Lundgren Sebastian, Fagerström-Vahman Helena, Zhang Cheng, Ben-Dror Liv, Mardinoglu Adil, Uhlen Mathias, Nodin Björn, Jirström Karin
1Department of Clinical Sciences Lund, Oncology and Pathology, Lund University, Lund, Sweden.
2Science for Life Laboratory, Department of Proteomics, School of Biotechnology, Royal Institute of Technology, Stockholm, Sweden.
Biomark Res. 2019 Jan 14;7:1. doi: 10.1186/s40364-018-0153-8. eCollection 2019.
There is a great unmet clinical need to identify patients with thin primary cutaneous melanomas (T1, Breslow thickness ≤ 1 mm) who have a high risk for tumour recurrence and death from melanoma. Kin of IRRE-like protein 1 (KIRREL/NEPH1) is expressed in podocytes and involved in glomerular filtration. Screening in the Human Protein Atlas portal revealed a particularly high expression of KIRREL in melanoma, both at the mRNA and protein levels. In this study, we followed up on these findings and examined the prognostic value of KIRREL in a population-based cohort. Immunohistochemical expression of KIRREL was examined in tissue microarrays with a subset of primary tumours and paired lymph node metastases from an original cohort of 268 incident cases of melanoma in the Malmö Diet and Cancer study. KIRREL mRNA expression was examined in 103 melanoma cases in The Cancer Genome Atlas (TCGA). Membranous/cytoplasmic expression of KIRREL was detected in 158/185 (85.4%) primary tumours and 18/19 (94.7%) metastases. High expression of KIRREL was significantly associated with several unfavourable clinicopathological factors. High KIRREL protein expression was an independent factor of reduced recurrence free and melanoma specific survival, particularly in thin melanomas, even outperforming absolute thickness and ulceration (HR = 30.85; 95% CI 1.54-616.36 and HR = 6.32 95% CI 1.19-33.65). High mRNA levels of KIRREL were not significantly associated with survival in TCGA. In conclusion, KIRREL is not only a novel potential diagnostic marker for melanoma, but may also be a useful prognostic biomarker for improved stratification of patients with thin melanoma. These findings may be of high clinical relevance and therefore merit further validation.
识别原发性皮肤薄型黑色素瘤（T1，Breslow厚度≤1mm）且有黑色素瘤肿瘤复发和死亡高风险的患者存在巨大的未满足临床需求。类IRRE样蛋白1（KIRREL/NEPH1）的亲属在足细胞中表达并参与肾小球滤过。在人类蛋白质图谱门户中的筛查显示，KIRREL在黑色素瘤中无论是mRNA水平还是蛋白质水平都有特别高的表达。在本研究中，我们追踪了这些发现，并在一个基于人群的队列中研究了KIRREL的预后价值。在马尔默饮食与癌症研究中，对来自268例黑色素瘤初发病例原始队列的原发性肿瘤和配对淋巴结转移的子集进行组织微阵列检查，以检测KIRREL的免疫组化表达。在癌症基因组图谱（TCGA）中的103例黑色素瘤病例中检测KIRREL mRNA表达。在158/185（85.4%）的原发性肿瘤和18/19（94.7%）的转移灶中检测到KIRREL的膜性/细胞质表达。KIRREL的高表达与几个不利的临床病理因素显著相关。KIRREL蛋白高表达是无复发生存期和黑色素瘤特异性生存期缩短的独立因素，尤其是在薄型黑色素瘤中，甚至超过绝对厚度和溃疡（HR = 30.85；95% CI 1.54 - 616.36和HR = 6.32，95% CI 1.19 - 33.65）。在TCGA中，KIRREL的高mRNA水平与生存期无显著相关性。总之，KIRREL不仅是黑色素瘤一种新的潜在诊断标志物，而且可能是用于改善薄型黑色素瘤患者分层的有用预后生物标志物。这些发现可能具有高度临床相关性，因此值得进一步验证。
