Ten percent of all colon cancers arise in a familial setting when defined as two or more affected first-degree relatives . There is a also two-fold increase of developing colon cancer with an affected first-degree relative . Specifics of the genetic etiology of this group are not defined, leaving a gap in our knowledge of moderate risk genetic variants. A germline mutation in the MET gene, p.T992I, was identified in ~4.5% of colon cancers arising in first-degree relative pairs from two separate cohorts. The mutation was observed in less than 1% of colon cancer cases that occurred ≤ 50 years, suggesting that it does not promote very young CRC. MET p.T992I is also reported in the germline DNA of 4% of thyroid cancers , one endometrial and two melanoma cancer cases, and one normal individual . In cancers, the p.R970C and p.T992I mutations are thought to affect phosphorylation of the serine residue (p.S985) that negatively regulates MET kinase activity [8, 25]. By comparison, the specific missense mutations reported in hereditary papillary renal carcinoma (HPRC) surround two tyrosine residues within the catalytic site (p.Y1234 and p.Y1235) that positively regulate kinase activity (Figure 1). The phenotypic differences between p.T992I and HPRC MET mutations could be explained by the difference between factors driving negative versus positive activation of MET kinase.
We propose a model whereby the p.T992I mutation functions as a progression factor rather than an initiation factor in the canonical colon cancer model . Specifically, we hypothesize that an adenoma is initiated through somatic mutations in the canonical APC pathway, then the adenoma acquires other proliferative mutations, and in the presence of an underlying MET p.T992I mutation, is then able to move beyond the mucosal layer to become invasive colon cancer. This hypothesis is supported by the following observations. The individuals we identified with the MET p.T992I germline mutation do not have the hallmarks of inherited mutations in initiating factors such as multiple adenoma formation (APC gene) or microsatellite instability (mismatch repair genes). Additionally, CRC diagnosis under age 50 is infrequent. In fact, the chromosome 7q genetic locus is associated in affected relative pair studies when CRCs are included and adenomas are excluded [5–7]. The average age of CRC diagnosis in the general population is ~71 years, and it is estimated that 10 years are needed for a small polyp to progress to invasive CRC . A model of rapid progression of polyp to cancer in the presence of MET p.T992I is supported in that individuals with the p.T992I mutation are diagnosed with CRC at an average age of 63 years. This would be when the general population, on average, is developing adenomas that will progress to cancer. This mutation also occurs in a variety of cancers including colon, melanoma, endometrial, thyroid, and mesothelioma [15–18] with germline confirmation in colon, thyroid, uterine, and melanoma [16, 17] suggesting that it is not a tissue-specific mechanism. MET p.T992I mutation is proposed to function through inhibition of phosphorylation of Ser985, which, when phosphorylated, corresponds with reduced MET signaling (Figure 1) [28, 29]. In cell models, the specific mutation reported here generally affects invasive behaviors including changes in cell morphology, adhesion, motility, migration and anchorage-independent growth but not proliferation, such as IL-3 independent growth in Ba/F3 cells [18, 29]. Based on these reports, it is reasonable to predict that MET p.T992I requires a growth signal (activation) but then is disabled in its ability to turn off the activation through phosphorylation of p.S985. It has also been shown that over expression of MET is an early event in the colorectal adenoma-carcinoma sequence . In the context of a proliferating precancerous colonic adenoma, over expression MET p.T992I and the inability to turn off activation could allow the invasive behaviors to take place.
Although, the MET p.T992I genetic mutation has been commonly found in somatic colorectal cancer tissues, this is the first report also implicating this MET genetic mutation as a germline inherited risk factor for familial colorectal cancer. A strength of this study is the use of colorectal cancers enriched for a hereditary component. One of the limitations, however, is the small sample size and lack of a large unaffected cohort. Future independent studies on large case and carefully selected control sets are needed to replicate these results, confirm the conclusions, and provide an accurate estimate of the prevalence of this mutation in the cancer and normal populations.