Single-Cell mRNA Signaling Facilitates Diagnosis of Childhood and Adult Kidney Tumors

By Marilynn Larkin

July 02, 2021

NEW YORK (Reuters Health) - Single-cell mRNA sequencing, a high-resolution technology that can identify different cell types in a tissue, has confirmed the origins of seven types of kidney cancers, including several rare subtypes, and differentiates developmental from adult-onset tumors.

"The main takeaway from a clinical perspective is that transcriptomic information, measured by RNA sequencing, can improve cancer classification," Dr. Matthew Young of the Wellcome Sanger Institute in Cambridge, UK, told Reuters Health by email. "Accurate classification is important as it can determine the approach to treatment. For example, Wilms tumor and clear cell renal cell carcinoma are both kidney tumors, but are treated very differently."

"Our approach uses bulk tumor transcriptomes and reference maps of normal kidney single-cell transcriptomes to identify tumor 'fetalness,' and which normal cell transcriptome each tumor most resembles," he explained.

As an example of the benefit of the approach, he said, the team considered a child's kidney tumor that could not be definitively classified using standard diagnostic tools. "Our approach implied a particular diagnosis, a Wilms-like tumor, which the subsequent course of the child's disease has proven likely to be correct."

Further, he said, "from a basic research perspective, we provide quantitative evidence that childhood kidney tumors are developmental, while adult kidney tumors are not. This was surprising, as there is a literature on cancer being characterized by dedifferentiation."

"But dedifferentiation is not a complete return to a true developmental state at the level of the entire transcriptome," he noted - in other words, contrary to prevailing theories, in most cases, adult kidney tumors do not dedifferentiate back to a fetal state.

As reported in Nature Communications, the team mined the Human Cell Atlas reference data and databases of tumor gene expression, and assessed mRNA signals in 1,300 childhood and adult renal tumors to investigate their origins. The tumors spanned seven types: congenital mesoblastic nephroma; nephroblastoma (Wilms tumor); clear cell sarcoma of the kidney; malignant rhabdoid tumor of the kidney; clear cell renal cell carcinoma; papillary renal cell carcinoma, subtypes type 1 and type 2; and chromophobe renal cell carcinoma, subtype "metabolically divergent ChRCC."

Using single-cell mRNA reference maps of normal tissues, they quantified the cellular signals in each tumor. As noted, by quantifying global differentiation, they found that childhood tumors exhibit fetal cellular signals, replacing the more vague description, "fetalness," with a quantitative measure of immaturity.

Specifically, they found "an intimate connection" between developmental mesenchymal populations and childhood renal tumors, and showed the diagnostic potential of their approach by helping to classify a patient's tumor that clinicians had been unable to diagnose.

By contrast, as Dr. Young noted, in adult cancers, their assessment refuted the idea that these cancers, which emerge from mature cell types, dedifferentiate towards a fetal state, at least, in most cases.

The authors conclude, "Our findings provide a cellular definition of human renal tumors through an approach that is broadly applicable to human cancer."

Dr. Elizabeth Mullen, Program Leader, Renal/Liver Tumors at Dana-Farber/Boston Children's Cancer and Blood Disorders Center, commented on the study in an email to Reuters Health: "The authors have presented intriguing data which deepens the understanding of the origins of pediatric renal cancer, and the relationship, or distinction, from adult kidney cancer."

"This is promising work," she said, "and will hopefully be expanded to provide single cell transcriptome information across a broader range of pediatric renal tumors, including histologically and genetically diverse Wilms tumors and other rare pediatric cancers."

"Treatment of pediatric cancers, which are very often rare or extremely rare, hinges on establishing as best possible a specific and accurate diagnosis for each child's tumor," she said. "The researchers describe an approach of combining reference data from single cell transcriptomes to annotate existing large repositories of tumor bulk transcriptomes to derive a new, cellular transcription definition of cancer. Further expansion of this work holds promise for the goal of providing better, more tailored therapy for children with pediatric renal tumors."

SOURCE: Nature Communications, online June 23, 2021.