# Copy Number Variation: Methods and Clinical Applications
## 3 Potential Biomedical Applications of CNV Detection  
CNVs can be analyzed from different biological sources, offering various valuable information, so there are plenty of biomedical applications where CNV detection may be useful. CNVs have been studied in neuropsychiatric [72; 73], developmental [74], and cardiovascular diseases [75]. Several studies have identified the role of CNVs in common diseases such as coronary artery disease or in rarer events such as sudden cardiac death. Such findings may be useful for clinicians for disease classification and detection in the future, particularly in the age of the whole genome sequencing [76]. On the other hand, CNVs have been identified as susceptibility factors for autoimmune diseases such as systemic lupus erythematosus (SLE). The human _C4_ gene is one of the most striking examples of genetic diversity, due to a great variation in number and size of gene copies between individuals. Low copy numbers of the _C4_ and _C4A_ gene are significant risk factors for the development of SLE in different populations. Meta-analysis by [PERSON] et al. showed that <4 copies of the _C4_ gene increase susceptibility to autoimmune diseases with an odds ratio of 1.46 (95% CI, 1.19-1.78) [77]. In addition, _C4A_ has been associated with disease severity. Thus, determination of _C4_ gene copy numbers may be useful in sub-phenotyping and managing SLE patients [78]. CNVs obtained from blood cells or tissues are suitable for the identification of germline or somatic variants. Tissue biopsy is a well-established procedure in cancer diagnosis for identification of human genomic alterations. However, this technique is invasive, time-consuming, not sufficient to examine the entire tumor profile, and not applicable in the follow-up of cancer treatment [79]. The current trend is moving towards non- or less-invasive sampling, such as liquid biopsy [80]. In combination with whole-genome copy number analysis, which does not require any prior knowledge about the characteristics of the primary tumor genome, it represents a promising clinical tool. [PERSON] et al. reviewed approaches for analyses of somatic copy number alterations at a genome-wide scale [81]. Both circulating tumor cells (CTCs) and cell-free DNA (cfDNA) were shown to be powerful sources in CNV profiling. [PERSON] et al. hypothesize that copy number changes are key events of metastasis. They observed cancer-associated CNVs in exomes of CTCs revealing information needed for individualized therapy, such as drug resistance and phenotypic transition and suggest that CNVs at certain genomic loci have the potential for CTC-based cancer diagnostics [82]. Several studies demonstrated that the detection of _ALK_ gene rearrangement in non-small-celllung cancer (NSCLC), a predictive biomarker for crizotinib treatment, may be performed using CTCs. The same group also reported that CTCs can be used for sensitive detection of _ROS1_ rearrangement in NSCLC patients. CTCs from _ROS1_-rearranged patients show heterogeneity of _ROS1_ gene abnormalities and elevated numerical chromosomal instability, suggesting a potential mechanism for resistance to crizotinib, a known ROS1-inhibitor [83]. Since tumor cells frequently undergo necrosis, they release tumor-specific cfDNA (ctDNA) into body fluids such as blood, urine, saliva, etc. [84]. It was shown that quantification of tumor-specific rearrangements in ctDNA by ddPCR is highly accurate for postsurgical discrimination between patients with an eventual diagnosis of clinical metastasis and long-term disease-free patients, with a sensitivity of 93% (95% CI, 66-100%) and specificity of 100% (95% CI, 61-100%). Moreover, ctDNA-based detection preceded clinical detection of metastasis in 86% of patients with an average lead time of 11 months, whereas patients with long-term disease-free survival had undetectable ctDNA postoperatively [85]. [PERSON] et al. presented a method enabling CNV detection from a 150-gene panel using a low amount of ctDNA.