Adrienne Johnson M.S is a bioinformatician specializing in cancer genomics and a leader in allele-specific copy number analysis. She is currently a Principal Scientist, Computational Genomics, at Repare Therapeutics where she focuses on the analysis of whole genomes and other biomarkers related to DNA damage repair targeted therapies. She has extensive experience in developing and implementing algorithms to discover, detect and analyze genomic biomarkers from next-generation sequencing data. She has worked in the precision oncology and molecular diagnostics industry for nine years including roles at Foundation Medicine and Gritstone Bio. She holds a Master of Science degree in bioinformatics from Northeastern University.
Adrienne Johnsona, Pier Selenicab, Joseph Schonhofta, Danielle Ulaneta, Victoria Rimkunasa, Jorge Reis-Filhob, Ian Silvermana, Meredith Pelsterc
aBioinformatics, Repare Therapeutics, Cambridge, MA, United States; Memorial Sloan Kettering Cancer Center, New York, NY, United States; cSarah Cannon Research Institute, Tennessee Oncology, Nashville, TN, United States
Pancreatic acinar cell carcinomas (PACCs) frequently harbor activating fusions in the MAPK pathway, and alterations in DNA damage response (DDR) and homologous recombination (HR) repair-related genes.
Here we report the case of a 65-year-old white male with PACC. The patient initially received pancreaticoduodenectomy and adjuvant therapy, but later developed metastatic disease in the liver. Multimodal genomic analysis of the primary resection identified an in-frame SEL1L::NTRK1 fusion and a somatic pathogenic frameshift mutation in NBN exon 10 (c.1146del; p.E383Kfs*21) coupled with loss of heterozygosity, resulting in biallelic inactivation.
A biopsy of the liver metastasis was retrieved following disease progression after 13 months of platinum-containing chemotherapy and primary resistance to an NTRK inhibitor. The patient was enrolled in TRESR (NCT04497116) and received the ATR inhibitor camonsertib but discontinued at 3 months due to progression. The patient died after two additional lines of therapy.
Both biopsies were evaluated initially with clinical-grade comprehensive genomic profiling and retrospectively with a targeted sequencing panel designed to detect mono- and biallelic inactivation of select DDR genes. Comparison of results from both biopsies revealed post-platinum emergence of a reversion mutation (c.1154_1155del) restoring the NBN reading frame and predicted to re-establish NBN function. Additional whole-genome sequencing of the metastatic liver biopsy identified partial HR deficiency signatures.
Here we report the discovery of a novel NBN reversion mutation. This case highlights the complex genomic landscape of PACCs and suggests that NBN alterations may play a role in the development and progression of this rare pancreatic cancer.