Use of genetics for the management of colorectal cancer is more commonplace and is fast becoming the norm, and knowledge of these tests by gastroenterologists will be necessary. DNA can be obtained from a patient via blood or buccal swab as well as fecal material to assess risk and assist the physician in the management of patients. Performing germline testing for prediction, prevention, and surveillance of patients at risk, genetic counseling, and obtaining information regarding family or personal history of cancer, age of onset, and clinical features are critical to this approach.
Over the past 2 decades, our knowledge of the genetics of adenomatous and hamartomatous syndromes has grown, linking genes and epigenetic changes in the germline to channeling care to modify the natural history of these syndromes for cancer onset. These include familial adenomatous polyposis (APC), MYH-associated polyposis (MYH), Lynch syndrome (DNA mismatch repair genes), Syndrome X (unknown), and the newly described polymerase epsilon and polymerase delta polyposis (POLE and POLD1) (1). With hamartomatous syndromes, we now understand the genetics for Cowden’s syndrome (PTEN), Peutz-Jeghers (STK11), juvenile polyposis (SMAD4, BMPR1A, ENG), hyperplastic/serrated polyposis (unknown), and a novel mechanism for hereditary mixed polyposis syndrome (overexpression of GREM1) (2).
Dr. John Carethers
At present, with suspicion of any of these syndromes, patient DNA is sent for individual gene evaluation. This will rapidly change to whole genome or whole exome sequencing as the costs for these technologies come down, and will provide much more information than individual gene tests. The additional incidental information from the rest of the genome may be the responsibility of the ordering physician to report back to the patient. The American College of Medical Genetics and Genomics indicates that 57 gene mutations from 24 different conditions should be reported now or in the future, regardless of the indication for ordering. The clinician should contextualize any incidental genetic findings, and is responsible for managing these. The implications of these recommendations speak to the need for an expertise management approach with this technology that will eventually become the norm.
Fecal and tumor DNA testing can screen, diagnose, and predict outcome for patients. Only 2 of 6 developed fecal DNA tests have reached the status of a CLIA laboratory test, with only 1 in current commercial use. These tests hold promise, but their diagnostic accuracy for screening is not known. The multisociety task force on colorectal cancer listed fecal DNA testing among tests that primarily detect cancer, but interval use was uncertain (3). At present, fecal DNA tests are not widely used.
In 2012, the Cancer Genome Atlas Network published data on the comprehensive mutations among 224 sporadic colorectal cancers (4). Much of this work confirmed many findings over the past quarter-century of research, plus some new findings, including sporadic polymerase epsilon mutations. Two groups of tumors emerged – hypermutated, consisting of DNA mismatch repair inactivation or polymerase epsilon mutation, and nonhypermutated tumors. The mutation profiles of these two groups are different, with hypermutated tumors targeting mutations in ACVR2, TGFBR2, BRAF, and DNA mismatch repair genes, while nonhypermutated tumors follow the classic Vogelstein model with APC, P53, KRAS, and PIK3CA mutations.
The mutational spectrum detail from tumor DNA can be a biomarker that might predict patient outcome or therapeutic response. For instance, the absence of a DNA mismatch repair gene from a tumor could identify a sporadic or germline cause, but either would represent a mismatch repair–deficient tumor that may not have any survival benefit to 5-fluorouracil-based chemotherapy (5). Tumor DNA can be predictive for outcome with aspirin use in patients with colon cancer. Aspirin is a COX-2 inhibitor that can downregulate the expression of PI3 kinase. Among patients whose tumors exhibit mutation of PI3 kinase, regular aspirin use reduced their probability of death compared to non-aspirin users. This effect was not seen in patients whose tumors had wild type PI3 kinase (6). Additionally, drugs such as cetuximab and panitumab, monoclonal antibodies that block EGFR and are used in stage IV colon cancer, block downstream signaling through the RAS/RAF/MAPK pathway, as well as PI3 kinase, abrogating cell growth. Colon tumors may overexpress EGFR, but in addition, tumors often exhibit mutational activation of RAS, RAF, and PI3 kinase. This mutational activation, now independent from the effects of EGFR, makes cetuximab and panitumab ineffective (7). Genotyping RAS/RAF before utilizing these drugs is now standard clinical practice.
What does the future hold? Whole exome and genome sequencing will become the standard to perform germline testing as costs come down. When the entire genome is sequenced, incidental findings on other known genes may have to be disclosed. There will be additional genetic biomarkers commercially to determine drug response and outcome, or for use in screening. Fecal DNA screening will undoubtedly improve, but has a way to go for accuracy.
