Immunofluorescence analysis of DNA damage response protein p53-binding protein 1 in a case of uterine dedifferentiated leiomyosarcoma arising from leiomyoma

AimsGenomic instability has been indicated during the dedifferentiation process from leiomyoma (LM) to leiomyosarcoma (LMS). Previously, we have described that nuclear expression pattern of DNA damage response protein p53-binding protein 1 (53BP1), detected by immunofluorescence, reflects the magnitude of genomic instability during malignancy. Here, we present a case of LMS arising from LM with molecular analysis of 53BP1, which showed transitional magnitude of DNA damage response within a tumor.Methods and resultsA fifty-year-old female with abdominal mass underwent hysterectomy. Histologically, the tumor consisted of LMS with highly atypical multinucleated giant cells as well as an LM component with transitional atypical spindle cells in the border area. LMS showed diffuse nuclear staining of 53BP1 expression, which has been previously described as high DNA damage response pattern. In contrast, the LM component lacked 53BP1 immunoreactivity and focal expression was observed in transitional lesion. Furthermore, double-labelled immunofluorescence revealed co-localization of 53BP1 with p53 and Ki-67 in the LMS component, which indicated abnormal DNA damage response in proliferative state.ConclusionsThis study revealed that diffuse-type 53BP1 expression may be beneficial to estimate genomic instability during dedifferentiation from LM to DLMS.     

Significance of p53-binding protein 1 nuclear foci in uterine cervical lesions: endogenous DNA double strand breaks and genomic instability during carcinogenesis

Matsuda K, Miura S, Kurashige T, Suzuki K, Kondo H, Ihara M, Nakajima H, Masuzaki H & Nakashima M
(2011) Histopathology 59 , 441–451 Significance of p53‐binding protein 1 nuclear foci in uterine cervical lesions: endogenous DNA double strand breaks and genomic instability during carcinogenesis Aims: A defective DNA damage response can result in genomic instability (GIN) and lead to transformation to cancer. As p53‐binding protein 1 (53BP1) localizes at the sites of DNA double strand breaks (DSBs) and rapidly forms nuclear foci (NF), the presence of 53BP1 NF can be considered to be an indicator of endogenous DSBs reflecting GIN. Our aim was to analyse the presence of DSBs by immunofluorescence for 53BP1 expression in a series of cervical lesions, to evaluate the significance of GIN during carcinogenesis. Methods and results: A total of 80 archival cervical tissue samples, including 11 normal, 16 cervical intraepithelial neoplasia (CIN)1, 15 CIN2, 24 CIN3 and 14 squamous cell carcinoma samples, were analysed for 53BP1 NF, human papillomavirus (HPV) infection, and p16^INK4a overexpression. The number of 53BP1 NF in cervical cells appeared to increase with progression during carcinogenesis. The distribution of 53BP1 NF was similar to that of the punctate HPV signals as determined by in‐situ hybridization and also to p16^INK4a overexpression in CIN, suggesting an association with viral infection and replication stress. Conclusions: Immunofluorescence analysis of 53BP1 expression can be a useful tool with which to estimate the level of GIN. During cervical carcinogenesis, GIN may allow further accumulation of genomic alterations, causing progression to invasive cancer.     

细胞周期素D1和抗原Ki-67在宫颈上皮内瘤样病变和宫颈鳞癌的表达及与人乳头瘤病毒感染转归的关系

目的 研究细胞周期素D1(cyclin D1)、抗原Ki-67在宫颈上皮内瘤样病变(CIN)和宫颈鳞癌发生发展中作用及其与人乳头瘤病毒(HPV)感染转归的关系.方法 2002年1月至2006年12月广州医学院第一附属医院HPV阳性患者104例,分2组:(1)研究组:82例,即病理确诊CIN Ⅰ组17例、CINⅡ组19例、CINⅢ组23例、宫颈鳞癌组23例.(2)对照组:柱状上皮异位22例.应用EnVision法检测宫颈病变组织中cyclin D1、Ki-67蛋白的表达,杂交捕获试验检测宫颈分泌物或阴道残端中HPV感染情况,随访各组患者术后1年内的HPV变化.结果 (1)cyclin D1在各组宫颈组织细胞核内均有表达.其阳性率CINⅢ组[82.61%(19/23)]、宫颈鳞癌组[86.96%(20/23)]与对照组[27.27%(6/22)]、CINⅠ组[58.82%(10/17)]比较,差异有统计学意义(P<0.05),在宫颈鳞癌组与CINⅡ组[68.42%(13/19)]阳性率比较差异有统计学意义(P<0.05).(2)Ki-67在各组宫颈组织细胞核内均有表达,其对照组阳性率[31.82%(7/22)]与CINⅢ组[86.96%(20/23)]、宫颈鳞癌组[91.30%(21/23)]比较差异有统计学意义(P<0.05),而在宫颈鳞癌组与CINⅠ组[58.82%(10/17)]、CIN Ⅱ组[63.16%(12/19)]比较差异有统计学意义(P<0.05).(3)术后1年内各组HPV的转阴率分别与cyclin D1、Ki-67的表达强度呈负相关(rs=-0.299,rs=-0.367,P<0.05).结论 cyclinD1和Ki-67在CIN和宫颈鳞癌的细胞增殖活动中起作用,且两者可能与HPV感染转阴率有关.