Whole genome sequencing: the future of molecular diagnostics in gynecological cancer? 

To mark Gynecological Oncology Awareness Month, we spoke with oncologist Eelke Gort about the role of molecular diagnostics in these female-specific cancers. “In an ideal world, whole genome sequencing would be part of standard diagnostics.” 

Gort is a medical oncologist at UMC Utrecht specializing in gynecological oncology. There are several types of gynecological cancers, he explains. “Endometrial cancer is the most common. Every year, about two thousand women in the Netherlands are diagnosed with it. Next come ovarian cancer, cervical cancer, and rarer cancers such as vulvar cancer and trophoblastic tumors. But there are also rare subtypes of the ‘larger’ cancers.” 

The role of WGS in tomorrow’s diagnostics 

Particularly in endometrial and ovarian cancer, molecular diagnostics have now become an established part of care. Treatment is tailored to the molecular characteristics of the tumor, which are usually determined using targeted gene panels. But that same information—and more—can also be obtained in one go through Whole Genome Sequencing (WGS). Gort: “In an ideal world, WGS would be part of standard diagnostics. You would then be able to collect all the information at once, instead of requesting separate panels each time. In the long run, that might even be cheaper than doing everything separately.” 

In addition, it would generate a wealth of scientific data, especially if linked to treatment outcomes, helping to identify which genetic factors influence whether a treatment will be effective. Gort: “I think it is a matter of the long haul, but it makes perfect sense that we are working toward that, because scientifically it offers so many possibilities if you can bring it all together in one database.” 

Hartwig Medical Foundation, he says, plays an important role in this. “I think it is wonderful that we have such a foundation in the Netherlands. We should certainly make more use of it. And I think we can also be proud that we have it.” 

According to Gort, Hartwig could also help accelerate the transition into the clinic. “In an ideal world we’d make it simple and fast, and Hartwig could be a very useful factor in that. I believe that is also Hartwig’s goal.” 

Today’s practice: targeted panels and guideline-based diagnostics 

However, WGS is not yet standard in clinical practice, and usually only specific panels are tested. “In endometrial cancer, it is now fully incorporated into the guidelines: molecular classification into four categories – POLE, MSI, TP53 and the non-specific subgroup. These are determined using DNA sequencing and protein staining.” Molecular diagnostics also play a clear role in ovarian cancer, particularly regarding BRCA mutations. “There it has also really become a fixed part of the guideline.” 

For other forms of gynecological tumors, there is not yet a standard role for molecular diagnostics. “Except in situations where regular treatments have been exhausted and you are looking for alternative treatment options. For example, if a tumor no longer responds to chemotherapy and you still want to be able to offer something. For these situations there are guidelines regarding which diagnostics should be used at what time: the lists of minimally clinically necessary targets.” 

In such cases, the search often focuses on rare abnormalities that may be treatable with targeted therapies. As with endometrial cancer classification, this search is typically carried out with targeted gene panels and less often with WGS. “As a doctor, you don’t really need it at first, because you can’t do anything with it yet,” says Gort. “What most oncologists want to know is: is there MSI, is there a BRCA mutation, are there NTRK fusions? Because that determines whether a particular drug should or should not be used. In that respect, we work quite strictly according to established protocols.”  

Thus, the standard treatment is first initiated based on a limited set of molecular markers, while the search for rare mutations usually comes later. “You could obtain all that information in one go with WGS, but it does have to be meaningful. You shouldn’t just test everyone if in the end you don’t do anything with the results. You should only do it when it is cost-effective.” 

WGS in research 

The situation is different in research. Gort is involved in several studies such as CPCT, DRUP and GENAYA, in which tumors are mapped with WGS by Hartwig Medical Foundation. “Information is knowledge, so it always offers a chance for better treatment and better prognoses,” he says. “Especially in a research context, out of my academic curiosity, I would like to have WGS from all patients right at the beginning. But I think we already know quite a lot about many tumors.” 

“I think the exception is the rare tumors,” Gort continues. “If you add up all the rare tumors, together they still form a considerable group. And those are precisely the cases for which we often have less knowledge and fewer treatment options available. With WGS you can increase the chance that there is still an option after all.” 

Looking ahead 

If the speed and costs of WGS continue to improve, Gort sees opportunities for broader application. “Then that could very well happen, especially since we are already using molecular diagnostics at an early stage in endometrial and ovarian cancer. If it becomes more efficient to do everything at once, then that really opens up new possibilities.” 

Want to know more about the molecular biology of gynecological cancers? Hartwig has developed a Tumor Landscape with visual overviews of the molecular characteristics of these tumors, derived from WGS. These provide insight into the diversity and complexity of cancer, the possibilities for treatment, and the value of data-driven care. Tumor Landscapes of other cancers can be found at https://www.hartwigmedicalfoundation.nl/data/vignettes/.