Fast Five Quiz: Cancer Diagnostics and Precision Medicine
Over the past decade, precision medicine has transformed cancer diagnostics and treatment by tailoring therapy to a patient's tumor biology based on molecular alterations rather than histologic subtypes or origins. Precision oncology often relies on molecular profiling through next-generation sequencing (NGS) to identify genomic events that can guide management. Techniques like targeted panels, whole-exome sequencing (WES), and whole-genome sequencing (WGS) provide different analysis levels, chosen based on tumor type, tissue, and therapy relevance.
How much do you know about cancer diagnostics and precision medicine? Test your knowledge with this quick quiz.
WGS is an NGS method that analyzes the entire DNA sequence of an organism, including both coding and noncoding regions. WGS offers broad genomic coverage, detecting structural variants, intergenic mutations, and copy number changes often missed by targeted methods. Clinically, it has been useful in identifying ERBB2 ( HER2 ) amplifications in breast cancer or complex epidermal growth factor receptor ( EGFR ) alterations in lung cancer that might not be captured by smaller panels, helping guide targeted therapy. However, its lower sequencing depth (30-60×) typically limits the detection of low-frequency variants in heterogeneous tumors, such as a subclonal TP53 mutation affecting a small subset of cells and potentially impacting treatment response, which WGS may miss due to its lower depth.
WES focuses only on the protein-coding regions, offering greater depth than WGS but limited breadth; however, it misses important regulatory and noncoding mutations. For example, TERT promoter mutations in glioblastoma are clinically relevant but lie outside the exome and would be missed by WES.
Targeted panels are NGS tests that focus on specific disease-related genes and, until recently, were the predominant method used for comprehensive genomic profiling in clinical settings. They offer high depth for detecting low-frequency, actionable mutations but have limited coverage and might miss rare alterations outside the selected genes.
Sanger sequencing is a method that reads DNA by generating fragments of varying lengths using chain-terminating nucleotides. It is accurate for small regions but has low throughput and cannot detect low-frequency mutations, making it unsuitable for large-scale cancer genomics. Unlike WGS, which surveys the entire genome, Sanger covers only targeted regions, so it does not offer broad genomic coverage and is therefore not the correct answer.
Learn more about molecular profiling in oncology diagnostics.
TS panels analyze specific genes relevant to oncology, and by focusing on a smaller subset of the genome (a few dozen to a few hundred genes), these panels require fewer sequencing data, resulting in faster turnaround times and simplified data interpretation compared with WGS or WES. This targeted approach enhances sensitivity for detecting clinically actionable somatic mutations, especially in small or heterogeneous tumor samples. For example, targeted NGS panels in non-small cell lung cancer (NSCLC) can rapidly detect EGFR mutations, ALK rearrangements, and other actionable alterations, allowing oncologists to initiate targeted therapies based on the mutation profile promptly.
TS also demands less data storage and computational processing compared with WGS or WES, resulting in faster turnaround times and lower costs. These attributes make TS especially well-suited for clinical settings where accuracy, speed, and cost-effectiveness are paramount
Learn more about clinical practice guidelines in the use of precision medicine in oncology.
Tissue is generally preferred for initial genomic profiling because it contains a higher concentration of tumor DNA, allowing for more accurate detection of somatic mutations. This is especially important in early-stage cancers or tumors that do not shed much DNA into the bloodstream to be detectable by liquid biopsy. The tissue also allows for additional analyses like immunohistochemistry for PD-L1 or assessment of tumor histology to guide therapy. Further, immunohistochemistry plays an important role in precision medicine by identifying protein biomarkers to help determine the use of immune checkpoint inhibitors in NSCLC, triple-negative breast cancer, and urothelial carcinoma.
Blood-based tests (ie, liquid biopsies) generally yield lower tumor DNA and do not inherently offer deeper sequencing but are generally more cost-effective than tissue biopsies. Regulatory agencies currently accept blood-based tests (eg, FDA-approved liquid biopsies), but they are typically used when tissue is unavailable or there is insufficient tissue.
Learn more about tissue-based profiling
Liquid biopsy, particularly through the analysis of circulating tumor DNA (ctDNA), has emerged as a valuable tool for monitoring MRD after treatment. By detecting small amounts of tumor-derived genetic material in the blood, liquid biopsy enables early identification of molecular relapse, often before clinical or radiographic evidence of recurrence is apparent. This makes it particularly useful in post-treatment surveillance of cancers such as colorectal, breast, and NSCLC.
Diagnosing lymphomas typically requires tissue biopsy to assess architectural patterns and immunophenotyping; it is also commonly regarded as the standard for diagnosis.
PD-L1 expression is a protein-based biomarker typically measured by immunohistochemistry on tissue samples, not usually through ctDNA. However, researchers have stated, 'ctDNA response is a potential biomarker for predicting the efficacy and prognosis of first-line PD-1 inhibitor therapy combined with chemotherapy' in patients with advanced gastric cancer. ctDNA also has been shown to predict responses in patients using PD-1/PD-L1 immune checkpoint inhibitors.
Tumor staging usually relies on imaging modalities and pathologic evaluation rather than ctDNA analysis alone.
Learn more about clinical practice guidelines in the use of precision medicine in oncology.
A high TMB is considered useful because it is associated with abnormal proteins that make the tumor more recognizable to the immune system. TMB is measured using NGS by counting the number of somatic, nonsynonymous mutations per megabase of DNA; it is typically assessed using WES or large targeted panels. A TMB of 10 or more mutations per megabase is considered 'high,' based on data from the KEYNOTE-158 trial. This led to the FDA approval of an immune checkpoint inhibitor for TMB-high solid tumors, for example.
High TMB is not usually linked to fewer side effects; side effect profiles tend to depend on the therapy, not mutation count. Low TMB has been shown to lead to fewer neoantigens and typically less immune visibility. Typically, TMB directly measures the number of mutations, not PD-L1 protein expression.
Learn more about immunotherapy diagnostics.
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