Correlation of genomic alterations assessed by next-generation sequencing (NGS) of tumor tissue DNA and circulating tumor DNA (ctDNA) in metastatic renal cell carcinoma (mRCC): potential clinical implications

Abstract

IntroductionTumor tissue and circulating tumor DNA (ctDNA) next-generation sequencing (NGS) testing are frequently performed to detect genomic alterations (GAs) to help guide treatment in metastatic renal cell carcinoma (mRCC), especially after progression on standard systemic therapy. Our objective was to assess if GAs detected by ctDNA NGS are different from those detected by tumor tissue NGS, specifically in patients with mRCC, and if these platforms are interchangeable or complimentary.ResultsWhen controlling for genes tested by both platforms, the median mutation rate for ctDNA was similar to tissue (median 3.0 vs. 1.0, p = 0.14). However, the concordance rate between the two platforms was only 8.6%. When comparing GAs by molecular pathway, GAs in tumor tissue were more common for the DNA repair and epigenetic pathways.Materials and MethodsResults of NGS testing from tumor tissue and ctDNA from 19 sequential mRCC patients were compared. GAs in each were statistically evaluated using the Wilcoxon signed-rank test. The Fischer's exact test was used to compare the incidence of mutations in selected molecular pathways.ConclusionsWhen controlling for genes tested by both platforms, similar number of GAs were detected by both tissue and ctDNA based NGS. However, there was discordance in the type of GAs detected suggesting that ctDNA NGS may be more reflective of dynamic tumor genomic heterogeneity. Hence, these two platforms may be considered complementary to each other, rather than interchangeable, for assessment of tumor GAs to guide selection of targeted clinical trial therapies.

Matched Whole-Genome Sequencing (WGS) and Whole-Exome Sequencing (WES) of Tumor Tissue with Circulating Tumor DNA (ctDNA) Analysis: Complementary Modalities in Clinical Practice

“…We focused on the effects of timing of genomic analysis, metastatic burden, tumor mutational burden, and systemic treatment on concordance among various cancer types. Consistent with prior studies, our analysis demonstrated a 58% concordance rate at the patient level and a 16% positive concordance rate at the gene level [11,12,13,14,35,36].…”

Matched Whole-Genome Sequencing (WGS) and Whole-Exome Sequencing (WES) of Tumor Tissue with Circulating Tumor DNA (ctDNA) Analysis: Complementary Modalities in Clinical Practice

“…We focused on the effects of timing of genomic analysis, metastatic burden, tumor mutational burden, and systemic treatment on concordance among various cancer types. Consistent with prior studies, our analysis demonstrated a 58% concordance rate at the patient level and a 16% positive concordance rate at the gene level [11,12,13,14,35,36].…”

Correlation of Somatic Genomic Alterations Between Tissue Genomics and ctDNA Employing Next-Generation Sequencing: Analysis of Lung and Gastrointestinal Cancers

“…observed a 10.8% concordance rate in 45 patients with breast cancer (30). The "concordance for negatives" rate was more than 90% in our dataset, which is similar to other studies (30,31,(37)(38)(39)(40).…”

Rational Development of Liquid Biopsy Analysis in Renal Cell Carcinoma

“…Additionally, they may have advantages for biomarker analysis as they protect their cargo from degradation [ 42 ]; however, harnessing information from EVs for liquid biopsy requires sensitive assays given the low abundance of circulating cancer-related EVs. Our results from RCC animal studies, as well as those on patient material supported the evidence from previous studies [ 4 , 5 , 32 ] that soluble ctDNA is appropriate for interrogating prognostic biomarkers in RCC; however, also indicated that evDNA is a strong candidate and should be considered in future investigations and with room for refinements (multiplexing, selective capture, others). Taken together, the current study provides a robust workflow and rationale for larger future studies to investigate the utility of ctDNA and evDNA for capturing diagnostic and prognostic biomarkers in RCC.…”

Matched Whole-Genome Sequencing (WGS) and Whole-Exome Sequencing (WES) of Tumor Tissue with Circulating Tumor DNA (ctDNA) Analysis: Complementary Modalities in Clinical Practice

“…We focused on the effects of timing of genomic analysis, metastatic burden, tumor mutational burden, and systemic treatment on concordance among various cancer types. Consistent with prior studies, our analysis demonstrated a 58% concordance rate at the patient level and a 16% positive concordance rate at the gene level [11,12,13,14,35,36].…”

Correlation of Somatic Genomic Alterations Between Tissue Genomics and ctDNA Employing Next-Generation Sequencing: Analysis of Lung and Gastrointestinal Cancers

“…observed a 10.8% concordance rate in 45 patients with breast cancer (30). The "concordance for negatives" rate was more than 90% in our dataset, which is similar to other studies (30,31,(37)(38)(39)(40).…”

Rational Development of Liquid Biopsy Analysis in Renal Cell Carcinoma

“…Additionally, they may have advantages for biomarker analysis as they protect their cargo from degradation [ 42 ]; however, harnessing information from EVs for liquid biopsy requires sensitive assays given the low abundance of circulating cancer-related EVs. Our results from RCC animal studies, as well as those on patient material supported the evidence from previous studies [ 4 , 5 , 32 ] that soluble ctDNA is appropriate for interrogating prognostic biomarkers in RCC; however, also indicated that evDNA is a strong candidate and should be considered in future investigations and with room for refinements (multiplexing, selective capture, others). Taken together, the current study provides a robust workflow and rationale for larger future studies to investigate the utility of ctDNA and evDNA for capturing diagnostic and prognostic biomarkers in RCC.…”

Matched Whole-Genome Sequencing (WGS) and Whole-Exome Sequencing (WES) of Tumor Tissue with Circulating Tumor DNA (ctDNA) Analysis: Complementary Modalities in Clinical Practice

“…We focused on the effects of timing of genomic analysis, metastatic burden, tumor mutational burden, and systemic treatment on concordance among various cancer types. Consistent with prior studies, our analysis demonstrated a 58% concordance rate at the patient level and a 16% positive concordance rate at the gene level [11,12,13,14,35,36].…”

Correlation of Somatic Genomic Alterations Between Tissue Genomics and ctDNA Employing Next-Generation Sequencing: Analysis of Lung and Gastrointestinal Cancers

“…observed a 10.8% concordance rate in 45 patients with breast cancer (30). The "concordance for negatives" rate was more than 90% in our dataset, which is similar to other studies (30,31,(37)(38)(39)(40).…”

Rational Development of Liquid Biopsy Analysis in Renal Cell Carcinoma

“…Additionally, they may have advantages for biomarker analysis as they protect their cargo from degradation [ 42 ]; however, harnessing information from EVs for liquid biopsy requires sensitive assays given the low abundance of circulating cancer-related EVs. Our results from RCC animal studies, as well as those on patient material supported the evidence from previous studies [ 4 , 5 , 32 ] that soluble ctDNA is appropriate for interrogating prognostic biomarkers in RCC; however, also indicated that evDNA is a strong candidate and should be considered in future investigations and with room for refinements (multiplexing, selective capture, others). Taken together, the current study provides a robust workflow and rationale for larger future studies to investigate the utility of ctDNA and evDNA for capturing diagnostic and prognostic biomarkers in RCC.…”