RESUMO
This study investigates the molecular characteristics and therapeutic implications of the BRCA1 L1780P mutation, a rare variant prevalent among Korean hereditary breast cancer patients. Using patient-derived xenograft (PDX) models and cell lines (PDX-derived cell line) from carriers, sequencing analyses revealed loss of heterozygosity (LOH) at the BRCA1 locus, with one patient losing the wild-type allele and the other mutated allele. This reversion mutation may cf. resistance to homologous recombination deficiency (HRD)-targeting drugs such as PARP inhibitors (PARPi) and ATM inhibitors (ATMi). Although HRDetect and CHORD analyses confirmed a strong association between the L1780P mutation and HRD, effective initially, drug resistance developed in cases with reversion mutations. These findings underscore the complexity of using HRD prediction in personalized treatment strategies for breast cancer patients with BRCA1/2 mutations, as resistance may arise in reversion cases despite high HRD scores.
RESUMO
Genomic and transcriptomic profiling has enhanced the diagnostic and treatment options for many cancers. However, the molecular characteristics of parathyroid cancer remain largely unexplored, thereby limiting the development of new therapeutic interventions. Herein, we conducted genomic and transcriptomic sequencing of 50 parathyroid tissues (12 carcinomas, 28 adenomas, and 10 normal tissues) to investigate the intrinsic and comparative molecular features of parathyroid carcinoma. We confirmed multiple two-hit mutation patterns in cell division cycle 73 (CDC73) that converged to biallelic inactivation, calling into question the presence of a second hit in other genes. In addition, allele-specific repression of CDC73 in copies with germline-truncating variants suggested selective pressure prior to tumorigenesis. Transcriptomic analysis identified upregulation of the expression of E2F targets, KRAS and TNF-alpha signaling, and epithelial-mesenchymal transition pathways in carcinomas compared to adenomas and normal tissues. A molecular classification model based on carcinoma-specific genes clearly separated carcinomas from adenomas and normal tissues, the clinical utility of which was demonstrated in two patients with uncertain malignant potential. A deeper analysis of gene expression and functional prediction suggested that Wilms tumor 1 (WT1) is a potential biomarker for CDC73-mutant parathyroid carcinoma, which was further validated through immunohistochemistry. Overall, our study revealed the genomic and transcriptomic profiles of parathyroid carcinoma and may help direct future precision diagnostic and therapeutic improvements.