High overall copy number variation burden by genome-wide methylation profiling holds negative prognostic value in surgically treated pancreatic ductal adenocarcinoma

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

“…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 ].…”

“…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 ].…”

“…The most recurrent amplification on chromosome 8 was 8p11.21 (FGFR1, IDO1, ZNF703) [ 110 , 123 , 126 , 129 ], observed in both sporadic and familial PDAC. 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.…”

“…Another study demonstrated that the assessment of overall CNV burden through genome-wide methylation profiling could be a valuable prognostic tool in patients with surgically treated PDAC [ 129 ]. By analyzing DNA extracted from 108 chemotherapy-naïve, surgical PDAC specimens, the researchers were able to gather data on the DNA methylation status of more than 850,000 CpG sites located in various regions such as the promoter, enhancer, and gene body.…”

“…In particular, the CNVs involved deletions of CDKN2A/B, KDM6A, and SMAD4 and focal amplifications of MYC, FGFR1, or CDK6. Overall, low CNV burden was observed in Group A tumors, while high CNV burden was observed in Group B tumors, and this higher CNV burden in Group B was further associated with a poor prognosis and shorter overall survival [ 129 ]. Notably, this study was performed on PDAC-enriched FFPE tissues, and further studies are necessary to establish the possibility of performing CNV burden analysis on endoscopic ultrasound-guided fine-needle biopsies from non-resectable PDAC patients, as well as whether this has any prognostic value [ 140 , 141 ].…”