Circulating Free DNA Analysis in Gastrointestinal Cancer, Genitourinary Cancer, Rare Cancer

Metastasis is a leading cause of cancer related deaths and is also one of the poorly understood aspects of cancer progression. During metastatic outgrowth, a cancer cell from a primary tumor locally invades the surrounding tissue, undergoes intravasation to enter hematogenous circulation and translocates to distant tissues through extravasation, survives and adapts to the foreign microenvironment leading to formation of a macroscopic secondary tumor (Figure 1, Chaffer and Weinberg (2011)). Several cancer therapies have been introduced in the last few decades from cytotoxics to targeted agents. However, these therapies fail to modulate growth of metastatic tumor cells which are often resistant, with most cancer patients succumbing to metastatic disease. There is a key need to further the understanding of metastatic disease in order to develop newer therapies. A central and somewhat unaddressed question is whether this acquisition of malignant traits occurs as an inevitable consequence of tumor progression or as an accidental product thereof. A widely accepted but not so well proven model of primary tumor formation suggests that cancer cells acquire a sequence of genetic and epigenetic alterations, each of which confers one or another form of increased fitness.

Figure 1: The metastatic cascade. Metastasis can be envisioned as a process that occurs in two major phases: (i) physical translocation of cancer cells from the primary tumor to a distant organ and (ii) colonization of the translocated cells within that organ. (A) To begin the metastatic cascade, cancer cells within the primary tumor acquire an invasive phenotype. (B) Cancer cells can then invade into the surrounding matrix and toward blood vessels, where they intravasate to enter the circulation, which serves as their primary means of passage to distant organs. (C) Cancer cells traveling through the circulation are Circulating free DNA. They display properties of anchorage-independent survival. (D) At the distant organ, Circulating free DNA exit the circulation and invade into the microenvironment of the foreign tissue. (E) At that foreign site, cancer cells must be able to evade the innate immune response and also survive as a single cell (or as a small cluster of cells). (F) To develop into an active macrometastatic deposit, the cancer cell must be able to adapt to the microenvironment and initiate proliferation.

It is somewhat accepted that tumors are clonally derived through unregulated growth of single cells that have likely accumulated the necessary number and types of heritable genetic and genomic alterations. Despite the monoclonal origin of cancer, the investigators see many tumors display a large amount of genetic, genomic and signaling heterogeneity. This heterogeneity is also believed to be one of the main drivers of metastasis. This heterogeneity has implications for understanding the disease progression landscape on one hand and diagnosis and treatment decisions on other. It is therefore of direct clinical importance to study the similarities and differences between the primary tumor and metastatic variants