ELOC-Mutated Renal Cell Carcinoma is a Rare Indolent Tumor With Distinctive Genomic Characteristics.

ELOC-mutated renal cell carcinoma (ELOC-RCC) is a subtype of RCC first recognized by the World Health Organization in 2022, molecularly defined by the presence of ELOC mutations and the lack of VHL mutations. Here, we present an institutional series of ELOC-RCC and provide an in-depth genetic comparison to VHL-null clear cell RCC (VHL-ccRCCs). Among 1209 RCCs in our institutional cytogenetics database, we identified 16 candidate cases that were originally classified as ccRCC and exhibited monosomy 8 and intact chromosome 3p. Seven of these 16 candidate cases were diagnosed as ELOC-RCCs based on histomorphology, immunohistochemistry, and whole-exome sequencing results. By contrast, ELOC-RCCs had a simpler karyotype of monosomy 8 with few other alterations. Adding 6 additional ELOC-RCC cases identified from The Cancer Genome Atlas cohort, all 13 ELOC-RCCs exhibited biallelic ELOC inactivation without VHL mutations. These ELOC mutations (Y79C/L/S/N, E92K, A106D, and C112Vfs∗3) were all located within or close to the VHL-binding domains in ELOC protein; 69% of the ELOC-RCC cases exhibited its characteristic histomorphology. Compared with stage- and grade-matched VHL-ccRCCs, patients with ELOC-RCCs had superior overall survival (hazard ratio, 0.32; 95% confidence intervals, 0.16-0.61; P = .02) and progression-free survival (hazard ratio, 0.16; 95% confidence intervals, 0.06-0.42; P = 0.04). ELOC-RCCs had significantly fewer somatic copy number alterations and a greater abundance of the mutational signature SBS1 than VHL-ccRCCs. ELOC-RCCs lacked common chromosomal alterations or gene mutations seen in ccRCC, including PBRM1, SETD2, BAP1, TSC1, TSC2, or mTOR. Most ELOC-RCCs had linear phylogenetic trees with clonal and truncal ELOC mutations, whereas additional alterations to ELOC or 8q losses occurred as a subclonal event. Although 11 of 13 ELOC-RCCs were confined to the kidney, 2 ELOC-RCCs were high-stage and exhibited a large solid alveolar pattern, tumor necrosis, more somatic copy number alterations, and an additional monoallelic VHL copy loss. Taken together, ELOC-RCCs exhibit distinctive genomic features and indolent behavior in general, supporting it as an independent diagnostic entity.