Genetic testing for colorectal cancer (CRC)

What is colorectal cancer?

Colorectal cancer is widespread and often occurs as transformation within adenomatous polyps.

More than half of the cases occur in the rectum and sigmoid, and 95% are adenocarcinomas. Colon and rectal cancers are often grouped in one because they have a lot in common.

What is Genetic testing for colorectal cancer?

An NGS-based assay includes a panel of genes concurred with the clinical use of approved targeted drugs and drugs from prospective clinical trials for colorectal cancer.

Alterations in these genes lead to tumor development and are used as diagnostic, prognostic, and predictive cancer markers.

"First Genetics Lab" performs testing using the high‑throughput sequencing system named "F‑Genetics" and reagents for high‑throughput next generation sequencing (NGS) of genes associated with human cancer genesis, that are registered as medical devices (Federal Service for Surveillance in Healthcare: РЗН 2020/10521, РЗН 2022/16970)

The assay detects:

Hotspots (SNV/InDels)
Copy number variations (CNV)
Chromosomal aberrations (Gene fusions)

Consulting with a clinical geneticist and an oncologist to interpret test results and select cancer therapy is required

Hotspots (SNV/InDels)

14 genes

AKT1

ALK

BRAF

CTNNB1

ERBB2

ERBB3

FGFR2

FGFR3

HRAS

KRAS

MET

NRAS

PIK3CA

RET

Copy number variations (CNV)

11 genes

ALK

BRAF

ERBB2

FGFR1

FGFR2

FGFR3

FGFR4

KRAS

MET

MYC

PIK3CA

Chromosomal aberrations (Gene fusions)

11 genes

ALK

BRAF

ERBB2

FGFR1

FGFR2

FGFR3

MET

NTRK1

NTRK2

NTRK3

RET

Testing indications:

For patients diagnosed with colorectal cancer for:

Therapy selection
Therapy monitoring and correction if the cancer recurrence occurs
Clinical trials enrollment

Targeted therapy

Targeted therapy is the type of treatment that targets specific molecules/proteins on the cancer cell surface or inside the cancer cells, blocking the growth and spread of cancer cells and limiting damage to healthy cells.

Not all tumors have the same targets. Genetic tests are used to find out what treatment is the most effective. Many clinical studies are underway.

Targeted therapy. Indications for drugs

PRINCIPLES OF MOLECULAR REVIEW (NCCN Guidelines Version 1.2022)

KRAS, NRAS, and BRAF Mutation Testing	All patients with metastatic colorectal cancer should have their tumor genotyped for RAS (KRAS and NRAS) and BRAF mutations. KRAS or NRAS mutations (ex 2, 3, 4) should not be treated with either cetuximab or panitumumab. BRAF V600E mutation makes response to panitumumab or cetuximab highly unlikely unless given with a BRAF inhibitor Encorafenib + (cetuximab or panitumumab). BRAF V600E mut +MLH1 protein expression absence — preclude Lynch Syndrome in 99% of cases.
HER2 Testing	Anti-HER2 therapy (Trastuzumab + [pertuzumab or lapatinib] or fam-trastuzumab deruxtecan-nxki) is only indicated in HER2-amplified tumors that are also RAS and BRAF wild type.
NTRK Fusions	The overall incidence of NTRK fusions is approximately 0.35%. But the numbers may increase in KRAS, NRAS, BRAF negative, and MSI-H tumors. The rate of NTRK false-positive samples by IHC is 1 in 5. So, when IHC used it also should be confirmed by RNA NGS. NTRK inhibitors (Larotrectinib or entrectinib) have been shown to have activity ONLY in those cases with NTRK fusions and NOT with NTRK point mutations.
Microsatellite Instability (MSI) or Mismatch Repair (MMR) testing	is recommended in all newly diagnosed patients with colon cancer. [Nivolumab ± ipilimumab] or pembrolizumab are indicated only for dMMR/MSI-H.

NGS method

NGS can simultaneously read hundreds of millions of short sequences of DNA and detect all types of mutations, including

Hotspots (SNV/InDels)

Copy number variations (CNV)

Chromosomal aberrations (Gene fusions)

Advantages

High sensitivity and specificity of the method
Fast turnaround time
Simultaneous detection of all types of mutations, including chromosomal aberrations
Minimum requirements for sample quantity and quality
Shorter testing times