Identification of copy number variation-driven molecular subtypes informative for prognosis and treatment in pancreatic adenocarcinoma of a Chinese cohort

Abstract

Background: Pancreatic adenocarcinoma (PAAD) is one of the most lethal carcinomas, and the current histopathological classifications are of limited use in clinical decision-making. There is an unmet need to identify new biomarkers for prognosis-informative molecular subtyping and ultimately for precision medicine. Methods: We profiled genomic alterations for 608 PAAD patients in a Chinese cohort, including somatic mutations, pathogenic germline variants and copy number variations (CNV). Using the CNV information, we performed unsupervised consensus clustering of these patients, differential CNV analysis and functional/ pathway enrichment analysis. Cox regression was conducted for progression-free survival analysis, the elastic net algorithm used for prognostic model construction, and rank-based gene set enrichment analysis for exploring tumor microenvironments. Findings: Our data did not support prognostic value of point mutations in either highly mutated genes (such as KRAS, TP53, CDKN2A and SMAD4) or homologous recombination repair genes. Instead, associated with worse prognosis were amplified genes involved in DNA repair and receptor tyrosine kinase (RTK) related signalings. Motivated by this observation, we categorized patients into four molecular subtypes (namely repairdeficient, proliferation-active, repair-proficient and repair-enhanced) that differed in prognosis, and also constructed a prognostic model that can stratify patients with low or high risk of relapse. Finally, we analyzed publicly available datasets, not only reinforcing the prognostic value of our identified genes in DNA repair and RTK related signalings, but also identifying tumor microenvironment correlates with prognostic risks. Interpretation: Together with the evidence from genomic footprint analysis, we suggest that repair-deficient and proliferation-active subtypes are better suited for DNA damage therapies, while immunotherapy is highly recommended for repair-proficient and repair-enhanced subtypes. Our results represent a significant step in molecular subtyping, diagnosis and management for PAAD patients.

Aberrant Cholesterol Metabolism and Wnt/β‐Catenin Signaling Coalesce via Frizzled5 in Supporting Cancer Growth

“…DNA extraction and sequencing were performed as previously described with some modifications. [ 27 ] QIAamp DNA Micro Kit (Cat No./ID: 56304) was used to extract genomic DNA from tissue samples, and NanoDrop2000 was used to detect the concentration and purity of DNA. DNA was segmented to a length range of 150–300 bp using Covaris M220 DNA ultrasonic fragmentation instrument.…”

Open-source curation of a pancreatic ductal adenocarcinoma gene expression analysis platform (pdacR) supports a two-subtype model

“…Furthermore, others have indicated that data that is readily accessible through online repositories has, in some cases, been either poorly formatted or poorly annotated for subsequent analysis 43,44 . In certain instances, this may lead to misguided or misinformed conclusions in well-meaning investigations [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] . Clearly, these challenges pose a major hurdle in the development of novel hypotheses, particularly for those without first-hand familiarity with how the data were generated.…”

“…First, validation is frequently only performed on one publicly available dataset. Second, there are multiple examples of inappropriate use of The Cancer Genome Atlas (TCGA) Program PDAC dataset [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] . The mRNA dataset includes 182 samples, but only 150 have been confirmed histologically as PDAC.…”

An 8q24 Gain in Pancreatic Juice Is a Candidate Biomarker for the Detection of Pancreatic Cancer

“…The presence of chromosomal aberrations is a common molecular feature in human cancer, including loss of tumor suppressor genes or gain of oncogenes, driving oncogenic signaling and cancer development. Specifically, in PC, the amplification of genes involved in DNA repair and tyrosine kinase signaling are associated with poor survival [ 2 ]. The detection of such alterations in cell-free DNA (cfDNA) released from tumor cells (circulating tumor DNA (ctDNA)) has shown promise for several cancers in (pre-) clinical studies [ 3 , 4 ].…”