Alternative titles; symbols
Other entities represented in this entry:
ORPHA: 160, 33276;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7p15.3 | {Kaposi sarcoma, susceptibility to} | 148000 | Autosomal dominant | 3 | IL6 | 147620 |
A number sign (#) is used with this entry because of identification of at least 1 polymorphism that renders HIV-infected men susceptible to Kaposi sarcoma; see 147620.0001.
See 614836 for information on a locus on chromosome 3p22 that is associated with susceptibility to infection by human herpesvirus-8, the etiologic agent of Kaposi sarcoma.
Kaposi sarcoma (KS) is an invasive angioproliferative inflammatory condition that occurs commonly in men infected with human immunodeficiency virus (HIV; see 609423). In the early stages of KS, lesions appear reactive and are stimulated to grow by the actions of inflammatory cytokines and growth factors. In the late stages of KS, a malignant phenotype that appears to be monoclonal can develop. Infection with human herpesvirus-8 (HHV-8), also known as KS-associated herpesvirus (KSHV), is necessary but not sufficient for KS development. Coinfection with HIV markedly increases the likelihood of KS development, and additional environmental, hormonal, and genetic cofactors likely contribute to its pathogenesis (summary by Foster et al., 2000).
Suthaus et al. (2012) noted that HHV-8 is the etiologic agent not only of KS, but also of primary effusion lymphoma and plasma cell-type multicentric Castleman disease (MCD).
KS usually presents as red-purple nodules, plaques, and macules. Initial lesions are usually on the limbs and are often associated with edema due to tumor infiltration of superficial lymphatics. Zeligman (1960) observed the disorder in father and son. Although a characteristic ethnic occurrence (Italian and Jewish) has been noted, this was perhaps only the second instance of familial incidence.
Finlay and Marks (1979) reported 70-year-old mother and 44-year-old son. They reviewed other familial occurrence and commented on the possibility that close and prolonged contact in families may be a factor. They also suggested that an insect vector may be involved in the geographic concentration.
DiGiovanna and Safai (1981) reviewed 90 cases seen at Memorial Sloan-Kettering Cancer Center between 1954 and 1975 and found only 1 instance of documented familial occurrence. Their review of the literature revealed only 7 examples of 2 or more affected family members. Of 77 cases in which the information was available, 54 were immigrants from high-incidence areas. Of 87 cases with the relevant information, 52 were Jewish and 17 Italian.
Durack (1981) pointed to Kaposi sarcoma as an 'opportunistic tumor' because it develops in homosexual men who also get opportunistic infections such as Pneumocystis carinii and show evidence of an acquired cellular immunodeficiency (Gottlieb et al., 1981).
Masur et al. (1981) found among 11 cases of Pneumocystis pneumonia in men who were homosexual and/or drug abusers, 1 case of Kaposi sarcoma and 1 of angioimmunoblastic lymphadenopathy.
Kaposi sarcoma is the most common neoplasm affecting patients with AIDS, and HIV infection is an important risk factor in its development: the KS risk of AIDS patients is 20,000-fold over that of the general population. Kedes et al. (1996) noted that strong epidemiologic data indicate that HIV is not the sole determinant of KS risk. The tumor also occurs in selected HIV-negative groups, including immunosuppressed transplant recipients and some African and Mediterranean populations. Even among HIV-infected individuals, the risk for KS varies widely with high rates observed in HIV-positive homosexual men and very low rates among HIV-infected hemophiliacs and children. These and other data suggested that a second, sexually transmitted cofactor may be involved in KS etiology or pathogenesis, an inference that was further sustained by the occasional instance of KS in HIV-negative homosexual men.
Chang et al. (1994) had identified genomic sequences of a novel herpesvirus, termed KSHV or HHV-8, in Kaposi sarcoma tissues by PCR-based methods. These sequences were found in virtually all AIDS-KS specimens and in a majority of HIV-negative KS cases as well. In addition, HHV-8 sequences were found both in Castleman disease, a rare lymphoproliferative disorder often associated with KS, and in HIV-positive cases of a rare form of diffuse body cavity-based lymphomas.
Using an immunofluorescence assay, Kedes et al. (1996) examined serum samples from 913 patients for the presence of antibodies specific for infection by HHV-8. The distribution of HHV-8 seropositivity conformed to that expected for a sexually transmitted pathogen and tracked closely with the risk for KS development.
Using a sensitive indirect immunofluorescence assay, Gao et al. (1996) found KSHV-related antibodies in 71 to 88% of serum samples from U.S., Italian, and Ugandan AIDS patients with Kaposi sarcoma, as well as in all serum samples examined from HIV-seronegative Kaposi sarcoma patients. Although none of the U.S. blood donors examined were KSHV seropositive, intermediate and high seroprevalence rates were found in Italian and Ugandan control populations.
Cool et al. (2003) suggested an association between KSHV expression and primary pulmonary hypertension (178600).
Multicentric Castleman Disease
Suthaus et al. (2012) noted that HHV-8 is the etiologic agent not only of KS, but also of primary effusion lymphoma and plasma cell-type MCD. MCD is a rare condition characterized by abnormal populations of polyclonal plasmablasts in multiple lymph nodes with a propensity toward development of lymphoma.
Cesarman (2003) pointed out that KSHV is present in approximately half the cases of multicentric Castleman disease in immunocompetent patients and almost all of those infected with HIV. Castleman disease has been linked to an excess production of interleukin-6 (IL6; 147620). KSHV encodes its own viral homolog of this cytokine, as well as both latent and lytic genes, which can potently induce the cellular expression of interleukin-6.
To determine whether Kaposi sarcoma is a monoclonal disorder, Rabkin et al. (1997) assessed the methylation pattern of the androgen-receptor gene (AR; 313700) in multiple lesions from women with AIDS. In polyclonal tissues, about half the copies of each AR allele were methylated, whereas in cells derived from a single clone all copies of only 1 allele were methylated. To minimize contamination by normal DNA, Rabkin et al. (1997) used microdissection to isolate areas composed primarily of spindle cells, the putative tumor cells of Kaposi sarcoma. In 8 patients with a total of 32 tumors, they found that 28 tumors had highly unbalanced methylation patterns, i.e., predominant methylation of 1 AR allele. In all the tumors that had unbalanced methylation from a given patient, the same allele predominated. These data indicated that Kaposi sarcoma is a disseminated monoclonal cancer and that the changes that permit the clonal outgrowth of spindle cells occur before the disease spreads.
Chow et al. (2001) noted that KSHV encodes a functional homolog of IL6 (termed vIL6; 25% sequence homology) that is expressed in KSHV-infected cells and is able to induce angiogenesis and hematopoiesis in IL6-dependent cell lines. In contrast to IL6, which binds to gp130 (IL6ST; 600694) only after it forms a complex with IL6RA (IL6R; 147880), vIL6 directly activates gp130.
Hong et al. (2004) showed that infection of differentiated blood vascular endothelial cells (BECs) with KSHV led to their lymphatic reprogramming. Induction of approximately 70% of the main lymphatic lineage-specific genes, including PROX1 (601546), a master regulator of lymphatic development, was observed, as well as downregulation of blood vascular genes. Wang et al. (2004) found that in vitro infection of both lymphatic endothelial cells (LECs) and BECs with KSHV induced transcriptional reprogramming. The lymphangiogenic molecules VEGFD (300091) and angiopoietin-2 (ANGPT2; 601922) were found to be elevated in the plasma of individuals with AIDS and Kaposi sarcoma.
Using clarified saliva and biotinylated HHV-8, Grange et al. (2005) detected binding to the 78-kD lactoferrin (LF, or LTF; 150210) protein. Binding did not require glycosylation. Approximately 8% of HHV-8-uninfected individuals tested expressed a form of LF that was not recognized by HHV-8. Endoprotease cleavage of native LF generated a nonglycosylated 8-kD peptide corresponding to amino acids 606 to 679 in the C-terminal region of LF that bound HHV-8. Grange et al. (2005) concluded that LF in saliva is a ligand for HHV-8 and possibly a carrier of viral particles.
Grange et al. (2012) showed that LF or the 8-kD LF C-terminal peptide enhanced KSHV infection of a human epithelial cell line and primary human foreskin fibroblasts.
Suthaus et al. (2012) found that mice constitutively expressing vIL6 had Il6 levels comparable to those observed in HHV-8-infected patients and contained elevated amounts of phosphorylated Stat3 (102582) in spleen and lymph nodes, where vIL6 was produced. These mice also developed key features of MCD, such as splenomegaly, multifocal lymphadenopathy, hypergammaglobulinemia, and plasmacytosis. Upon transfer of the vIL6 gene to Il6-deficient mice, the MCD-like phenotype was not observed, suggesting that endogenous IL6 in the mouse is a critical cofactor in the disease. Suthaus et al. (2012) proposed that human IL6 plays an important role in the pathogenesis of HHV-8-associated MCD.
In studies in Iceland and the Faroe Islands, Hjalgrim et al. (1998) found an unusually high incidence of non-AIDS-related Kaposi sarcoma. The basis for this high frequency was not evident.
Guttman-Yassky et al. (2003) investigated trends in the incidence of classic Kaposi sarcoma in Israeli Jews between 1960 and 1998. World standardized incidence rates of 20.7 and 7.5 per million among men and women, respectively, were calculated. The highest incidence rates were displayed by men who originated from Africa and by Asian-born women.
Foster et al. (2000) found a strong association between the IL6 gene promoter polymorphism (-174G-C; 147620.0001) and susceptibility to Kaposi sarcoma in HIV-infected men. Homozygotes for IL6 allele G, associated with increased IL6 production, were overrepresented among patients with Kaposi sarcoma, whereas allele C homozygotes were underrepresented.
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Chow, D., He, X., Snow, A. L., Rose-John, S., Garcia, K. C. Structure of an extracellular gp130 cytokine receptor signaling complex. Science 291: 2150-2155, 2001. [PubMed: 11251120] [Full Text: https://doi.org/10.1126/science.1058308]
Cool, C. D., Rai, P. R., Yeager, M. E., Hernandez-Saavedra, D., Serls, A. E., Bull, T. M., Geraci, M. W., Brown, K. K., Routes, J. M., Tuder, R. M., Voelkel, N. F. Expression of human herpesvirus 8 in primary pulmonary hypertension. New Eng. J. Med. 349: 1113-1122, 2003. [PubMed: 13679525] [Full Text: https://doi.org/10.1056/NEJMoa035115]
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Gottlieb, M. S., Schroff, R., Schanker, H. M., Weisman, J. D., Fan, P. T., Wolf, R. A., Saxon, A. Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: evidence of a new acquired cellular immunodeficiency. New Eng. J. Med. 305: 1425-1431, 1981. [PubMed: 6272109] [Full Text: https://doi.org/10.1056/NEJM198112103052401]
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Hjalgrim, H., Tulinius, H., Dalberg, J., Hardarson, S., Frisch, M., Melbye, M. High incidence of classical Kaposi's sarcoma in Iceland and the Faroe Islands. Brit. J. Cancer 77: 1190-1193, 1998. [PubMed: 9569061] [Full Text: https://doi.org/10.1038/bjc.1998.198]
Hong, Y.-K., Foreman, K., Shin, J. W., Hirakawa, S., Curry, C. L., Sage, D. R., Libermann, T., Dezube, B. J., Fingeroth, J. D., Detmar, M. Lymphatic reprogramming of blood vascular endothelium by Kaposi sarcoma-associated herpesvirus. Nature Genet. 36: 683-685, 2004. [PubMed: 15220917] [Full Text: https://doi.org/10.1038/ng1383]
Kedes, D. H., Operskalski, E., Busch, M., Kohn, R., Flood, J., Ganem, D. The seroepidemiology of human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus): distribution of infection in KS risk groups and evidence for sexual transmission. Nature Med. 2: 918-924, 1996. Note: Erratum: Nature Med. 2: 1041 only, 1996. [PubMed: 8705863] [Full Text: https://doi.org/10.1038/nm0896-918]
Masur, H., Michelis, M. A., Greene, J. B., Onorato, I., Vande Stouwe, R. A., Holzman, R. S., Wormser, G., Brettman, L., Lange, M., Murray, H. W., Cunningham-Rundles, S. An outbreak of community-acquired Pneumocystis carinii pneumonia: initial manifestation of cellular immune dysfunction. New Eng. J. Med. 305: 1431-1438, 1981. [PubMed: 6975437] [Full Text: https://doi.org/10.1056/NEJM198112103052402]
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Suthaus, J., Stuhlmann-Laeisz, C., Tompkins, V. S., Rosean, T. R., Klapper, W., Tosato, G., Janz, S., Scheller, J., Rose-John, S. HHV8-encoded viral IL-6 collaborates with mouse IL-6 in the development of multicentric Castleman disease in mice. Blood 119: 5173-5181, 2012. [PubMed: 22490805] [Full Text: https://doi.org/10.1182/blood-2011-09-377705]
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Zeligman, I. Kaposi's sarcoma in a father and son. Bull. Johns Hopkins Hosp. 107: 208-212, 1960. [PubMed: 13788156]