Branching Copy-Number Evolution and Parallel Immune Profiles across the Regional Tumor Space of Resected Pancreatic Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal disease. The only option for curative treatment is resection of the tumor followed by standard adjuvant chemotherapy. Yet, early relapse due to chemoresistance is almost inevitable. Herein, we delineated the genetic intratumor heterogeneity in resected PDAC, with the aim to identify evolutionary patterns that may be associated with overall survival (OS) following treatment with curative intent. Potential relationships with the adjacent immune microenvironment were also examined. The genetic and immune landscapes of the regional tumor space were analyzed in nine patients with resected PDAC. Targeted deep sequencing and genome wide SNP array were followed by clonal deconvolution and phylogenetic analysis. A mathematical complexity score was developed to calculate the network extent of each phylogeny. Spatial variation in abundancy and tumor nest infiltration of immune cells was analyzed by double IHC staining. Copy-number heterogeneity was denoted as the major contributing factor to the branching architectures of the produced phylogenetic trees. Increased tree complexity was significantly inversely associated with OS, and larger regional maximum aberrations (higher treetops) were associated with increased PD-L1 expression on tumor cells. Contrastingly, an FREM1 gene amplification, found in one patient, coincided with a particularly vigorous immune response. Findings from this limited case series suggest that complex evolutionary patterns may be associated with a shorter survival in surgically treated patients with PDAC. Some hypothesis-generating associations with the surrounding immune microenvironment were also detected. Implications: Evolutionary copy-number patterns may be associated with survival in patients with resected PDAC.

Copy Number Variations in Pancreatic Cancer: From Biological Significance to Clinical Utility

“…As expected, CNVs were almost always observed in the classical mutation genes in PDAC, including amplification of the oncogene KRAS (12p12.1) and deletions of the tumor suppressor genes TP53 (17p13.1), CDNK2A (9p21.3), and SMAD4 (18q21.2) to further confirm their role in the disease [75,76,[115][116][117][118][119][120][121][122][123][124][125][126][127][128][129]. Interestingly, the frequencies of CNVs are consistent throughout various ethnicities, even though disparities have been observed in the frequency of driver mutations in PDAC, such as a lower frequency of KRAS mutations in Korea [130,131] and Japan [125].…”

“…Interestingly, the frequencies of CNVs are consistent throughout various ethnicities, even though disparities have been observed in the frequency of driver mutations in PDAC, such as a lower frequency of KRAS mutations in Korea [ 130 , 131 ] and Japan [ 125 ]. For instance, one study performed microarray and CNV analyses of 93 pancreatic cancer data derived from the Japanese version of the Cancer Genome Atlas (JCGA) and revealed frequent CNVs as gains in 3q, 7q, and 2q and losses in 7q, 12q, 19q, and 19p [ 125 ], which are consistent with CNVs in other ethnicities [ 75 , 76 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 ].…”

“…In chromosome 1, the amplifications of 1p12 (NOTCH2) [115,118,123] and 1p13.1-p12 (REG4) [75,116,117] and the deletion of 1p36.11 (ARID1A) [75,117,126] were the more recurrent CNVs. REG4 overexpression was associated with poor prognosis and resistance to gemcitabine treatment in one study, suggesting that adjuvant therapies that target reg4 could enhance the usual gemcitabine-based treatment of pancreatic cancer [75,116,117]. ASAP2 (2p25.1) amplification has been associated with lower overall survival (OS) as well as lower relapse-free survival (RFS) [134,135].…”

“…One study demonstrated that the loss of 8p was exclusively observed in patients with shorter survival and associated this with specific CNV acquisitions due to potential positive selection and genetic drift. The genes that have been associated with this location are 8p, 8p23.2 (CSMD1) in sporadic PDAC, 8p23.1 (MCPH1 and ANGPT2), and 8p22 (NAT1) in FPC [ 116 , 117 , 136 ].…”

Comprehensive Analysis of TICRR in Hepatocellular Carcinoma Based on Bioinformatics Analysis

“…As an important part of the tumor microenvironment, the role of immune microenvironment is atracting more and more attention in the research of tumor immune microenvironment (Dhiman et al 2021 ). Tumor immune microenvironment is not only the cause of tumor occurrence and development, but also the result of tumor tumorigenesis and progression (Petersson et al 2022 ).…”