CanVaS: Documenting the genetic variation spectrum of Greek cancer patients

Abstract

National genetic variation registries vastly increase the level of detail for the relevant population, while directly affecting patient management. Herein, we report CanVaS, a Cancer Variation reSource aiming to document the genetic variation of cancer patients in Greece. CanVaS comprises germline genetic data from 7,363 Greek individuals with a personal and/or family history of malignancy. The dataset incorporates ~24,000 functionally annotated rare variants in 97 established or suspected cancer susceptibility genes. For each variant, allele frequency for the Greek population, interpretation for clinical significance, anonymized family and segregation information, as well as phenotypic traits of the carriers, are included. Moreover, information on the geographic distribution of the variants across the country are provided, enabling the study of Greek population isolates. Direct comparisons between Greek (sub)populations with relevant genetic resources is supported, allowing fine-grain localized adjustment of guidelines and clinical decision-making. Most importantly, anonymized data are available for download, while the Leiden Open Variation Database schema is adopted, enabling integration/interconnection with central resources. CanVaS could become a stepping-stone for a countrywide effort to characterize the cancer genetic variation landscape, concurrently supporting national and international cancer research. The database can be accessed at: https://ithaka.rrp.demokritos.gr/CanVaS

CanVaS: Documenting the genetic variation spectrum of Greek cancer patients

“…Overall, this approach empowers subpopulation analysis, study of Greek population isolates, and investigation of possible founder effects. The strong founder effects observed in Greek subpopulations has been recently highlighted in a genetic analysis performed in Cretan isolates, where it was shown that three pathogenic variants in BRCA1 andBRCA2 , unique to the Cretan subpopulation, namely NM -007294.3:c.5492del in BRCA1 and NM 000059.3:c.7806-2A>T and NM 000059.3:c.6842-2675 7008-5558del, both in BRCA2, account for 48% of identified PVs in BRCA1 and BRCA2 among breast and ovarian cancer patients of Cretan descent (Apostolou et al, 2020).…”

“…Genetic testing was performed on patients' DNA, using either Sanger sequencing, Next Generation Sequencing (NGS)-implemented multigene panel or Multiplex Ligation-dependent Probe Amplification (MLPA) as previously described (Fostira et al, 2020). More specifically, individuals referred for genetic testing between 1999-2012 were tested through Sanger sequencing exclusively.…”

“…In order to provide a first paradigm tackling the aforementioned open challenges, we established CanVaS, a national database that records germline genetic variation and associated clinical data of Greek cancer patients. With CanVaS, we manage to document the genetic heterogeneity of cancer susceptibility genes in Greeks, a population of unique genetic makeup, exhibiting extended genetic heterogeneity, but also strong founder effects (Apostolou et al, 2020;Apostolou et al, 2017;Konstantopoulou et al, 2014;Pertesi, Konstantopoulou, & Yannoukakos, 2011). Most importantly, all the genetic data are accompanied with detailed phenotypic and clinical traits of tested individuals, whether a pathogenic variant has been identified or not, enabling genotype-phenotype correlation analysis.…”