Aberrant MAD2 expression in soft‐tissue sarcoma

Abstract

Soft-tissue sarcomas can be divided into translocationassociated (TA) and non-TA sarcomas, the latter of which is often characterized by pleomorphic cytomorphology and aneuploidy. The aberrant expression of MAD2, an essential component of the mitotic spindle checkpoint, has been recently shown to promote aneuploidy. The aim of the present paper was to assess MAD2 status on immunohistochemistry in 50 TA sarcomas with known fusion genes and 50 non-TA pleomorphic sarcomas. MAD2 was overexpressed in 26 TA (52%) and 33 non-TA sarcomas (66%). Notably, the MAD2 overexpression was frequently detected in TA sarcomas with atypical or high-grade morphology, such as round cell liposarcoma and fibrosarcomatous dermatofibrosarcoma protuberans. The MAD2 overexpression was significantly frequent in non-TA sarcomas compared with TA tumors without such atypical or high grade morphology (P = 0.012). In addition, sarcomas with MAD2 overexpression were significantly rich in abnormal mitotic figures, including multipolar mitoses and anaphase bridges, compared to MAD2-negative tumors (P = 0.003), although the overall mitotic activity was equivalent between the sarcomas with or without the MAD2 overexpression. These data suggest that the aberrant MAD2 expression is potentially associated with pleomorphic morphology and abnormal mitosis in soft-tissue sarcomas, as well as with high-grade tumor progression in its TA subset.Key words: immunohistochemistry, MAD2, soft-tissue sarcoma, spindle checkpoint A substantial subgroup of soft-tissue sarcomas are characterized by almost uniform or monotonous cytomorphology and simple karyotypic abnormalities harboring tumor-type specific chromosomal translocations.1 In contrast, sarcomas other than the translocation-associated (TA) tumors are often pleomorphic tumors with complex karyotypic aberrations and chromosomal instability or aneuploidy. But the mechanisms underlying such a phenotypic and molecular genetic correlation in soft-tissue sarcomas still remain to be elucidated.Montgomery et al. recently demonstrated that distinct chromosomal missegregation (e.g. anaphase bridge) and long or heterogeneous telomere lengths are particularly identified in non-TA pleomorphic sarcomas. 2,3 This suggested the significance of such morphological and genetic characteristics in the aforementioned dichotomous grouping of sarcomas.2,3 Although the detailed molecular consequences of the abnormal chromosomal segregation and telomere lengths in sarcomas remain to be clarified, these abnormalities are assumed to give rise to chromosomal instability or aneuploidy.Accurate chromosomal segregation is an essential event in mitosis, and it is strictly monitored by a control mechanism known as the mitotic spindle checkpoint, which ensures that the chromosomes are properly aligned and attached to microtubules with their kinetochores at metaphase. Errors in this mechanism result in chromosomal missegregation and subsequent mitotic catastrophes, which can thus lead to chromosomal instability and the formation of tetraploid o...

Upregulation of Mad2 facilitates in vivo and in vitro osteosarcoma progression

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Depression of MAD2 inhibits apoptosis and increases proliferation and multidrug resistance in gastric cancer cells by regulating the activation of phosphorylated survivin

“…The downregulation of MAD2 is responsible for mitotic checkpoint abrogation and chromosomal instability in human cancers [11][12][13][14][15]. Wang et al [34] reported that MAD2-induced sensitisation to VCR is associated with Raf/Bcl-2 phosphorylation and mitotic arrest in nasopharyngeal carcinoma.…”

“…missegregation and mitotic catastrophes [2][3][4][5]. The mutation of the Mad2 gene is very rare in many kinds of human cancer [6][7][8][9], but deletion or downregulation of MAD2 has also been reported in several human cancers such as lung cancer [10], breast cancer [11], nasopharyngeal cancer [12], soft-tissue sarcoma [13,14], and ovarian carcinoma [15].…”

Clinicopathologic significance of mitotic arrest defective protein 2 overexpression in hepatocellular carcinoma

“…Immunostaining was scored as the ratio of the number of strongly stained nuclei to the total number of cells as described in our previous article [17]. Less than 10% staining of tumor nuclei was designated as representing a low level of MAD2 expression, and more than 10% staining was considered a high level of MAD2 expression [18]. The Ki-67 labeling index was calculated as a percentage of immunopositive cells.…”