Challenges of Genomic Testing for Hereditary Breast and Ovarian Cancers

McAlarnen, Lindsey A.; Stearns, Kristen; Uyar, Denise

doi:10.2147/tacg.s245021

Cited by 16 publications

(17 citation statements)

References 63 publications

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“…Taking into consideration cohorts of patients closer to the one present in this work, positive rates of about 15% were found (about 10% in BRCA1/2 and about 5% in other genes) ( 31 – 33 ). Nevertheless, more recent studies show a higher fraction of non- BRCA1/2 genes mutations ( 11 , 14 ) principally due to the inclusion of lower-risk patients and larger multi-gene panels tested. Based on all these data and on the observation of the frequent co-occurrence of different cancer types (not only breast and ovarian, but also colon, melanoma, pancreas and prostate cancers) within the affected families, a custom panel including 44 genes to be simultaneously analyzed through an enrichment-based protocol followed by NGS analysis was set up.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, recent studies have reported that a total of about 11% of all pathogenic germline variants in Caucasian patients and about 9% in Asians (affected patients) affect genes different from the traditional BRCA1/2 ( 12 ). In particular, new evidences are emerging regarding the contribution of other genes involved in DNA damage repair mechanisms, like PALB2, CHEK2, ATM, BRIP1 , and others ( 11 , 12 ).…”

Section: Introductionmentioning

confidence: 99%

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Multi-gene panel testing increases germline predisposing mutations’ detection in a cohort of breast/ovarian cancer patients from Southern Italy

Nunziato

Maggio²,

Pensabene³

et al. 2022

Front. Med.

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Breast cancer is the most common neoplasia in females worldwide, about 10% being hereditary/familial and due to DNA variants in cancer-predisposing genes, such as the highly penetrant BRCA1/BRCA2 genes. However, their variants explain up to 25% of the suspected hereditary/familial cases. The availability of NGS methodologies has prompted research in this field. With the aim to improve the diagnostic sensitivity of molecular testing, a custom designed panel of 44 genes, including also non-coding regions and 5’ and 3’ UTR regions, was set up. Here, are reported the results obtained in a cohort of 64 patients, including also few males, from Southern Italy. All patients had a positive personal and/or familial history for breast and other cancers, but tested negative to routine BRCA analysis. After obtaining their written informed consent, a genomic DNA sample/patient was used to obtain an enriched DNA library, then analyzed by NGS. Sequencing data analysis allowed the identification of pathogenic variants in 12 of tested patients (19%). Interestingly, MUTYH was the most frequently altered gene, followed by RNASEL, ATM, MSH6, MRE11A, and PALB2 genes. The reported resultsreinforce the need for enlarged molecular testing beyond BRCA genes, at least in patients with a personal and familial history, strongly suggestive for a hereditary/familial form. This gives also a hint to pursue more specific precision oncology therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Multi-gene panel testing increases germline predisposing mutations’ detection in a cohort of breast/ovarian cancer patients from Southern Italy

Nunziato

Maggio²,

Pensabene³

et al. 2022

Front. Med.

View full text Add to dashboard Cite

show abstract

“…Genetic testing is now commonly recommended at the time of cancer diagnosis depending on factors such as age, personal/familial history of breast or ovarian cancer, and immunohistochemical subtype of BC. The panel not only contains BRCA1 and BRCA2, but also additional genes associated with moderate to high risk of breast and ovarian cancer such as PALB2, TP53, PTEN, ATM, and CHK2 [24].…”

Section: Hrd Diagnosis 221 Hereditary Breast and Ovarian Cancer Panelmentioning

confidence: 99%

Recent Advances in Enhancing the Therapeutic Index of PARP Inhibitors in Breast Cancer

Franchet

Hoffmann

2021

Cancers

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As poly-(ADP)-ribose polymerase (PARP) inhibition is synthetic lethal with the deficiency of DNA double-strand (DSB) break repair by homologous recombination (HR), PARP inhibitors (PARPi) are currently used to treat breast cancers with mutated BRCA1/2 HR factors. Unfortunately, the increasingly high rate of PARPi resistance in clinical practice has dented initial hopes. Multiple resistance mechanisms and acquired vulnerabilities revealed in vitro might explain this setback. We describe the mechanisms and vulnerabilities involved, including newly identified modes of regulation of DSB repair that are now being tested in large cohorts of patients and discuss how they could lead to novel treatment strategies to improve the therapeutic index of PARPi.

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“…The reclassification of VUS is essential to ensure appropriate patient care, and functional assays provide critical information for their interpretation [ 8 , 9 , 10 , 11 ]. RNA splicing is one of the gene expression steps that may be impaired by genetic variants [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Minigene Splicing Assays Identify 20 Spliceogenic Variants of the Breast/Ovarian Cancer Susceptibility Gene RAD51C

Sanoguera-Miralles

Bueno-Martínez

Valenzuela-Palomo

et al. 2022

Cancers

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RAD51C loss-of-function variants are associated with an increased risk of breast and ovarian cancers. Likewise, splicing disruptions are a frequent mechanism of gene inactivation. Taking advantage of a previous splicing-reporter minigene with exons 2-8 (mgR51C_ex2-8), we proceeded to check its impact on the splicing of candidate ClinVar variants. A total of 141 RAD51C variants at the intron/exon boundaries were analyzed with MaxEntScan. Twenty variants were selected and genetically engineered into the wild-type minigene. All the variants disrupted splicing, and 18 induced major splicing anomalies without any trace or minimal amounts (<2.4%) of the minigene full-length (FL) transcript. Twenty-seven transcripts (including the wild-type and r.904A FL transcripts) were identified by fluorescent fragment electrophoresis; of these, 14 were predicted to truncate the RAD51C protein, 3 kept the reading frame, and 8 minor isoforms (1.1–4.7% of the overall expression) could not be characterized. Finally, we performed a tentative interpretation of the variants according to an ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology)-based classification scheme, classifying 16 variants as likely pathogenic. Minigene assays have been proven as valuable tools for the initial characterization of potential spliceogenic variants. Hence, minigene mgR51C_ex2-8 provided useful splicing data for 40 RAD51C variants.

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Challenges of Genomic Testing for Hereditary Breast and Ovarian Cancers

Cited by 16 publications

References 63 publications

Multi-gene panel testing increases germline predisposing mutations’ detection in a cohort of breast/ovarian cancer patients from Southern Italy

Multi-gene panel testing increases germline predisposing mutations’ detection in a cohort of breast/ovarian cancer patients from Southern Italy

Recent Advances in Enhancing the Therapeutic Index of PARP Inhibitors in Breast Cancer

Minigene Splicing Assays Identify 20 Spliceogenic Variants of the Breast/Ovarian Cancer Susceptibility Gene RAD51C

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