NGS Panel Testing of Triple-Negative Breast Cancer Patients in Cyprus: A Study of BRCA-Negative Cases

Abstract

In Cyprus, approximately 9% of triple-negative (estrogen receptor-negative, progesterone receptor-negative, and human epidermal growth factor receptor 2-negative) breast cancer (TNBC) patients are positive for germline pathogenic variants (PVs) in BRCA1/2. However, the contribution of other genes has not yet been determined. To this end, we aimed to investigate the prevalence of germline PVs in BRCA1/2-negative TNBC patients in Cyprus, unselected for family history of cancer or age of diagnosis. A comprehensive 94-cancer-gene panel was implemented for 163 germline DNA samples, extracted from the peripheral blood of TNBC patients. Identified variants of uncertain clinical significance were evaluated, using extensive in silico investigation. Eight PVs (4.9%) were identified in two high-penetrance TNBC susceptibility genes. Of these, seven occurred in PALB2 (87.5%) and one occurred in TP53 (12.5%). Interestingly, 50% of the patients carrying PVs were diagnosed over the age of 60 years. The frequency of non-BRCA PVs (4.9%) and especially PALB2 PVs (4.3%) in TNBC patients in Cyprus appears to be higher compared to other populations. Based on these results, we believe that PALB2 and TP53 along with BRCA1/2 genetic testing could be beneficial for a large proportion of TNBC patients in Cyprus, irrespective of their age of diagnosis.

Determination of genetic predisposition to early breast cancer in women of Kazakh ethnicity

“…However, compared to the Kazakh women, no PVs were detected in the PALB2, SDHB, ATM, BLM, FANCM, NBN, PMS1, PMS2 , and XPA genes among the 94 cancer-associated genes analyzed in the Greek and Indian populations, which may be due to the smaller samples. Interestingly, when the same panel of 94 cancer genes was examined in the group of TNBC BRCA -negative patients from Cyprus, germline PVs of the PALB2 gene were found in older women but not in young [ 25 ]. At the same time, in a large-scale study of BC women aged 35–59 years, who were mainly of Northern and Western European descent, PVs in CHEK2, ATM, PALB2, and PMS2 genes were the most frequent among the 25 cancer genes tested, after PVs in BRCA1/2 [ 26 ].…”

Combining Organoid Models with Next-Generation Sequencing to Reveal Tumor Heterogeneity and Predict Therapeutic Response in Breast Cancer

“…Given that targeted therapy must be based on identifying dominant drivers of oncogenesis, NGS should be a powerful implement for clinical decision-making and the development of biological agents [32]. For example, the application of NGS to studies of BRCA mutations in population-based cohorts has contributed to the update of clinical recommendations for disease screening and medication intervention, such as PARPi [33][34][35]. Despite the promising guiding significance of NGS, one problem is that NGS-detected alterations in gene signatures rely on the functional annotation to elucidate subsequent biological changes.…”

Detection of Germline Variants in 450 Breast/Ovarian Cancer Families with a Multi-Gene Panel Including Coding and Regulatory Regions

“…Studies conducted on a larger number of TNBC patients have come to concordant results regarding the association of these cases with pathogenic variants in the PALB2 , BRIP1 , RAD51C , and RAD51D genes [ 30 , 36 , 37 , 38 ]. Our results partially agree with these data, having identified pathogenic variants in TNBC patients with ATM , RAD51D , BRIP1 , and TP53 variants.…”

“…However, it is certainly very interesting that 50% of the TNBC cases analyzed had pathogenic coding variants: it is a higher proportion compared to that obtained in other cohorts of TNBC patients filtered in the population solely on the basis of their tumor phenotype [ 36 , 37 ]. It is probable that the higher percentage registered in our cases depends on the double filtering, based not only on patient tumor phenotype but also on the patient breast cancer family history.…”