueno-Martínez

et al. 2023

Clinical Chemistry

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Background Disrupted pre-mRNA splicing is a frequent deleterious mechanism in hereditary cancer. We aimed to functionally analyze candidate spliceogenic variants of the breast cancer susceptibility gene CHEK2 by splicing reporter minigenes. Methods A total of 128 CHEK2 splice-site variants identified in the Breast Cancer After Diagnostic Gene Sequencing (BRIDGES) project (https://cordis.europa.eu/project/id/634935) were analyzed with MaxEntScan and subsetted to 52 variants predicted to impact splicing. Three CHEK2 minigenes, which span all 15 exons, were constructed and validated. The 52 selected variants were then genetically engineered into the minigenes and assayed in MCF-7 (human breast adenocarcinoma) cells. Results Of 52 variants, 46 (88.5%) impaired splicing. Some of them led to complex splicing patterns with up to 11 different transcripts. Thirty-four variants induced splicing anomalies without any trace or negligible amounts of the full-length transcript. A total of 89 different transcripts were annotated, which derived from different events: single- or multi-exon skipping, alternative site-usage, mutually exclusive exon inclusion, intron retention or combinations of the abovementioned events. Fifty-nine transcripts were predicted to introduce premature termination codons, 7 kept the original open-reading frame, 5 removed the translation start codon, 6 affected the 5′UTR (Untranslated Region), and 2 included missense variations. Analysis of variant c.684-2A > G revealed the activation of a non-canonical TG-acceptor site and exon 6 sequences critical for its recognition. Conclusions Incorporation of minigene read-outs into an ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology)-based classification scheme allowed us to classify 32 CHEK2 variants (27 pathogenic/likely pathogenic and 5 likely benign). However, 20 variants (38%) remained of uncertain significance, reflecting in part the complex splicing patterns of this gene.

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Variantes genéticas recurrentes y priorización de variantes de significado clínico desconocido asociadas al síndrome de cáncer de mama y ovario hereditario en familias de la Región de Murcia

Rosado-Jiménez,

Mestre-Terkemani,

García-Aliaga

et al. 2023

Advances in Laboratory Medicine / Avances en Medicina De Laboratorio

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Resumen Objetivos El Síndrome de Cáncer de Mama y Ovario Hereditario (SCMOH) presenta un patrón de herencia autosómica dominante en genes de susceptibilidad al cáncer y su riesgo está principalmente vinculado a mutaciones germinales en BRCA1 y BRCA2. Sin embargo, la implementación de paneles genéticos mediante secuenciación masiva en la práctica asistencial, ha ampliado el espectro mutacional de este síndrome hereditario y el número de variantes de significado clínico desconocido (VUS) detectadas en los estudios genéticos. Métodos El estudio de prevalencia del SCMOH realizado en 2928 familias de la Región de Murcia ha permitido identificar las variantes patogénicas recurrentes y mutaciones fundadoras, principalmente asociadas a genes BRCA1 y BRCA2. En el estudio de VUS destaca la aplicación de un algoritmo de priorización diseñado por nuestro grupo de trabajo. Resultados Las variantes c.68_69del, c.212+1G>A, y c.5123C>A fueron detectadas en un 30 % de los portadores de BRCA1 mientras que la deleción del exón 2 junto con c.3264dupT, c.3455T>G y c.9117G>A se han encontrado en un 30 % de los portadores de BRCA2. Un total de 16 VUS (15 %) fueron priorizadas. Conclusiones La correlación genotipo-fenotipo resultó compatible con lo reportado previamente en la literatura científica. Además, se ha constatado el efecto fundador de c.1918C>T (BRCA1) y c.8251_8254del (ATM) en población murciana y la deleción del exon2 (BRCA2) como mutación fundadora española. La implementación del algoritmo ha permitido priorizar aquellas VUS susceptibles de patogenicidad en las que sería recomendable realizar estudios complementarios para así, poder determinar su efecto clínico y su posible implicación en el SCMOH.

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CHEK2 Pathogenic Variants in Greek Breast Cancer Patients: Evidence for Strong Associations with Estrogen Receptor Positivity, Overuse of Risk-Reducing Procedures and Population Founder Effects

Cited by 5 publications

References 34 publications

Multi-Gene Mutation Profiling by Targeted Next-Generation Sequencing in Premenopausal Breast Cancer

Multi-Gene Mutation Profiling by Targeted Next-Generation Sequencing in Premenopausal Breast Cancer

Systematic Minigene-Based Splicing Analysis and Tentative Clinical Classification of 52 CHEK2 Splice-Site Variants

Variantes genéticas recurrentes y priorización de variantes de significado clínico desconocido asociadas al síndrome de cáncer de mama y ovario hereditario en familias de la Región de Murcia

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