Consistent Rearrangement of Chromosomal Band 6p21 with Generation of Fusion GenesJAZF1/PHF1andEPC1/PHF1in Endometrial Stromal Sarcoma

Abstract

Endometrial stromal sarcomas (ESS) represent <10% of all uterine sarcomas. Cytogenetic data on this tumor type are limited to 32 cases, and the karyotypes are often complex, but the pattern of rearrangement is nevertheless clearly nonrandom with particularly frequent involvement of chromosome arms 6p and 7p. Recently, a specific translocation t(7;17)(p15;q21) leading to the fusion of two zinc finger genes, juxtaposed with another zinc finger (JAZF1) and joined to JAZF1 (JJAZ1), was described in a subset of ESS. We present three ESS whose karyotypes were without the disease-specific t(7;17) but instead showed rearrangement of chromosomal band 6p21, twice as an unbalanced t(6p;7p) and once as a three-way 6;10;10 translocation. All three tumors showed specific rearrangement of the PHD finger protein 1 (PHF1) gene, located in chromosomal band 6p21. In the two tumors with t(6;7), PHF1 was recombined with the JAZF1 gene from 7p15, leading to the formation of a JAZF1/PHF1 fusion gene. The third tumor showed a t(6p;10q;10p) as the sole karyotypic abnormality, leading to the fusion of PHF1 with another partner, the enhancer of polycomb (EPC1) gene from 10p11; EPC1 has hitherto not been associated with neoplasia. The PHF1 gene encodes a protein with two zinc finger motifs whose involvement in tumorigenesis and/or tumor progression has not been reported before, but its rearrangement clearly defines a new pathogenetic subgroup

Polycomb Group Protein PHF1 Regulates p53-dependent Cell Growth Arrest and Apoptosis

“…EPC1 (enhancer of Polycomb) gene from 10p11 in the third tumor, which had a t(6p;10q;10p) translocation as the sole karyotypic abnormality (18). JAZF1/PHF1 fusion gene was also presented in a low-grade endometrial stromal sarcoma cell line JHU-ESS1 (19).…”

The MYST family of histone acetyltransferases and their intimate links to cancer

“…The presence of HBO1 in complexes with the tumour suppressors ING4 and -5 (Doyon et al, 2006) further implies that it may play a role in protection from malignancy. ING4 has been shown to suppress loss of contact inhibition in cultured cells and is inactivated in (Micci et al, 2006), and model of the potential consequences on chromatin function. Domains are labelled as in Figure 1a; EPc A: EPc A domain; Tudor: Tudor domain.…”

“…An intriguing potential link between the NuA4 subunit EPC1 and malignancy came from a recent observation that its coding region can be fused to that of PHF1 (plant homeodomain finger protein 1) through a chromosomal rearrangement found in a subset of uterine sarcomas (Figure 3a) (Micci et al, 2006). The resulting chimaeric protein has an open reading frame consisting of the first 581 residues from EPC1 and the entire coding region of PHF1.…”

Practical issues related to uterine pathology: endometrial stromal tumors

“…32 The second most frequent abnormality is t(6;7)(p21;p15), a so-called variant translocation of the t(7;17), because of the involvement of 7p15 and 6p21 instead of 17q21 resulting in a JAZF1-PHF1 fusion gene. 31,33 The PHF1 gene at 6p21 can also fuse with EPC1 at 10p11 and MEAF6 at 1p34. Of note, there appears to be a correlation in ESS showing sex cord-like differentiation having PHF1 genetic rearrangement.…”