Metastases May Form Early in Development of Colorectal Cancer

Signs and symptoms may include blood in the stool, a change in bowel movements, weight loss, and feeling tired all the time.

Most colorectal cancers are due to old age and lifestyle factors, with only a small number of cases due to underlying genetic disorders. A new study suggests that many colorectal cancer metastases may have arisen and spread even before the primary tumor was large enough to be detected. Both the timing and molecular determinants of metastasis are unknown, hindering treatment and prevention efforts.

Scientists at Stanford University School of Medicine (Stanford, CA, USA) characterized the evolutionary dynamics of this lethal metastasis process by analyzing exome-sequencing data from 118 biopsies from 23 patients with colorectal cancer with metastases to the liver or brain. Through a phylogenetic analysis, the team traced the origins of these metastatic tumors. For all but one of the cases analyzed, they found the distant metastases corresponded to a monophyletic clade.

Within this cohort, the scientists noted high concordance among putative driver genes. Mutations in KRAS, TP53, SMAD4, and others were similar in primary and metastatic tumor pairs. In addition, primary and metastatic tumor pairs were also likely to share somatic single nucleotide variants (SNVs) and small indels. They noted most of these metastases actually diverged early in the emergence of the primary tumor. Most of the liver and all of the brain metastases harbored many private clonal somatic SNVs, but no subclonal ones. This indicated to the team that a single cell or a small group of genetically similar cells seed most metastases. They found that in their dataset 83%of the primary metastatic tumor pairs from 17 of the 21 patients likely underwent metastatic dissemination when the primary tumor was below the limits of clinical detection, which is smaller than 0.01 cm3 in size.

The scientists found in a separate cohort of 2,751 patients with colorectal cancer, including 938 patients with metastatic cancer, that most metastases harbored a set of core colorectal cancer driver genes, but also an additional candidate metastasis driver gene. In particular, they noted that the gene PTRT, a part of the STAT3 signaling pathway, appears to be a highly specific driver of metastasis. This suggested to them that early dissemination can occur in many colorectal cancer patients, underscoring the need for early detection, possibly through detecting cell-free tumor DNA as these small tumors fall at the limits of detection for imaging approaches. The study was published on June 17, 2019, in the journal Nature Genetics.

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Stanford University School of Medicine