Search for Novel Predisposing Gene Variants and Cancer Predictive Markers in Hereditary Colon Cancer Syndromes

The introduction of Next Generation Sequencing (NGS) technology in clinical practice has had a profound impact in the identification of gene variants responsible for heritable diseases...


Opinion
The introduction of Next Generation Sequencing (NGS) technology in clinical practice has had a profound impact in the identification of gene variants responsible for heritable diseases.
The high throughput capability of NGS allows the simultaneous screening of the whole coding genome (usually defined clinical exome) at affordable costs and with reasonable turnaround times.
While the traditional single gene sequencing approach had low detection power, NGS greatly expanded the number of tested genes in many genetic conditions where disease predisposition can be due to causative mutations in many different genetic loci.
In Colorectal Cancer (CRC), which account for 10% of all newly diagnosed cancers and is responsible for 9% of all cancer deaths, family history is a major risk factor [1][2][3]. It is estimated that approximately a quarter of all CRCs is due to familial inheritance with 5-8% of cases attributable to single gene inherited predisposition [4,5]. Traditionally, three major types of inherited predisposition to CRC are recognized being the Lynch syndrome (previously These three CRC-predisposing conditions are mainly caused by pathogenic variants in six primary genes (MLH1, MSH2, MSH6, PMS2, APC, and MUTYH). However, several additional genes are also known to cause hereditary CRCs or conferring an increased risk for colorectal cancer. Thanks to NGS technology, the labor extensive and time-consuming Sanger sequencing approach has been replaced by multigene panels that allow for an inexpensive and comprehensive screening for numerous hereditary CRC genes. Yet, NGS has been less successful in identifying novel CRC-predisposing genes [6,7].    Figure 2). Despite the huge emphasis that the concept of "liquid biopsy" has provoked in cancer screening as an attractive tool for early detection and minimally invasive diagnosis of cancer, the sensitivity and the specificity achieved so far prevented these tests to be used in general population screening (reviewed in [11][12][13][14][15]).
The liquid biopsy approach has been focused on analyzing either Circulating Tumor Cells (CTCs), cell-free circulating tumor DNA (ctDNA) and/or tumor-derived extracellular vesicles (exosomes).
Liquid biopsy approaches have been proven extremely useful in monitoring cancer recurrence, progression, efficacy of therapeutic intervention as well as disease profiling, considering the clonal heterogeneity of human cancers [16,17]. Blood-based screening methods were less effective in detection of cancer in early preclinical stages. However, a recent study demonstrated that using a machine learning approach it is possible to achieve high sensitivity and specificity applying whole-genome sequencing of cell-free DNA on a cohort of predominantly early stage CRCs [18]. In this light, tumors exhibiting Microsatellite Instability (MSI), may represent a promising target for future applications. In fact, several recent works have determined that the MSI phenotype may be detected directly from cell-free DNA [19][20][21][22][23].
In conclusion, recent advances should help in a more effective monitoring of patients with high CRC risk and the long-term surveillance of their health status.

Declaration of Conflict Interest
The author declares no potential conflict of interest with respect to the research, authorship, and/or publications of this article

Funding
This work was supported by a grant from Fondazione Puglia entitled "Ricerca di nuovi geni di predisposizione e di markers predittivi di neoplasia nelle sindromi di predisposizione ereditaria al cancro del colon retto".