What tools oncologists can use to read 2-generation sequencing (NGS) reports in depth

Clinicians who submit NGS test requests will receive a genetic test report
.
The content of the report should generally provide detailed information about the NGS test method used, the NGS test results, and the interpretation of the clinical significance of the
NGS results.
Due to rapid advances in genomic medicine, not all clinicians are familiar with and correctly interpret NGS test results
.
With the development of large-scale genome sequencing projects for hematological and solid tumors, and the accumulation of an increasing amount of relevant data, new genetic variant information is constantly being integrated and supplemented into many public databases
.
In many publicly available cancer databases, there are explanations
for specific sequence and functional changes in somatic gene mutations.
These cancer databases include:

Cancer Gene Census (http://cancer.
sanger.
ac.
uk/cancer genome/projects/census/);

Cancer Somatic Mutation Catalog (COSMIC) (http://cancer.
sanger.
ac.
uk/cancergenome/ projects/cosmic/);

Cancer Genome Atlas (TCGA); http://cancergenome.
nih.
gov/), etc
.

For the genetic variants detected by NGS testing, there is a clear need to evaluate
their functional changes and effects.
This assessment depends largely on how often and how well
the gene mutation occurs in the tumor.
Cancer-specific databases often provide detailed information on the probability and incidence of certain gene sequence variants in different types of tumors, particularly key information about potential targeted therapies, and are often linked to
other relevant databases and published literature.
It should be noted that because the sources of submitted genetic variant data are different and the published clinical literature is often not standardized in a uniform manner, the probability and distribution rate of gene sequence variants in these databases in different tumors may need to be interpreted
with caution.

The biggest difficulty in the clinical application of NGS detection is how to interpret the effect of gene mutation on the function of the gene in the context of cancer biology and what guiding significance
it has for clinical treatment.
In principle, from the perspective of comprehensive interpretation and clinical application, NGS test results usually need to be evaluated from the following four levels: (1) detection of related genes; (2) specific gene mutations; (3) the sensitivity or resistance of the relevant drug; (4) Tumor specificity
.
Most of the available databases tend to simply provide and highlight certain aspects of their concerns; For example, some databases focus on the relationship between genetic variants and tumors, while others focus on the relationship between
genetic variants and tumor targets or drugs.
Most of the databases originally designed were primarily used for germline variant studies and preclinical studies, and were of limited
use for clinical applications.
For example:

Targeted Therapy Database (http://bidd.
nus.
edu.
sg/group/cjttd/)；

Drug banks ( style="color: #545454;">Pharmacogenomics Knowledge Database ( style="color: #545454;">Drug Gene Interaction Database (http://dgidb.
genome.
wustl.
edu/), etc.
;

These are all available database resources, but they all have certain limitations
.
Recent progress has been in the use of more databases, with a greater focus on using
these database pathways as decision-making tools for clinical treatment.

Such databases include:

Vanderbilt-Ingram Cancer Center: My Cancer Genome ( style="color: #545454;">CIViC30 (https://civic.
genome.
wustl.
edu)； 

The Precision Medicine Knowledge Base (https://pmkb.
weill.
cornell.
edu)；

The Jackson Laboratory Clinical Knowledge Base ( clinical-genomics/ckb);

Cancer Genome Interpreter (https://cancergenomeinterpreter.
org);

Cancer Driver Log (http://candl.
osu.
edu);

Tumor porta, http://tumorportal.
org;

Targeted Cancer Care, Massachusetts General Hospital (https:// targetedcancercare.
massgeneral.
org)

Personalized Cancer Therapy (https://pct.
Md anderson.
org)；

OncoKB28 ( org).
 

Some other related databases can be found in the table below.

The above databases are constructed differently, and not all databases contain enough clinical information to aid
clinical treatment decisions.
In addition, not all databases come with comment section functionality
for group operations to improve data availability.
Recently, genomic industry organizations such as the Clinical Genomic (ClinGen) Somatic Cancer Clinical Field Working Group have begun to focus on the standardization and standardization of
NGS test interpretation.
The Variant Interpretation for Cancer Consortium has developed a standard operating procedure to improve consistency
in properly classifying the carcinogenicity of somatic gene mutations 。 (Horak，Standards for the classification of pathogenicity of somatic variants in cancer，Genet Med 2022 May; 24(5):986-998)
。

In conclusion, because different databases have their own advantages and disadvantages
.
When using a database, oncologists need to understand the characteristics of the content of the database, know how the data is integrated, and avoid over-interpreting the data and results obtained, which is important
to correctly guide clinical treatment.
Of course, in day-to-day clinical practice, it is unlikely that we will knowingly oversee the strengths and weaknesses
of individual databases.
Therefore, the minimum requirement for oncologists may be to understand which databases each of the molecular pathology laboratories rely on to analyze and report NGS sequencing results
.
The NGS test report should also clearly state the database used, which will facilitate the correct understanding and use of the NGS report
.
Although NGS reports usually provide the tester's interpretation of the data results, as an oncologist, having an in-depth understanding of the main details of NGS testing will help provide a more comprehensive and accurate personalized treatment plan
for the patients treated 。 Similarly, interdisciplinary discussions of NGS reports in molecular oncology panels are important
for the correct interpretation of test results, especially for in-depth interpretations of uncertain significance (VUS) of unclear signage, to provide actionable responses and potential treatment options.
Tang Jiao Yan Ying