1707P The landscape of PALB2 alteration in Chinese solid tumor patients

Abstract

Partner and localizer of BRCA2 (PALB2) is a nuclear protein that localizes to sites of DNA double-strand breaks and interacts with BRCA1 and BRCA2 to promote DNA repair. The differences in mutation profiles of PALB2 gene in pan-cancer can help understand pathogenesis, prognosis, and identify targets for therapy. Using commercial NGS assays, we retrospectively analyzed genomic DNA alterations in normal-paired samples from 3880 patients with malignancies between 2019 to 2021, and alterations including single base substitution, short and long insertion/deletions, copy number variations, gene fusions and rearrangements. PALB2 gene was altered in 2.0% (78 of 3880) of all solid tumors, comparable to 1.5% (158 of 10336) of PALB2 alterations in the MSK-IMPACT Clinical Sequencing Cohort (MSKCC, Nat Med 2017). The frequency of PALB2 variations was assessed in multiple cancer types, including bladder cancer 6.1% (2/33), thyroid cancer 4.9% (2/41), colorectal cancer 4.0% (19/478), prostatic cancer 3.8% (1/26), small cell lung cancer 3.4% (1/29), pancreatic cancer 2.5% (4/160), gastrointestinal stromal tumor 2.3% (1/44), liver cancer 2.2% (5/230), biliary tract tumor 2.1% (3/141) and non-small cell lung cancer 2.0% (28/1402). A total 93 genetic alterations were identified in 78 patients, including 58 missense mutations (63%), 18 nonsense (12%), 12 frameshift (10%), 3 splicing (8%), 5 copy number loss (5%), 1 in-frame insertion (2%), 1 in-frame deletion (2%). Among these patients, 14 had pathogenic or likely pathogenic germline PALB2 heterozygous mutations, including prostatic cancer 3.8% (1/26), biliary tract tumor 2.1% (3/141), pancreas tic cancer 1.3% (2/160), colorectal cancer 0.8% (4/478), liver cancer 0.4% (1/230) and non-small cell lung cancer 0.2% (3/1821). Furthermore, in our cohort, PALB2 mutation carriers also owned other actionable, the most frequent one was TP53 (65%), followed by LRP1B (28%), KRAS (27%) and PIK3CA (24%). PALB2 deleterious mutations are highly diverse and present at low to moderate frequencies across many cancers. PALB2 alterations warrant further investigation as predictive biomarkers of response to PARP inhibitors or platinum-based therapy.