Germline Susceptibility to Renal Cell Carcinoma and Implications for Genetic Screening.

IF 5.3 2区医学 Q1 ONCOLOGY JCO precision oncology Pub Date : 2024-07-01 DOI:10.1200/PO.24.00094

Kate I Glennon, Mikiko Endo, Yoshiaki Usui, Yusuke Iwasaki, Rodney H Breau, Anil Kapoor, Mark Lathrop, Simon Tanguay, Yukihide Momozawa, Yasser Riazalhosseini

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Abstract

Purpose: Genetic susceptibility to nonsyndromic renal cell carcinoma (RCC) remains poorly understood, especially for different histological subtypes, as does variations in genetic predisposition in different populations. The objectives of this study were to identify risk genes for RCC in the Canadian population, investigate their clinical significance, and evaluate variations in germline pathogenic variants (PVs) among patients with RCC across the globe.

Materials and methods: We conducted targeted sequencing of 19 RCC-related and 27 cancer predisposition genes for 960 patients with RCC from Canada and identified genes enriched in rare germline PVs in RCC compared with cancer-free controls. We combined our results with those reported for patients from Japan, the United Kingdom, and the United States to investigate PV variations in different populations. Furthermore, we evaluated the performance of referral criteria for genetic screening for including patients with rare PVs.

Results: We identified 39 germline PVs in 56 patients (5.8%) from the Canadian cohort. Compared with cancer-free controls, PVs in CHEK2 (odds ratio [OR], 4.8 [95% CI, 2.7 to 7.9], P = 3.94 × 10^-5) and ATM (OR, 4.5 [95% CI, 2.0 to 8.7], P = .016) were significantly enriched in patients with clear cell, whereas PVs in FH (OR, 215.1 [95% CI, 64.4 to 597.8], P = 6.14 × 10^-9) were enriched in patients with non-clear cell RCCs. PVs in BRCA1, BRCA2, and ATM were associated with metastasis (P = .003). Comparative analyses showed an enrichment of TP53 PVs in patients from Japan, of CHEK2 and ATM in patients from Canada, the United States and the United Kingdom, and of FH and BAP1 in the United States.

Conclusion: CHEK2, ATM, and FH are risk genes for RCC in the Canadian population, whereas PVs in BRCA1/2 and ATM are associated with risk of metastasis. Globally, clinical guidelines for genetic screening in RCC fail to include more than 70% of patients with rare germline PVs.

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肾细胞癌的种系易感性及其对基因筛查的影响。

目的：人们对非综合征肾细胞癌（RCC）的遗传易感性仍然知之甚少，特别是对不同组织学亚型的易感性，以及不同人群遗传易感性的差异也是如此。本研究的目的是确定加拿大人群中的 RCC 风险基因，研究其临床意义，并评估全球 RCC 患者的种系致病变体 (PV) 变化：我们对来自加拿大的960名RCC患者的19个RCC相关基因和27个癌症易感基因进行了靶向测序，发现了与无癌症对照组相比，RCC患者中罕见种系PVs丰富的基因。我们将我们的研究结果与日本、英国和美国患者的研究结果相结合，研究了不同人群的 PV 变异。此外，我们还评估了基因筛查转介标准在纳入罕见 PV 患者方面的性能：我们在加拿大队列的 56 名患者（5.8%）中发现了 39 个种系 PV。与无癌症对照组相比，CHEK2（几率比 [OR]，4.8 [95% CI，2.7 至 7.9]，P = 3.94 × 10-5）和 ATM（OR，4.5 [95% CI，2.0 至 8.7]，P = .016）明显富集于透明细胞患者，而 FH（OR，215.1 [95% CI，64.4 至 597.8]，P = 6.14 × 10-9）中的 PVs 则富集于非透明细胞 RCC 患者。BRCA1、BRCA2和ATM的PV与转移相关（P = .003）。比较分析表明，日本患者的TP53 PVs富集，加拿大、美国和英国患者的CHEK2和ATM PVs富集，美国患者的FH和BAP1 PVs富集：结论：在加拿大人群中，CHEK2、ATM 和 FH 是 RCC 的风险基因，而 BRCA1/2 和 ATM 的 PV 与转移风险有关。在全球范围内，RCC 基因筛查的临床指南未能将 70% 以上的罕见种系 PV 患者包括在内。

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