Abstract
BackgroundPALB2, a gene in the homologous recombination repair (HRR) pathway of the DNA damage response (DDR), is associated with the efficacy of platinum-based chemotherapy, immunotherapy, and PARP inhibitor therapy in several tumors. However, the PALB2 characteristics, its correlation with immunotherapy biomarker, and the prognostic effect of immunotherapy in non-small cell lung cancer (NSCLC) were unknown.MethodsTumor tissue samples from advanced Chinese NSCLC patients were analyzed by next-generation sequencing (NGS) (panel on 381/733-gene). Tumor mutation burden (TMB) is defined as the total number of somatic non-synonymous mutations in the coding region. Microsatellite instability (MSI) was evaluated by NGS of 500 known MSI loci. Programmed Cell Death-Ligand 1 (PD-L1) expression was evaluated using immunohistochemistry (Dako 22C3 or SP263). One independent cohort (Rizvi2018.NSCLC.240.NGS cohort) containing genomic and clinical data from 240 patients with advanced NSCLC and two cohorts (the OAK and POPLAR study cohort) containing genomic and clinical data from 429 patients with advanced NSCLC were used to analyze the prognostic effect of PALB2 on immunotherapy.ResultsGenetic mutation of 5,227 NSCLC patients were analyzed using NGS, of which 162 (3.1%) harbored germline PALB2 mutation (PALB2gmut) and 87 (1.66%) harbored somatic PALB2 mutation (PALB2smut). In NSCLC patients with PALB2gmut and PALB2smut, the most frequently mutated gene was TP53 (65%, 64%). PALB2smut (14.52 Muts/Mb) was associated with higher TMB (p < 0.001) than PALB wild-type (PALB2wt) (6.15 Muts/Mb). However, there was no significant difference in TMB between PALB2gmut (6.45 Muts/Mb) and PALB2wt (6.15 Muts/Mb) (p = 0.64). There was no difference in PD-L1 expression among PALB2gmut, PALB2smut, and PALB2wt. In the Rizvi2018.NSCLC.240.NGS cohort, there was no difference in progression-free survival (PFS) (HR =1.06, p = 0.93) between PALB2 mutation (3.15 months) and PALB2wt (3.17 months). The OAK and POPLAR study cohort of NSCLC patients showed that there was no difference in overall survival (OS) (HR =1.1, p = 0.75) between PALB2 mutation (10.38 months) and PALB2wt (11.07 months).ConclusionsThese findings suggest that PALB2 may not be used as a biomarker for determining prognosis on immunotherapy in NSCLC.
Highlights
The DNA damage response (DDR) is a collective term for the plethora of different intra- and intercellular signaling events and enzyme activities that result from the induction and detection of DNA damage [1]
There are many pieces of research related to DDR at present, which shows that DDR can predict the risk of breast cancer, ovarian cancer, and other cancers and is related to the efficacy of various treatments, such as the presence of BRCA [a member of the homologous recombination repair (HRR) pathway] mutation that has been reported to correlate with the risk of breast cancer and the efficacy of Polyadenosine diphosphate-ribose polymerase (PARP) inhibitors, and the reports that multiple DDR pathway genes, including BRCA, predict the efficacy of immunotherapy for advanced urothelial carcinoma [2,3,4]
The results showed that neither PALB2smut nor PALB2gmut was associated with these immunotherapy biomarkers, except that PALB2smut was associated with significantly higher Tumor mutation burden (TMB)
Summary
The DNA damage response (DDR) is a collective term for the plethora of different intra- and intercellular signaling events and enzyme activities that result from the induction and detection of DNA damage [1]. The DDR system comprises eight pathways, namely, mismatch repair (MMR), base excision repair (BER), checkpoint factors, Fanconi anemia (FA), HRR, nucleotide excision repair (NER), non-homologous end-joining (NEJ), and DNA translesion synthesis (TLS) [5]. It is necessary to analyze the PALB2 mutation characteristics in the Chinese NSCLC population and demonstrate whether PALB2 mutation is Abbreviations: NSCLC, Non-small cell lung cancer; DDR, DNA damage response ; HRR, Homologous recombination repair; NGS, Next-generation sequencing; PALB2gmut, Germline PALB2 mutation; PALB2mut, Somatic PALB2 mutation; PARP, Polyadenosine diphosphate-ribose polymerase; PD-L1, Programmed Cell Death-Ligand 1 ; MSI, Microsatellite Instability; TMB, Tumor mutation burden; PFS, Progression-free survival; OS, Overall survival; MMR, Mismatch repair; BER, Base excision repair; FA, Fanconi anemia; NER, Nucleotide excision repair; NHEJ, Nonhomologous end-joining; TLS, DNA translesion synthesis; SNVs, Single nucleotide variants ; CNVs, Copy number variations. The PALB2 characteristics, its correlation with immunotherapy biomarker, and the prognostic effect of immunotherapy in non-small cell lung cancer (NSCLC) were unknown
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