Liquid Biopsy as a Source of Nucleic Acid Biomarkers in the Diagnosis and Management of Lynch Syndrome

Abstract

Lynch syndrome (LS) is an autosomal dominant inherited cancer predisposition disorder, which may manifest as colorectal cancer (CRC), endometrial cancer (EC) or other malignancies of the gastrointestinal and genitourinary tract as well as the skin and brain. Its genetic cause is a defect in one of the four key DNA mismatch repair (MMR) loci. Testing of patients at risk is currently based on the absence of MMR protein staining and detection of mutations in cancer tissue and the germline, microsatellite instability (MSI) and the hypermethylated state of the MLH1 promoter. If LS is shown to have caused CRC, lifetime follow-up with regular screening (most importantly, colonoscopy) is required. In recent years, DNA and RNA markers extracted from liquid biopsies have found some use in the clinical diagnosis of LS. They have the potential to greatly enhance the efficiency of the follow-up process by making it minimally invasive, reproducible, and time effective. Here, we review markers reported in the literature and their current clinical applications, and we comment on possible future directions.

Telomere Length Changes in Cancer: Insights on Carcinogenesis and Potential for Non-Invasive Diagnostic Strategies

“…Over the past decade, much effort has been devoted to the development of non-invasive approaches for cancer diagnosis and monitoring to replace the conventional invasive techniques [ 129 , 130 , 131 ]. Although associations between TL and cancer risk or prognosis have been extensively investigated in tumor tissues [ 69 ], cell-free telomeric DNA (cf-telDNA) remains poorly explored despite its potential suitability to become an informative genetic biomarker for many cancers ( Table 2 ).…”

Current and new frontiers in hereditary cancer surveillance: Opportunities for liquid biopsy

“…The identification of potential cell-free DNA-based and RNA-based biomarkers extracted from liquid biopsy might have a future role in the diagnosis of Lynch syndrome and in combination with, or as an alternative to, colonoscopy. 90 However, these markers need to be confirmed and standardized, cost-efficient testing methods prior to clinical implementation need to be developed. 90 A recent study reported that cfDNA multi-omic analysis distinguishes MPNST from plexiform neurofibromas with high sensitivity, and cfDNA levels in NF1 significantly correlate with MPNST tumor burden.…”

“… 90 However, these markers need to be confirmed and standardized, cost-efficient testing methods prior to clinical implementation need to be developed. 90 A recent study reported that cfDNA multi-omic analysis distinguishes MPNST from plexiform neurofibromas with high sensitivity, and cfDNA levels in NF1 significantly correlate with MPNST tumor burden. 91 By identifying distinctive pathways underlying MPNST pathogenesis, it this technique might allow clinicians to sub-classify MPNSTs to correlate with prognosis and develop personalized treatment plans.…”

Microsatellite instability assessment is instrumental for Predictive, Preventive and Personalised Medicine: status quo and outlook

“…This replication error phenotype is considered to be a hallmark of a hereditary cancer-prone syndrome, increasing individual risk for various malignancies. It is called Lynch syndrome (LS) [ 10 ] and MSI occurs in approximately 90% of cases [ 11 , 12 ]. Tumours are conventionally classified according to the proportion of unstable STR markers into the following classes: (i) MSI-H (microsatellite instability-high), (ii) MSI-L (MSI-low) and (iii) MSS (microsatellite stable) [ 13 ].…”