Table 3.
Prognostic and Predictive DNA Markers in Colorectal Cancer.*
| DNA Marker | Comments |
|---|---|
| Prognostic | |
| APC | A germ-line mutation defines the colorectal-cancer predisposition syndrome, familial adenomatous polyposis, with an 80 to 100% lifetime risk of colorectal cancer. Patients with germ-line APC mutations undergo prophylactic colectomy or proctocolectomy. |
| MLH1,MSH2, MSH6 | A germ-line mutation in these and, less commonly, in other mismatch-repair genes defines hereditary nonpolyposis colon cancer, with a 40 to 80% lifetime risk of colorectal cancer, as well as an increased risk of endometrial cancer. Patients with germ-line mismatch-repair gene mutations undergo frequent colonoscopic surveillance and may be considered for prophylactic colectomy and hysterectomy. |
| MLH1 methylation– associated silencing | The somatic inactivation of MLH1 in primary colorectal cancers is evidenced by either detection of DNA microsatellite instability or loss of tumor MLH1 protein expression on immunohistochemical analysis, and is more frequent in early-stage colorectal cancers than in advanced disease. Such inactivation may be a marker of more indolent disease or a better prognosis in the absence of adjuvant chemotherapy.103,104 |
| 18q Loss of heterozygosity | The somatic loss of heterozygosity at chromosomal location 18q, a site containing genes associated with colorectal cancer (e.g., SMAD4 and SMAD2), is associated with a poorer outcome in patients with stage II or stage III colon cancer than that in patients with tumors retaining both parental alleles at 18q.105 |
| Predictive | |
| KRAS | The somatic mutation produces unrestricted activity of signaling through the MAPK and PI3K cascades. Patients with stage IV colorectal cancer and activating mutations in KRAS do not have a response to EGFR-inhibitor therapy.92-94 |
| BRAF V600E | The somatic mutation activating this kinase causes unrestricted MAPK pathway signaling. Patients with stage IV colorectal cancer and the activating BRAF V600E mutation do not have a response to EGFR-inhibitor therapy.95 |
| MLH1 methylation-associated silencing | The loss of the mismatch-repair function contributes to the loss of other tumor suppressors (e.g., TGFBR2 and BAX). Patients with mismatch-repair–deficient tumors may not have a response to fluorouracil and may have an improved response to irinotecan-containing regimens.106,107 |
*
BAX denotes BCL2-associated X protein, EGFR epidermal growth factor receptor, MAPK mitogen-activated protein kinase, PI3K phosphatidylinositol 3-kinase, and TGFBR2 transforming growth factor receptor β type II.