Abstract
Simple SummaryThis prospective cohort study showed that circulating tumor DNA-genomic instability (ctDNA-GI) I-scores, which was defined as the natural logarithm of the sum of LOESS-normalized Z-scores of sequenced reads in 1 Mb bins, are prognostic of the outcome of either localized or metastatic pancreatic adenocarcinoma. At baseline, 24.1% of patients had high genomic instability with I-score. Multivariable analyses demonstrated I-score was a significant factor for progression-free survival and overall survival.Genomic instability of circulating tumor DNA (ctDNA) as a prognostic biomarker has not been evaluated in pancreatic cancer. We investigated the role of the genomic instability index of ctDNA in pancreatic ductal adenocarcinoma (PDAC). We prospectively enrolled 315 patients newly diagnosed with resectable (n = 110), locally advanced (n = 78), and metastatic (n = 127) PDAC from March 2015 through January 2020. Low-depth whole-genome cell-free DNA sequencing identified genome-wide copy number alterations using instability score (I-score) to reflect genome-wide instability. Plasma cell-free and matched tumor tissue DNA from 15 patients with resectable pancreatic cancer was sequenced to assess the concordance of chromosomal copy number alteration profiles. Associations of I-score with clinical factors or survival were assessed. Seventy-six patients had high genomic instability with I-score > 7.3 in pre-treatment ctDNA; proportions of high I-score were 5.5%, 5.1%, and 52% in resectable, locally advanced, and metastatic stages, respectively. Correlation coefficients between Z-scores of plasma and tissue DNA at segment resolution were high (r2 = 0.82). Univariable analysis showed the association of I-score with progression-free survival in each stage. Multivariable analyses demonstrated that clinical stage-adjusted I-scores were significant factors for progression-free and overall survival. In these patients, ctDNA genomic I-scores provided prognostic information relevant to progression-free survival in each clinical stage.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is a public health problem because of its dismal prognosis and increasing incidence
According to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. [16], tumor response was quantitatively defined as complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD)
GISTIC deletion regions included 364 genes and 22, which have been frequently deleted (Supplementary Table S5). We found that these GISTIC regions overlapped cancer-related genes as well, such as oncogenes, tumor suppressor genes, and genes related to poor prognosis when amplified or deleted [25,26,27,28,29]
Summary
Pancreatic ductal adenocarcinoma (PDAC) is a public health problem because of its dismal prognosis and increasing incidence. Genomic instability is a typical hallmark of cancer. It promotes inter- and intra-tumor heterogeneity and enables cancer cell adaptation to environmental stress, thereby driving aggressive tumor behavior and resistance to cancer therapies [3,4]. Recently integrated whole-genome analysis uncovered that the molecular subtypes of pancreatic cancer are linked to specific copy number aberrations in genes such as mutant KRAS and GATA6 [5]. These data support the premise that the constellation of genomic aberrations in the tumor gives rise to the molecular subtype associated with disease progression
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