Clinical Significance of Potential Unidentified HLA-G Isoforms Without α1 Domain but Containing Intron 4 in Colorectal Cancer Patients

The ectopic HLA-G expression in malignancies has been extensively explored and clinical significance of the molecule was widely acknowledged. Besides previously well-documented seven isoforms (HLA-G1 similar to-G7), other novel isoforms of HLA-G have been reported but their clinical relavenace remians evaluated. In this study, lesion HLA-G expression in 379 case-matched serial section primary colorectal cancers (CRC) were evaluated with mAb 4H84 (recognizing an epitope in HLA-G alpha 1 domain), and mAb 5A6G7 (recognizing an epitope encoded by intron 4), respectively. Data showed that HLA-G positive staining with mAbs 4H84 and 5A6G7 was 70.7 and 60.4%, respectively. When percentage of HLA-G expression detected with mAb 4H84 subtracted that with mAb 5A6G7, the difference ((Delta)HLA-G) with negative ((Delta)HLA-G(neg)), comparable ((Delta)HLA-G(com)) and positive ((Delta)HLA-G(pos)) were observed in 64 (16.9%), 159 (42.0%), and 156 (41.2%) cases, respectively. Noteworthy, unexpected immunostaining was observed in 44 (11.6%) lesions that no staining was detected with mAb 4H84 but positive with mAb 5A6G7 (4H84(neg)5A6G7(pos)). This staining pattern was unpredictable because all seven known HLA-G isoforms containing the alpha 1 domain could be recognized by the mAb 4H84. Moreover, patients with (Delta)HLA-G(neg) had obviously better survival than those with (Delta)HLA-G(com) and (Delta)HLA-G(pos) (p = 0.017), and (Delta)HLA-G could be an independent prognostic factor for CRC patients (p = 0.008). Our findings provides the first report that potential unidentified HLA-G isoforms is of distinct clinical significance in CRC patients.