Distinct Clonal Patterns Exist between Benign and Malignant Tissue

The study of how somatic mutations contribute to the transition from benign to malignant tissue is critical to the early diagnosis of cancer, but current methods are constrained through the ability to study only a limited number of spatial regions or single cells within a tissue section. To delineate the clonal architecture in tumors and coexisting benign tissue without being confined by histologic boundaries, Erickson, He, Berglund, and colleagues used spatially resolved transcriptomics to determine genome-wide copy-number variations (CNV). An entire prostate organ was used to evaluate the landscape of spatially inferred CNVs (siCNV) and demonstrated that most tissue areas were copy-number neutral, while certain regions had increased CNV activity, suggesting that genomic variability in specific tissue regions can be identified using siCNVs at the organ scale. Determination of the degree of clonal copy-number heterogeneity revealed that some gene expression factors were homogenous in genotype, while others were heterogeneous with some regions annotated as histologically benign displaying copy-number heterogeneity. Additionally, across cancer, clonal distribution of copy-number heterogeneity occurred in areas that were spatially homogenous, and construction of clonal trees indicated conserved siCNV features in specific locations, which provides insight into tumor clonal evolution. Moreover, investigation into the discord between cellular phenotype and inferred genotype showed that many CNVs had already occurred in benign tissue, especially on chromosomes 8 and 10 that harbor MYC and PTEN, supporting that observed clone groups can traverse histologic boundaries. Furthermore, these findings were also generalized to other organs and cancer types besides the prostate including the lymph node, skin, medulloblastoma, ductal breast cancer, and adult glioblastoma. In summary, this study used siCNV information along with spatial gene expression patterns to capture molecular as well as spatial continuums in both malignant and benign tissue and suggests use of this information for early detection and treatment options for various tumor types.

Erickson A, He M, Berglund E, Marklund M, Mirzazadeh R, Schultz N, et al. Spatially resolved clonal copy number alterations in benign and malignant tissue. Nature 2022;608:360–7.

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