Friedenson Bernard
Department of Biochemistry and Medical Genetics, Cancer Center, University of Illinois Chicago, 900 s Ashland, Chicago, IL, 60617, United States, 1 8479124216.
JMIRx Med. 2025 Jan 29;6:e50712. doi: 10.2196/50712.
The causes of breast cancer are poorly understood. A potential risk factor is Epstein-Barr virus (EBV), a lifelong infection nearly everyone acquires. EBV-transformed human mammary cells accelerate breast cancer when transplanted into immunosuppressed mice, but the virus can disappear as malignant cells reproduce. If this model applies to human breast cancers, then they should have genome damage characteristic of EBV infection.
This study tests the hypothesis that EBV infection predisposes one to breast cancer by causing permanent genome damage that compromises cancer safeguards.
Publicly available genome data from approximately 2100 breast cancers and 25 ovarian cancers were compared to cancers with proven associations to EBV, including 70 nasopharyngeal cancers, 90 Burkitt lymphomas, 88 diffuse large B-cell lymphomas, and 34 gastric cancers. Calculation algorithms to make these comparisons were developed.
Chromosome breakpoints in breast and ovarian cancer clustered around breakpoints in EBV-associated cancers. Breakpoint distributions in breast and EBV-associated cancers on some chromosomes were not confidently distinguished (P>.05), but differed from controls unrelated to EBV infection. Viral breakpoint clusters occurred in high-risk, sporadic, and other breast cancer subgroups. Breakpoint clusters disrupted gene functions essential for cancer protection, which remain compromised even if EBV infection disappears. As CRISPR (clustered regularly interspaced short palindromic repeats)-like reminders of past infection during evolution, EBV genome fragments were found regularly interspaced between Piwi-interacting RNA (piRNA) genes on chromosome 6. Both breast and EBV-associated cancers had inactivated genes that guard piRNA defenses and the major histocompatibility complex (MHC) locus. Breast and EBV-associated cancer breakpoints and other variations converged around the highly polymorphic MHC. Not everyone develops cancer because MHC differences produce differing responses to EBV infection. Chromosome shattering and mutation hot spots in breast cancers preferentially occurred at incorporated viral sequences. On chromosome 17, breast cancer breakpoints that clustered around those in EBV-mediated cancers were linked to estrogen effects. Other breast cancer breaks affected sites where EBV inhibits JAK-STAT and SWI-SNF signaling pathways. A characteristic EBV-cancer gene deletion that shifts metabolism to favor tumors was also found in breast cancers. These changes push breast cancer into metastasis and then favor survival of metastatic cells.
EBV infection predisposes one to breast cancer and metastasis, even if the virus disappears. Identifying this pathogenic viral damage may improve screening, treatment, and prevention. Immunizing children against EBV may protect against breast, ovarian, other cancers, and potentially even chronic unexplained diseases.
乳腺癌的病因尚不清楚。一种潜在的风险因素是爱泼斯坦-巴尔病毒（EBV），几乎每个人都会终身感染这种病毒。将EBV转化的人乳腺细胞移植到免疫抑制小鼠体内时会加速乳腺癌的发展，但随着恶性细胞的繁殖，病毒可能会消失。如果这种模式适用于人类乳腺癌，那么它们应该具有EBV感染特有的基因组损伤。
本研究检验了EBV感染通过导致永久性基因组损伤从而损害癌症防护机制而使人易患乳腺癌这一假说。
将约2100例乳腺癌和25例卵巢癌的公开可用基因组数据与已证实与EBV相关的癌症进行比较，包括70例鼻咽癌、90例伯基特淋巴瘤、88例弥漫性大B细胞淋巴瘤和34例胃癌。开发了用于进行这些比较的计算算法。
乳腺癌和卵巢癌中的染色体断点聚集在EBV相关癌症的断点周围。某些染色体上乳腺癌和EBV相关癌症的断点分布无法可靠区分（P>0.05），但与未感染EBV的对照不同。病毒断点簇出现在高危、散发性和其他乳腺癌亚组中。断点簇破坏了对癌症防护至关重要的基因功能，即使EBV感染消失，这些功能仍受到损害。作为进化过程中过去感染的CRISPR（成簇规律间隔短回文重复序列）样印记，在6号染色体上的Piwi相互作用RNA（piRNA）基因之间经常发现EBV基因组片段间隔排列。乳腺癌和EBV相关癌症都有使piRNA防御和主要组织相容性复合体（MHC）位点的保护基因失活的情况。乳腺癌和EBV相关癌症的断点及其他变异在高度多态的MHC周围汇聚。并非每个人都会患癌症，因为MHC差异会导致对EBV感染产生不同反应。乳腺癌中的染色体破碎和突变热点优先出现在整合的病毒序列处。在17号染色体上，聚集在EBV介导癌症断点周围的乳腺癌断点与雌激素效应有关。其他乳腺癌断点影响EBV抑制JAK-STAT和SWI-SNF信号通路的位点。在乳腺癌中还发现了一种特征性的EBV-癌症基因缺失，这种缺失会使代谢向有利于肿瘤的方向转变。这些变化促使乳腺癌发生转移，然后有利于转移细胞的存活。
EBV感染使人易患乳腺癌和转移，即使病毒消失。识别这种致病性病毒损伤可能会改善筛查、治疗和预防。给儿童接种EBV疫苗可能预防乳腺癌、卵巢癌和其他癌症，甚至可能预防慢性不明原因疾病。
