No evidence for a polyomavirus association or aetiology in AIDS-associated nonsmall cell lung cancer
Stebbing, Justina; Wickenden, Colina; Castellano, Leandroa; Sita-Lumsden, Ailsab; Nelson, Markb; Jacob, Jimmya; Naresh, Kikeric; Mauri, Francescoc; Bower, Markb
aDepartment of Oncology, Imperial College, Hammersmith Hospital, UK
bDepartment of HIV Medicine and Oncology, Imperial College, Chelsea and Westminster Hospital, UK
cDepartment of Pathology, Imperial College, Hammersmith Hospital, London, UK.
Received 24 November, 2009
Revised 31 January, 2010
Accepted 1 February, 2010
Correspondence to Justin Stebbing, MA, MRCP, FRCPath, PhD, Division of Surgery, Oncology, Reproductive Medicine and Anaesthesia, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK. E-mail: email@example.com
AIDS-associated lung cancer has an increasing incidence, unaccounted for by smoking, and occurs consistently at a younger age than matched controls. We investigated whether known and new cancer-associated polyomaviruses, including the newly identified Merkel cell virus, may play a role in its etiopathogenesis. Although viruses target conserved pathways in cellular evolution, we are unable to suggest that the viruses studied here induce novel mechanisms of oncogenic dysregulation in AIDS-associated lung cancer.
There is an increasing awareness of the importance of non-AIDS-defining cancers (NADCs) occurring in HIV-seropositive people since the introduction of highly-active antiretroviral therapy (HAART) [1,2]. Among these tumours, lung cancer occurs at an increased frequency compared to age-matched and sex-matched populations, an increase that is not accounted for by smoking alone. Moreover, the incidence of lung cancer in people with HIV is rising as overall survival improves due to HAART [3–5]. Although the majority of NADCs do not correlate with the degree of immunodeficiency in general , in a recent large French prospective cohort study, a lower CD4 cell count was associated with an increased risk of lung cancer; HAART was observed to be most beneficial if it restored and maintained the CD4 cell count above 500 cells/μl . In our cohort, prolonged HIV infection, HAART use and a nadir CD4 count below 200/μl were associated with an increased risk of lung cancer, but none reached statistical significance in the fully adjusted analysis . This increased risk was confined to the early HAART and established HAART eras [standardized incidence ratio (SIR) = 3.10, 95% confidence interval (CI) = 1.34–6.11 and SIR = 2.37, 95% CI = 1.14–4.36, respectively]. Most patients present with advanced stage lung cancer and the outcome is often very poor (D'Jaen et al., unpublished data), though direct comparisons to HIV-seronegative cases are lacking.
As the role of viral coinfection and viral carcinogenesis in the course of HIV infection is well established, we aimed to investigate a potential role for potentially oncogenic DNA viruses herein. We, thus, performed a pilot study to screen lung carcinoma specimens, retrospectively derived from patients treated in the HAART era, for one known cancer-causing γ-herpes virus (Kaposi's sarcoma-associated herpes virus) and the cancer-associated polyomaviruses (BK, JC, SV40 and the recently discovered Merkel cell virus); primer sequences are shown in Table 1 . The finding of any viruses would potentially create new opportunities for novel therapies of this devastating disease. In particular, the Merkel cell virus has emerged as a new pathogen and thus its role in coinfection in immunosuppressed individuals is clearly worth investigating [8–11]. Furthermore, a recent report has suggested its presence in a small proportion of small cell lung cancer specimens derived from apparently immunocompetent individuals .
Tumour samples were obtained from eight patients with a histologically confirmed diagnosis of HIV-associated nonsmall cell lung cancer diagnosed in the post HAART era. Seven were men and the mean age was 53 (range 32–69) years. The median duration of HIV infection at the time of lung cancer diagnosis was 10.6 (range 2–18) years and all but one were smokers. At the time of lung cancer diagnosis, the median CD4 cell count measured 419 /μl (range 196–1456) and all but one patient were receiving HAART. The final histological classification of the tumours was squamous cell cancer for five (62%) and adenocarcinoma for three (37%); the clinicopathological details are shown in Table 2. Patients were treated along conventional lines: two patients had surgery for stage I disease (both remain alive in remission), one patient with stage IIIA disease received chemoradiotherapy and four patients with stage IIIB and IV disease received palliative combination platinum-based chemotherapy, whereas the final patient with stage IV disease was treated with best supportive care alone at his wish. At a median follow-up of 1.8 years, only two patients are alive and the overall 1-year survival for the cohort is 50% (95% CI = 15–85%).
None of the samples tested positive for any of the viruses for which they were screened; appropriate controls, tested in a different setting to avoid contamination, were positive. These negative data suggest the lack of an association between AIDS-associated lung cancer and the DNA viruses for which screening was performed. A larger study at this point in time is not warranted, although other viruses merit further scrutiny, such as the novel xenotropic murine leukemia virus (XMRV) associated with prostate cancer , especially as it is susceptible to zidovudine (AZT)  (we elected to limit our study to novel oncogenic DNA viruses).
Although viruses target conserved pathways in cellular evolution, we are unable to suggest that the viruses tested in this study induce novel mechanisms of oncogenic dysregulation in AIDS-associated lung cancer [15,16], despite a number of features suggesting a different course to lung cancer in the HIV-seronegative population. It is possible that other DNA or RNA viruses may be linked to lung cancer.
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