Differential patterns of molecular alterations among sites of metastasis in RCC

Molecular features differ between primary and distant metastases in patients with renal cell carcinoma (RCC), according to a real-world analysis of 657 RCC samples.

RCC has a distinct pattern of metastatic spread with common sites of metastasis including the lung, bone, and liver [1]. Less common sites include the brain, adrenal gland, and pancreas. The site of metastasis is prognostic in RCC [2]. To get more insight into the biology driving tropism to specific organ sites, molecular features were characterised from RCC metastases across various metastatic sites. Dr Rana McKay (University of California San Diego, CA, USA) presented the results [3].

A total of 657 RCC samples derived from the kidney and distant metastatic sites from 653 patients underwent molecular profiling. The most common histology was clear-cell RCC (77.3%), followed by papillary (9.6%), chromophobe (4.6%), medullary (1.2%), collecting duct (0.9%), and mixed (6.2%). Specimen source included the kidney (51.8%), lung (10%), bone (7.6%), lymph nodes (5.6%), liver (4.3%), endocrine glands (3.5%), brain/CNS (2.1%), and other metastatic sites (15.1%).

Compared with kidney samples, several genes were mutated at higher rates for select metastatic sites, including PBRM1 (59.5% bone, 59.1% endocrine, and 45.9% lung vs 33.8% kidney; P<0.05) and KDM5C (27.8% endocrine, 29.2% lymph nodes, and 35.3% soft tissue vs 9.3% kidney; P<0.05). Additionally, SETD2 alterations were more prevalent in lung and gastrointestinal metastases, TP53 mutations were more prevalent in bone and CNS metastases, and PTEN mutations were more prevalent in liver and CNS metastases (see Figure). In addition, molecular subgroups – according to Motzer [4] – in bone metastases had a significantly higher proportion of tumours classified as ‘angio/stromal’, while liver metastases had a higher proportion of the ‘complement/Ω-oxidation’ subgroup. PD-L1 expression in metastatic sites was not significantly different from the kidney.

Figure: Gene mutations associated with metastasis site [3]



“In our contemporary real-world analysis, we demonstrated differential patterns of molecular alterations among sites of metastasis in RCC. Our observations elucidate the biology underlying heterogeneous disease outcomes associated with sites of metastasis. Application of predictive signatures by site of metastasis may help to inform personalised therapy strategies in advanced RCC,” concluded Dr McKay.

1. Dudani S, et al. JAMA Netw Open. 2021;4:e2021869.
2. Shaya JA, et al. Clin Genitourin Cancer. 2021;19:e367–e373.
3. McKay RR, et al. Molecular alterations across sites of metastasis in patients with renal cell carcinoma (RCC). Abstract 287, ASCO GU 2022, 17–19 February.
4. Motzer RJ, et al. Cancer Cell 2020;38:803–817.

 

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Posted on 8 April 2022