Routine germline sequencing aids decision-making in cancer care

A recent study emphasizes the critical need to integrate routine germline sequencing into clinical practice to prevent the misclassification of clonal hematopoiesis (CH) aberrations. Findings identified somatic CH mutations in a substantial subset of patients with advanced solid tumors. This has implications for accurate treatment decisions in cancer patients, as distinguishing between tumor-derived mutations and CH mutations is crucial.

In an exclusive interview, study author Dr. Karina Eterovic, R&D Director of Oncology Diagnostics at Eurofins Viracor Biopharma Services, discusses the complex interplay between clonal hematopoiesis and cancer genomics, in the context of precision of cancer diagnosis and treatment.

CH is characterized by the clonal expansion of blood cells driven by somatic pathogenic mutations; distinct from somatic, tumor-derived mutations. Inability to distinguish somatic, tumor-derived mutations from CH mutations can lead to inaccurate treatment decisions.

Eterovic discusses strategies to differentiate CH-related mutations from tumor-specific somatic mutations. Additionally, she describes the challenges of detecting CH in the absence of sequencing data and discusses the role of CH insights in the future of personalized cancer treatment strategies.

Clonal hematopoiesis in enhancing cancer care

The scientists involved in this research, included experts specializing in oncology diagnostic assays and biomarkers, and somatic testing for personalized cancer care. CH, marked by the expansion of blood cells originating from a singular genetic clone due to somatic mutations, is observed in hematopoietic stem cells and progenitor cells. The condition heightens the risk of haematological malignancies like myeloid neoplasms and has also been linked to cardiovascular disease. While CH is seen in less than 1% of individuals under 40, its prevalence increases with age, affecting over 15% of those aged 70 and above.

“In cancer genomics, timely and accurate identification of CH is critical,” shares Eterovic. “Not only is CH a potential precursor to blood cancers, and hence a potential risk factor, but its genomic features are often mistaken for tumor somatic mutations. Recent studies reveal a high incidence – sometimes exceeding 20% – of CH mutations in patients with solid tumors. Thus, misidentification of CH can lead to inappropriate treatment decisions, wasting precious treatment time that patients with cancer cannot afford.”

Germline sequencing as a differentiation tool

Differentiating CH-related mutations from tumor-specific somatic mutations can be challenging. “It requires comprehensive genomic profiling, utilizing both tumor and germline data, in what is referred to as ‘paired germline testing’,” explains Eterovic. “Clinicians compare genetic alterations in tumor tissue with those in germline tissue, such as blood samples, to discern tumor-specific mutations from those associated with clonal expansion of blood cells.”

In a prospective study with multiple types of solid tumors, the team evaluated the significance of paired germline testing and the prevalence of CH mutations in solid tumors, Eterovic and her team enrolled 56 patients with advanced cancers of various types. The team performed targeted sequencing of 523 genes on matched formalin-fixed paraffin-embedded (FFPE) and circulating tumor DNA (ctDNA) samples from each patient, and whole exome sequencing on paired blood samples.

“We detected CH mutations in 23.2% of the cohort across all three matched sample types. Notably, four of these CH mutations were classified as oncogenic or likely oncogenic, emphasizing their potential significance in cancer,” says Eterovic. The study results have been featured as an abstract at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting.

“Without paired-normal data, filtering strategies can be employed to exclude potential CH mutations in tumor-only sequencing”, Eterovic explains. “Research has identified a higher prevalence of CH mutations in certain well-known genes. Filtering for and identifying these mutations in tumors should raise suspicions of potential CH.”

Another approach involves filtering CH aberrations based on the variant allele frequency (VAF) of these mutations, which indicates the proportion of variant sequencing reads within a genetic locus. However, findings from the study show that the VAF of CH-related mutations varied widely, ranging from 0.85% to 38.4% in the FFPE and ctDNA samples.

This illustrates the complexity of distinguishing CH aberrations from tumor somatic events based solely on VAF cut-offs, as factors like age, smoking history, and prior cytotoxic therapy can all influence CH occurrence. Eterovic cautions that this variability in the VAF makes it an unreliable filter for excluding potential CH mutations.

CH insights in personalized cancer treatment strategies

The study led by Eterovic’s team highlights the relevance of paired normal and tumor sequencing in preventing misclassification of CH aberrations and ensuring accurate treatment decision-making. Integrating routine germline testing into cancer diagnostics and care is essential for optimizing personalized cancer treatment strategies.

Looking ahead, the field of CH holds promise in advancing precision oncology, notes Eterovic. Ongoing scientific efforts focus on understanding the mechanisms of clonal expansion, the effects of specific mutations, and the interplay between CH and cancer development.

As an advocate for the field’s natural progression, Eterovic predicts future work will focus on enhancing the sensitivity and specificity of CH detection methods, identifying predictive biomarkers, and exploring targeted interventions to mitigate CH-related complications. She eagerly anticipates the integration of CH status alongside tumor genetics into personalized medicine approaches, foreseeing this will improve patient outcomes.

Review the poster from the study discussed in this article to learn more about routine germline sequencing in cancer care.

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