Abstract P1-05-10: Investigating the Potential Role of Rare Germline Non-Coding Variants in Cancer Predisposition Genes in Patients with Triple-Negative Breast

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Abstract Current genetic screening for breast cancer predisposition is limited to the analysis of coding regions (exons) and intron/exon boundaries of BRCA1/2 genes. There is limited data on the prevalence and clinical significance of variants in the non-coding regions of these genes. Consequently, the majority of variants identified in these regions remain unclassified, and approximately 80% of germline BRCA1/2 tests are not considered in the daily management of patients with triple-negative breast cancer (TNBC). Emerging evidence suggests that non-coding variants can impact cancer risk and response to treatment. This study aimed to investigate the prevalence of variants in the non-coding regulatory regions of BRCA1/2 and other breast cancer predisposition genes in TNBC patients selected based on age at cancer diagnosis and/or family history of cancer. Additionally, we sought to explore the functional role of identified variants of uncertain significance (VUS) through ongoing analyses. We enrolled 144 TNBC patients who had previously tested negative for germline variants in the coding regions of BRCA1/2 and other cancer predisposition genes. Next-generation sequencing (NGS) analysis identified 635 rare variants in the non-coding regions of 28 selected genes involved in breast/ovarian cancer predisposition. In our TNBC cohort, we observed a higher prevalence of rare variants in the genes CDH1 (1.3%), STK11 (11.2%), ATM (10.7%), PTEN (7.40%), and PMS2 (5.04%). Germline variants in BRCA2 were statistically significantly associated with worse overall survival (p-value=0.017). CDH1 rare variants were associated with the highest percentage of non-pathologic complete response after neoadjuvant chemotherapy (p=0.0273). MLH1 and PALB2 rare variants were both associated with bilateral breast cancer (p=0.015 and p=0.0005, respectively). Rare variants of the ATM gene were associated with a positive family history (p=0.041). Preliminary single nucleotide variant (SNV) data analysis showed that the most significant functional score for alterations were detected in the promoter of MSH6, potentially associated with chromatin effects. Further analyses are ongoing to elucidate the functional impact of these variants. Due to the small sample size, these analyses should be considered exploratory, and larger studies are needed to confirm these findings and establish the clinical utility of screening for non-coding variants in TNBC patients. Citation Format: Michela Palleschi, Alessandra Virga, Emanuela Scarpi, Eugenio Fonzi, Filippo Merloni, Samanta Sarti, Rita Danesi, Mila Ravegnani, Chiara Casadei, Marianna Sirico, Caterina Gianni, Roberta Maltoni, Sara Bravaccini, Daniele Calistri, Valentina Arcangeli, Valentina Zampiga, Ilaria Cangini, Erika Bandini, Francesca Mannozzi, Fabio Falcini, Ugo De Giorgi, Paola Ulivi, Gianluca Tedaldi. Investigating the Potential Role of Rare Germline Non-Coding Variants in Cancer Predisposition Genes in Patients with Triple-Negative Breast [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-05-10.

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