Kwakman R, de Cuba E M V, de Winter J P, de Hingh I H J T, Delis-van Diemen P M, Tijssen M, Rooimans M A, Krijgsman O, Carvalho B, Peters G J, Bonjer H J, Meijer G A, Te Velde E A
Department of Surgical Oncology, Cancer Center Amsterdam and VU University Medical Center, De Boelelaan 1117, Amsterdam 1081 HV, The Netherlands.
Department of Clinical Genetics, Cancer Center Amsterdam and VU University Medical Center, De Boelelaan 1117, Amsterdam 1081 HV, The Netherlands.
Br J Cancer. 2015 Mar 3;112(5):851-6. doi: 10.1038/bjc.2015.18. Epub 2015 Feb 10.
Patients with peritoneal metastases (PMs) originating from colorectal carcinoma (CRC) are curatively treated by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin C (MMC). We aim to improve patient selection for HIPEC by predicting MMC sensitivity.
The MMC sensitivity was determined for 12 CRC cell lines and correlated to mRNA expression of 37 genes related to the Fanconi anaemia (FA)-BRCA pathway, ATM-ATR pathway and enzymatic activation of MMC. Functionality of the FA-BRCA pathway in cell lines was assessed using a chromosomal breakage assay and western blot for key protein FANCD2. Bloom syndrome protein (BLM) was further analysed by staining for the corresponding protein with immunohistochemistry (IHC) on both CRC cell lines (n=12) and patient material (n=20).
High sensitivity correlated with a low BLM (P=0.01) and BRCA2 (P=0.02) at mRNA expression level. However, FA-BRCA pathway functionality demonstrated no correlation to MMC sensitivity. In cell lines, weak intensity staining of BLM by IHC correlated to high sensitivity (P=0.04) to MMC. Low BLM protein expression was significantly associated with an improved survival in patients after CRS and HIPEC (P=0.04).
Low BLM levels are associated with high MMC sensitivity and an improved survival after HIPEC.
源自结直肠癌（CRC）的腹膜转移（PMs）患者通过细胞减灭术（CRS）和丝裂霉素C（MMC）的腹腔内热化疗（HIPEC）进行根治性治疗。我们旨在通过预测MMC敏感性来改善HIPEC的患者选择。
测定了12种CRC细胞系的MMC敏感性，并将其与37个与范可尼贫血（FA）-BRCA途径、ATM-ATR途径及MMC酶促活化相关的基因的mRNA表达相关联。使用染色体断裂试验和针对关键蛋白FANCD2的蛋白质印迹法评估细胞系中FA-BRCA途径的功能。通过对CRC细胞系（n = 12）和患者材料（n = 20）进行免疫组织化学（IHC）染色来进一步分析布鲁姆综合征蛋白（BLM）。
在mRNA表达水平上，高敏感性与低BLM（P = 0.01）和BRCA2（P = 0.02）相关。然而，FA-BRCA途径功能与MMC敏感性无相关性。在细胞系中，IHC检测到的BLM弱强度染色与对MMC的高敏感性相关（P = 0.04）。低BLM蛋白表达与CRS和HIPEC术后患者的生存期改善显著相关（P = 0.04）。
低BLM水平与高MMC敏感性及HIPEC术后生存期改善相关。
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