Microsatellite Instability in Anal Squamous Cell Carcinomas of HIV-Positive Versus HIV-Negative Patients

Background:

In the highly active antiretroviral therapy (HAART) era, the incidence of many cancers remains higher in the HIV-positive than in the general population. This is not only true for AIDS-defining malignancies, such as Kaposi's sarcoma or lymphoma, but also for other cancers, which comprise 58% of all neoplasms in a recently described US cohort [1]. This trend has generated renewed interest in understanding the molecular mechanisms of carcinogenesis in the immune suppressed patient. Potential explanations include prolonged survival of patients with HIV on HAART, high incidence of co-infection with oncogenic viruses, and exposure to risks such as smoking and alcohol [2].

Squamous cell carcinoma of the anus (SCCA) requires integration of human papillomavirus (HPV) DNA into anal canal cell chromosomes. HIV-positive men are at increased risk for developing anal cancer. A Swiss study linking the Swiss HIV cohort study and Swiss cantonal cancer registries has shown greatly elevated SIRs for anal cancer (SIR = 33.4, 95% CI = 10.5-78.6) [3]. Clearly, HPV-HIV coinfection plays a major role in SCCA development, but whether this contribution is associated with distinct molecular pathway of carcinogenesis, remains hypothetical [4].

Anal cancer occurs earlier in HIV-positive individuals (mean age 37 years) compared with HIV-negative men (58 years) and HIV-negative women (65 years). This difference of two decades in age of onset supports the hypothesis that the biology of SCCA differs between HIV-positive and HIV-negative patients [5]. The effect of HIV infection on the natural history of anal HPV infection is poorly understood, but most experts agree on two points: 1) 95% of HIV-positive homosexual men are co-infected with HPV; and 2) HIV infection favors persistence of HPV infection within the ano-genital tract (uterine cervix, vagina, and anal canal).

Two major and mutually exclusive types of genomic instability are involved in cancer progression. The first, known as chromosomal instability (CIN), results from a series of genetic changes, including activation of oncogenes and inactivation of tumor-suppressor genes such as p53 and APC. The second, known as microsatellite instability (MSI), results from somatic (acquired) inactivation of DNA mismatch repair genes (MMR), such as MLH1 (by hypermethylation of its promoter), typically leading to mutation of genes with coding microsatellites, such as BAT 25, BAT26 and CAT25, transforming growth factor receptor II (TGF-RII) and BAX [6].