The Importance of Analyzing the DNA of Rare Tumors

28-02-2025

One in four patients has a cancer type that is considered rare, meaning it occurs in fewer than six out of 100,000 people per year. This often means it’s often more complicated to get an understanding of what is happening and can take a long time before a diagnosis is made. A complete DNA analysis can sometimes help clarify the diagnosis and subsequently aid the creation of the treatment plan.

Reading the whole genome
Since 2022, in the Netherlands, Whole Genome Sequencing (WGS – the ‘reading’ of the entire DNA) is reimbursed as a standard test for tumors with an unknown primary location (CUP: Cancer of Unknown primary). Data from the Dutch Cancer Registry (maintained by IKNL) shows that CUPs are rare tumors (incidence of 5 in 100,000), with a poor prognosis (only 7% survival five years after diagnosis) indicating that accurate and timely treatment is crucial for these patients.

With WGS, a complete DNA analysis of the tumor can be performed. This data can be used to predict the type of cancer (for example, skin, lung, or colon cancer). Additionally, DNA analysis can provide clues for personalized treatments. For CUPs, this is the case for 70% of patients, which is extremely valuable because it allows them to be treated more quickly and precisely. We try to summarize these and other genomics findings in so called vignettes, a part of this graphical overview shows actionable findings and can be seen below for CUP patients:

***Figure 1: Overview of DNA Findings That May Be Relevant for Personalized Treatment.*** The color indicates under which label the medication might potentially be used. The color gradient shows how likely this is. Dark blue represents approved drugs, which can be more easily used, while light blue indicates an experimental treatment. The numbers represent the number of patients with at least one finding under this label, from the set of 462 patients with a PTO in the Hartwig database. The three rows represent the different testing strategies used in the Netherlands. The top row shows testing with WGS (whole DNA), the middle row shows a broad molecular panel (the ±500 genes relevant to cancer), and the bottom row shows a small panel (50 or fewer genes, only the most common genes). *Of the routine tests, WGS currently provides the most complete DNA overview.*

Sarcomas
In Sweden, Germany and England, studies have been conducted on how WGS can assist in diagnosing another rare type of tumor, sarcomas. A recent Swedish study recommends WGS for routine use of WGS for this tumor type. Sarcomas are tumors in the soft tissues and bones of patients. There are more than 70 different types (subtypes) of sarcomas, and the number of diagnoses is increasing [IKNL report].

DNA contains important information that can help determine the subtype of the tumor. For example, the Swedish study showed that in 7% of cases, the tumor was a different type of sarcoma than initially thought, and in many cases, it was a less or non-aggressive form. In these less aggressive forms, treatment could be delayed, while the tumor was closely monitored for any progression. They also identified DNA variants relevant for treatment in 15% of cases. In the Netherlands, sarcomas are sometimes tested with WGS in studies or for patients who are no longer responding to treatment.

Currently there is data available in the Hartwig Medical Database on 381 sarcoma patients, which researchers can request access too. In the data (vignette for sarcomas), some of these subgroups can be clearly seen, such as a subgroup with a CDK4 & MDM2 amplification (extra copies of genes that can cause the tumor cell to divide more rapidly).

***Figure 2***: A so-called ‘oncoprint’ for all sarcomas in the Hartwig database, a figure where each column summarizes the DNA data of one patient and each row describes a gene. The data is sorted in such a way that patients with similar DNA profiles are placed next to each other, and the genes where variations are most frequently found are at the top. The colors indicate the type of variation. Red represents extra copies, blue indicates the loss of a copy of the gene, yellow represents small DNA changes that can deactivate the gene, and light blue represents fusion genes (two genes that are stuck together).

In the entire Hartwig database, this type of change occurs rarely (2-3%). However, in sarcomas, we see this much more frequently (12%). The subgroup with this change is primarily composed of liposarcomas (see also this scientific article), tumors that arise in fat tissue, where the frequency of this DNA change increases to 62% (see also the liposarcoma vignette).

***Figure 3****: An oncoprint (see the caption for Figure 2) of the liposarcoma patients in the Hartwig database. This subtype has DNA characteristics that clearly distinguish it from other sarcoma subtypes.*

These and other findings have already led to the development of specific treatments for CDK4 amplification tumors (see also this publication), known as CDK4 inhibitors. Several studies, along with those from Sweden and Germany, show that there is still much to learn about these rare tumors. WGS is the most complete method for DNA analysis. For current patients, this test can therefore mean a different treatment or, in some cases, no treatment if it’s not (yet) necessary.

For research on rare tumors, it is important for hospitals and countries to collaborate more effectively to integrate as much DNA and clinical data as possible. Only with large enough datasets can patterns (and clinical response) be accurately identified. This way, the clinical applicability of subtyping can be validated and implemented into routine care. Over the past 10 years, the Hartwig Medical Foundation has worked both in the Netherlands and worldwide to enable the best treatment for patients. And we will continue to do so.

Sources

https://nkr-cijfers.iknl.nl