Research Article: Assessment of circulating copy number variant detection for cancer screening

Date Published: July 7, 2017

Publisher: Public Library of Science

Author(s): Bhuvan Molparia, Eshaan Nichani, Ali Torkamani, Alvaro Galli.


Current high-sensitivity cancer screening methods, largely utilizing correlative biomarkers, suffer from false positive rates that lead to unnecessary medical procedures and debatable public health benefit overall. Detection of circulating tumor DNA (ctDNA), a causal biomarker, has the potential to revolutionize cancer screening. Thus far, the majority of ctDNA studies have focused on detection of tumor-specific point mutations after cancer diagnosis for the purpose of post-treatment surveillance. However, ctDNA point mutation detection methods developed to date likely lack either the scope or analytical sensitivity necessary to be useful for cancer screening, due to the low (<1%) ctDNA fraction derived from early stage tumors. On the other hand, tumor-derived copy number variant (CNV) detection is hypothetically a superior means of ctDNA-based cancer screening for many tumor types, given that, relative to point mutations, each individual tumor CNV contributes a much larger number of ctDNA fragments to the overall pool of circulating free DNA (cfDNA). A small number of studies have demonstrated the potential of ctDNA CNV-based screening in select cancer types. Here we perform an in silico assessment of the potential for ctDNA CNV-based cancer screening across many common cancers, and suggest ctDNA CNV detection shows promise as a broad cancer screening methodology.

Partial Text

According to the National Cancer Institute, 5-year survival rates of cancer patients are the highest when cancer is detected and treated at an early, localized, stage. Currently, there are a number of different cancer-type specific biomarkers used to indirectly detect cancer at an early stage; however most of them are associated with alarmingly high false positive rates (FPRs). For example, ovarian cancer screening using the CA-125 biomarker [1] along with transvaginal ultrasonography has a sensitivity of ~90% but a FPR of 57%[2]. Mammography for breast cancer screening has a FPR of 40–60% over 10 years of screening [3], Cologuard® for colorectal cancer screen has a FPR of 13.4% [4], and PSA for prostate cancer screening has a FPR of 20–30% when the test aims to detect >80% of cancers [5]. False positive results, and sometimes screening methods themselves, tend to lead to invasive and uncomfortable procedures that are associated with risk to otherwise healthy individuals; e.g. radiation exposure during mammography and surgery or biopsy in the case of other tumor types. These unnecessary procedures, unfortunately, lead to adverse events in approximately 15% of cases [6]. High false positive rates along with high adverse event rates for follow-up procedures place a significant proportion of the healthy population at unnecessary risk. Thus, an alternative and highly accurate non-invasive method for early cancer detection would both reduce the rate and impact of false positive results on otherwise healthy individuals, and could lead to substantial improvements in survival and quality of life of cancer patients. One possible approach is to utilize circulating tumor DNA (ctDNA) as a causal, rather than correlative, biomarker for the detection of cancer.

The promise of improved cancer outcomes via early detection has been hampered by the high false positive rates associated with modern cancer screening techniques. This is likely due to the fact that many current cancer screening techniques rely on correlative rather than causal biomarkers. On the other hand, ctDNA based cancer screening techniques have the potential to be highly accurate due to the fact that they directly interrogate the causal genomic drivers of tumorigenesis.




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