2024 年 32 巻 1 号 p. 17-30
Introduction: Individuals with cancer face an elevated risk of subsequent tumors following their initial malignancy. However, the etiology of this secondary occurrence remains unclear.
Patients and Methods: A cohort of 2,707 participants underwent human leukocyte antigen (HLA) testing. We analyzed the incidence and survival outcomes of multiple primary malignancies (MPMs), subsequent metachronous MPMs (sM-MPMs), and gastric malignancy (GM) in the remnant stomach (GMRS) as post-therapeutic GMs. We identified human endogenous retroviruses (HERV) gene-derived peptides (HHPs) from four previous studies, predicted candidate amino acid sequences of human immunodeficiency virus and HHPs, and matched them to candidate genes through a peptide search in UniProt.
Results: Among the participants, 311 (11.5%) were diagnosed with an MPM and 161 (6.3%) with an sM-MPM, and both groups exhibited unfavorable survival outcomes, whereas 289 (13.1%) with GMRS showed favorable survival. Patients with HLA-A31, with or without an MPM/sM-MPM, demonstrated either favorable or unfavorable survival, respectively, compared with those without this antigen. Furthermore, patients harboring HLA-A31-restricted HHP “NEQIVIGR,” which matched to human endogenous retrovirus-H long terminal repeat (LTR)-associating 2 (HHLA2), exhibited good survival but increased risks of both an MPM and sM-MPM. Conversely, HLA-A31/-B39/-B46-restricted HHPs “ILVPSAILA” and “EAMNTTSLL,” matching to HHLA2 and HHLA1, respectively, were associated with unfavorable survival and decreased risks of both an MPM and sM-MPM.
Conclusion: Our findings elucidate a novel pathogenesis of MPM, sM-MPM, and GMRS. Understanding the mechanisms underlying the correlation between HLA/HERV-encoded peptide interactions and the pathogenesis of these malignancies will yield new candidates for cancer therapies from a unique perspective.
