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Liquid Biopsy im kolorektalen Karzinom

Ein Überblick zur ctDNA-Analyse in der Tumordiagnostik
  • A. HauptsEmail author
  • W. Roth
  • N. Hartmann
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Zusammenfassung

Die routinemäßige molekulare Charakterisierung von Kolonkarzinomen erfolgt an Biopsien oder Resektaten. Dieser Goldstandard zur Klassifikation des Tumors kann jedoch die Tumorheterogenität nicht vollständig repräsentieren, denn eine Gewebeprobe stellt nur eine regionale Momentaufnahme dar. Zur Bestimmung des Mutationsprofils potenziell aller Tumorherde sowie zur Überprüfung des Mutationsstatus in regelmäßigen Abständen kann die minimal-invasive Liquid-Biopsy-Diagnostik verwendet werden. Dabei wird die im Blut zirkulierende, zellfreie DNA von Tumorzellen („circulating cell-free tumour DNA“, ctDNA) isoliert, die von apoptotischen oder nekrotischen Zellen freigesetzt oder aktiv von zirkulierenden Tumorzellen („circulating tumour cells“, CTCs) ins Blut abgegeben wird. Die Herausforderung bei der Analyse besteht in der geringen Menge an ctDNA im BIut und deren starker Fragmentierung sowie dem Vorliegen eines hohen Wildtyphintergrundes aufgrund von zellfreier DNA („cell-free DNA“, cfDNA), die von gesunden Zellen abgegeben wird. Dieser Übersichtsartikel beschreibt die Anwendungsfelder, das Potenzial und die Herausforderungen der ctDNA-Analyse im Allgemeinen und insbesondere in Bezug auf einen Einsatz zur Tumordiagnostik von kolorektalen Karzinomen (CRCs). Dabei wird besonders die Anwendung der Liquid Biopsy bei CRC-Patienten unter Anti-EGFR-Therapie diskutiert, weil das Monitoring zur Detektion von Resistenzmutationen (z. B. KRAS-Mutationen) von klinischer Relevanz ist. Außerdem wird die Konkordanz der gewebe- und blutbasierten Tumor-DNA-Analyse betrachtet und diskutiert, ob und inwieweit die Methodik der Liquid Biopsy den molekularpathologischen Standard der gewebebasierten DNA-Analyse zukünftig ergänzen kann.

Schlüsselwörter

Humanes KRAS-Protein ctDNA-Analyse Kolorektale Tumoren Zirkulierende Tumor-DNA Zirkulierende Tumorzellen 

Liquid biopsy in colorectal cancer

An overview of ctDNA analysis in tumour diagnostics

Abstract

In current routine diagnostics, the gold standard to determine the genomic profile of colorectal cancers (CRCs) is using biopsy or surgically resected tissues. However, such a tissue sample cannot represent the entire tumour heterogeneity, because it only shows a local and temporal snapshot. As a complement to tumour tissue genotyping, liquid biopsies enable minimally invasive detection of all potential tumour-specific mutations and their dynamic changes for molecular profiling. Furthermore, they can be repeated in certain intervals for monitoring response to treatment, occurrence of drug resistance and detection of relapse. This review focusses on analyzing circulating cell-free tumour DNA (ctDNA), which is mostly released from apoptotic or necrotic tumour cells into the bloodstream or by active secretion of circulating tumour cells (CTCs). Nevertheless, there are some challenges in analyzing ctDNA. First, ctDNA represents only a small fraction of total circulating DNA, because there is an enormous wild-type background of cell-free DNA (cfDNA) released by healthy cells. Second, ctDNA is highly fragmented and the amount of ctDNA in the blood is very low. In this review, we discuss the potential, fields of application as well as challenges and limitations of liquid biopsy approaches. In more detail, we discuss the possibility of using liquid biopsies as a future application for molecular characterization of CRCs, particularly for monitoring CRC patients during anti-EGFR therapy to detect resistance mutations (e.g. KRAS mutations) or further therapy-relevant mutations. In addition, we investigate whether blood-based molecular profiling is a reliable addition to routine diagnostic approaches of tissue-based molecular characterization.

Keywords

Human KRAS protein ctDNA analysis  Colorectal neoplasms Circulating tumor DNA Circulating neoplastic cells 

Notes

Einhaltung ethischer Richtlinien

Interessenkonflikt

A. Haupts, W. Roth und N. Hartmann geben an, dass kein Interessenkonflikt besteht.

Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

The supplement containing this article is not sponsored by industry.

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Copyright information

© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2019

Authors and Affiliations

  1. 1.Institut für PathologieUniversitätsmedizin MainzMainzDeutschland

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