DNA damage repair pathway alterations in metastatic clear cell renal cell carcinoma and implications on systemic therapy

Abstract

BackgroundLoss-of-function alterations in DNA damage repair (DDR) genes are associated with human tumorigenesis and may determine benefit from immune-oncology (I/O) agents as shown in colon cancer. However, biologic significance and relevance to I/O in metastatic clear cell RCC (ccRCC) are unknown.MethodsGenomic data and treatment outcomes were retrospectively collected for patients with metastatic ccRCC. Tumor and germline DNA were subject to targeted next generation sequencing across >400 genes of interest, including 34 DDR genes. Patients were dichotomized according to underlying DDR gene alteration into (1) deleterious DDR gene alterations present (Del DDR); (2) wild-type (WT) and variants of unknown significance (VUS) DDR gene alterations present (WT/VUS DDR). Association between DDR status and therapeutic benefit was investigated separately for I/O and vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) therapy.ResultsDel DDR were detected in 43/229 patients (19%). The most frequently altered genes were CHEK2 and ATM. Clonality analysis was performed in 27 somatic DDR mutations and 17 were clonal (63%). For patients with I/O treatment, Del DDR status was associated with superior overall survival (log-rank p=0.049); after adjusting for International Metastatic Renal Cell Carcinoma Database Consortium risks and extent of prior therapy, the HR for Del DDR was 0.41 (95% CI: 0.14–1.14; p=0.09). No association was seen with VEGF-TKI treatment (log-rank p=0.903).ConclusionDel DDR alterations are recurrent genomic events in patients with advanced RCC and were mostly clonal in this cohort. Loss-of-function events in these genes may affect outcome with I/O therapy in metastatic RCC, and these hypothesis-generating results deserve further study.

CHEK2 Germline Variants in Cancer Predisposition: Stalemate Rather than Checkmate

“…Among them, germline mutations in CHEK2 found in nine (3.4%) patients outnumbered the most frequent alterations in RCC-associated mutations (7× FH [2.8%]; 3× BAP1 [1.2%]). Consistently, 7/229 (3.1%) mutation carriers with germline CHEK2 variants were identified among metastatic clear cell renal cancer patients by Ged and colleagues [ 217 ]. CHEK2 germline mutations were also the most frequent alterations found in 19/844 (2.25%) patients with early onset RCC developed before the age of 60 [ 218 ].…”

The Clinical Significance of DNA Damage Repair Signatures in Clear Cell Renal Cell Carcinoma

“…The association of mutations in DNA repair genes and immune regulatory genes with bladder cancer has also been documented ( Vidotto et al, 2019 ). Moreover, it has been reported that alterations in DDR genes which cause loss of function are frequent in metastatic ccRCC, which may certainly affect the effectiveness of immunotherapy ( Ged et al, 2020 ). We therefore performed this bioinformatics analysis to explore the potential relationship between DDR and immune evasion.…”

“…As an aggressive tumor, RCC is characterized by high genomic mutation levels ( Alexandrov et al, 2013 ; Cancer Genome Atlas Research Network, 2013 ; Ged et al, 2020 ). Many studies reported the prognostic and biological significance of the cancer-driven genetic alterations including von Hippel-Lindau, TP53 as well as PTEN mutations in RCC ( Chen et al, 2019 ; Huang et al, 2020 ).…”

Clinicopathological and Genomic Analysis of a Chinese ccRCC Patient with Multiple Morphologies and Rapid Progression : A Case Report

“…BRCA2 and ATR involved in DNA damage response pathway, NFkappa B signaling gene CYLD and Hippo-YAP signaling gene YAP1, protein digestion and absorption gene COL5A3 was speci cally detected in peritoneal metastatic node but not in other primary areas, indicating that these gene mutations might play an important role in promoting tumor metastasis. Importantly, the alterations (especially deleterious gene mutations) of DDR genes exhibited potential value of predicting response to immune checkpoint inhibitors for metastatic RCC patients [25]. Given the key role of these signaling pathways in the feature of DNA repair, cell proliferation and metastasis, these mutations might contribute to this patient's rapid progression and high aggressiveness.…”