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Abstract The advent of high-throughput technology challenges the traditional histopathological classification of cancer, and proposes new taxonomies derived from global transcriptional patterns. Although most of these molecular re-classifications did not endure the test of time, they provided bulk of new information that can reframe our understanding of human cancer biology. Here, we focus on an immunologic interpretation of cancer that segregates oncogenic processes independent from their tissue derivation into at least two categories of which one bears the footprints of immune activation. Several observations describe a cancer phenotype where the expression of interferon stimulated genes and immune effector mechanisms reflect patterns commonly observed during the inflammatory response against pathogens, which leads to elimination of infected cells. As these signatures are observed in growing cancers, they are not sufficient to entirely clear the organism of neoplastic cells but they sustain, as in chronic infections, a self-perpetuating inflammatory process. Yet, several studies determined an association between this inflammatory status and a favorable natural history of the disease or a better responsiveness to cancer immune therapy. Moreover, these signatures overlap with those observed during immune-mediated cancer rejection and, more broadly, immune-mediated tissue-specific destruction in other immune pathologies. Thus, a discussion concerning this cancer phenotype is warranted as it remains unknown why it occurs in immune competent hosts. It also remains uncertain whether a genetically determined response of the host to its own cancer, the genetic makeup of the neoplastic process or a combination of both drives the inflammatory process. Here we reflect on commonalities and discrepancies among studies and on the genetic or somatic conditions that may cause this schism in cancer behavior.

The advent of high-throughput technology challenges the traditional histopathological classification of cancer, and proposes new taxonomies derived from global transcriptional patterns. Although most of these molecular re-classifications did not endure the test of time, they provided bulk of new information that can reframe our understanding of human cancer biology. Here, we focus on an immunologic interpretation of cancer that segregates oncogenic processes independent from their tissue derivation into at least two categories of which one bears the footprints of immune activation. Several observations describe a cancer phenotype where the expression of interferon stimulated genes and immune effector mechanisms reflect patterns commonly observed during the inflammatory response against pathogens, which leads to elimination of infected cells. As these signatures are observed in growing cancers, they are not sufficient to entirely clear the organism of neoplastic cells but they sustain, as in chronic infections, a self-perpetuating inflammatory process. Yet, several studies determined an association between this inflammatory status and a favorable natural history of the disease or a better responsiveness to cancer immune therapy. Moreover, these signatures overlap with those observed during immune-mediated cancer rejection and, more broadly, immune-mediated tissue-specific destruction in other immune pathologies. Thus, a discussion concerning this cancer phenotype is warranted as it remains unknown why it occurs in immune competent hosts. It also remains uncertain whether a genetically determined response of the host to its own cancer, the genetic makeup of the neoplastic process or a combination of both drives the inflammatory process. Here we reflect on commonalities and discrepancies among studies and on the genetic or somatic conditions that may cause this schism in cancer behavior. [ABSTRACT FROM AUTHOR]

Recurrent metastatic melanoma provides a unique opportunity to analyze disease evolution in metastatic cancer. Here, we followed up eight patients with an unusually prolonged history of metastatic melanoma, who developed a total of 26 recurrences over several years. Cell lines derived from each metastasis were analyzed by comparative genomic hybridization and global transcript analysis. We observed that conserved, patient-specific characteristics remain stable in recurrent metastatic melanoma even after years and several recurrences. Differences among individual patients exceeded within-patient lesion variability, both at the DNA copy number (P<0.001) and RNA gene expression level (P<0.001). Conserved patient-specific traits included expression of several cancer/testis antigens and the c-kit proto-oncogene throughout multiple recurrences. Interestingly, subsequent recurrences of different patients did not display consistent or convergent changes toward a more aggressive disease phenotype. Finally, sequential recurrences of the same patient did not descend progressively from each other, as irreversible mutations such as homozygous deletions were frequently not inherited from previous metastases. This study suggests that the late evolution of metastatic melanoma, which markedly turns an indolent disease into a lethal phase, is prone to preserve case-specific traits over multiple recurrences and occurs through a series of random events that do not follow a consistent stepwise process. [ABSTRACT FROM AUTHOR]