Deciphering intratumor heterogeneity in clear cell renal cell carcinoma utilizing clinicopathologic and molecular platforms

Erica Vormittag-Nocito; Rahul Mannan; Xiaoming Wang; Anya Chinnaiyan; Yuping Zhang; Sylvia Zelenka-Wang; Xuhong Cao; Todd M Morgan; Khaled Hafez; Ulka Vaishampayan; Eman Abdulfatah; Arul M Chinnaiyan; Saravana M Dhanasekaran; Rohit Mehra

doi:10.1016/j.humpath.2022.10.009

Deciphering intratumor heterogeneity in clear cell renal cell carcinoma utilizing clinicopathologic and molecular platforms

Hum Pathol. 2022 Dec:130:95-109. doi: 10.1016/j.humpath.2022.10.009. Epub 2022 Oct 27.

Affiliations

¹ Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
² Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, Ann Arbor, MI, USA.
³ Michigan Center for Translational Pathology, Ann Arbor, MI, USA.
⁴ Michigan Center for Translational Pathology, Ann Arbor, MI, USA; Rogel Cancer Center, Michigan Medicine, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.
⁵ Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.
⁶ Department of Hematology/Oncology, University of Michigan, Ann Arbor, MI, USA.
⁷ Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, Ann Arbor, MI, USA; Rogel Cancer Center, Michigan Medicine, Ann Arbor, MI, USA; Howard Hughes Medical Institute, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.
⁸ Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, Ann Arbor, MI, USA; Rogel Cancer Center, Michigan Medicine, Ann Arbor, MI, USA. Electronic address: mrohit@med.umich.edu.

PMID: 36511267
DOI: 10.1016/j.humpath.2022.10.009

Abstract

Clear cell renal cell carcinoma (CCRCC) is a common renal malignancy known for its lethality and chromosome 3p aberrancies associated with loss of VHL. It has been shown that additional prognostic molecular markers exist in other transcriptional modifiers such as BAP1 and SETD2. Molecular heterogeneity has been described between primary and metastatic sites as well as genetic diversity in spatial tumor analysis; however, morphologic and proteogenomic heterogeneity information is lacking. We assessed 77 nephrectomy specimens with a diagnosis of CCRCC for morphologic architectural patterns including nodular growth patterns and variations in WHO/ISUP grade. Evaluation of highly heterogeneous areas with immunohistochemical (IHC) staining for BAP1, UCHL1, SETD2, and CAIX was performed and correlated with morphologic and histology data. Ultimately, high variability in the morphologic and histological findings matched the complexity of the IHC findings. Alterations in expression of CAIX and UCHL1 correlated with alterations in transcriptional regulators BAP1 and SETD2 within the tumor. High-grade morphology, such as eosinophilia, were areas enriched for alteration of biomarker expression. This highly complex data set of morphologic and biomarker characteristics highlights the heterogeneity of morphology amongst high-grade CCRCC tumors.

Keywords: BAP1; CAIX; Clear cell renal cell carcinoma; Gene expression; Immunohistochemistry; Kidney cancer; Mutation; SETD2; Tumor heterogeneity; UCHL1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carcinoma, Renal Cell* / genetics
Carcinoma, Renal Cell* / metabolism
Carcinoma, Renal Cell* / surgery
Humans
Kidney Neoplasms* / pathology
Mutation
Prognosis
Tumor Suppressor Proteins / genetics

Substances

Tumor Suppressor Proteins

Grants and funding

HHMI/Howard Hughes Medical Institute/United States