The conundrum of causality in tumor virology: the cases of KSHV and MCV

Abstract

Controversy has plagued tumor virology since the first tumor viruses were described over 100 years ago. Methods to establish cancer causation, such as Koch's postulates, work poorly or not at all for these viruses. Kaposi's sarcoma herpesvirus (KSHV/HHV8) and Merkel cell polyomavirus (MCV) were both found using nucleic acid identification methods but they represent opposite poles in the patterns for tumor virus epidemiology. KSHV is uncommon and has specific risk factors that contribute to infection and subsequent cancers. MCV and Merkel cell carcinoma (MCC), in contrast, is an example in which mutations to our normal viral flora contribute to cancer. Given the near-ubiquity of human MCV infection, establishing cancer causality relies on molecular evidence that does not fit comfortably within traditional infectious disease epidemiological models. These two viruses reveal some of the challenges and opportunities for inferring viral cancer causation in the age of molecular biology.

Keywords: Cancer virus; Carcinogenic mechanisms; Causal inference; Causality; Kaposi's sarcoma herpesvirus; Merkel cell polyomavirus.

Figure 1

Major theorists in causal inference.

Figure 2

A) Example of a circuit in which Switch 1 (but not Switch 2) is “causing” a light to turn on, although neither switch is necessary (From [122]). B) Example for EBV causality for Burkitt lymphoma using this reasoning. In this example, EBV is not necessary. Since other factors (“switches”) also needed, such as cMyc rearrangements or immune suppression, it is not sufficient either.

Figure 3. A) Kaposi’s sarcoma

Micrograph of a Kaposi’s sarcoma lesion showing spindle tumor cells of endothelial/lymphatic origin. The tumor cells are associated with infiltrating lymphoid cells and abnormal microvasculature, some still containing red blood cells. (hematoxylin and eosin staining). B) KSHV LANA1. Micrograph of Kaposi’s sarcoma tissue section immunostained with an antibody targeting the latency associated nuclear antigen 1 (LANA1). KS spindle tumor cells show nuclear distribution of LANA1 expression.

Figure 4

A) Dermatologic, clinical appearance of Merkel cell carcinoma as a raised, red nodule on skin (courtesy of Dr. K. Busam). B) Histologic appearance of Merkel cell carcinoma showing sheets of small, round, blue tumor cells with high mitotic activity (arrowheads). C) MCV Large T antigen expression in Merkel cell carcinoma showing predominantly nuclear localization of the viral oncoprotein.