Advances in technology and decreased testing costs have led to a rise in the number of genes associated with inherited cancer risk for which testing is clinically available. At the same time, national practice guidelines have been revised to reflect the changes in expanded test offerings.
One cancer type that recently had significant guideline changes by the National Comprehensive Cancer Network (NCCN) is colorectal cancer (CRC). The NCCN updated its Genetic/Familial High-Risk Assessment: Colorectal guidelines this year to include several genes newly associated with increased risk for CRC.1 In addition, management guidelines for more well-described syndromes, such as Lynch syndrome (LS), were also modified.
NCCN Modifications to CRC Genetic Guidelines
GREM1. A 40kb duplication upstream of GREM1 in individuals of Ashkenazi Jewish ancestry is associated with hereditary mixed polyposis syndrome. Currently, the lifetime CRC risk is unknown but is assumed to be high. Colonoscopy should begin between age 25 and 30 years and be repeated every 2 to 3 years if normal. If polyps are found, colonoscopy should be repeated every 1 to 2 years, and removal of the colon should be considered if polyp burden becomes unmanageable.
POLD1 and POLE. Mutations in POLD1 and POLE are associated with polymerase proofreading–associated polyposis. Currently, the lifetime risk for CRC is unknown but is assumed to be high. The phenotype appears to overlap with LS (typically 0 or few colonic polyps) and familial adenomatous polyposis (hundreds of colonic polyps). Colonoscopy should begin between age 25 and 30 years and be repeated every 2 to 3 years if normal. If polyps are found, colonoscopy should be repeated every 1 to 2 years, and removal of the colon considered if polyp burden becomes unmanageable.
MLH1, MSH2, MSH6, PMS2, EPCAM. Mutations in MLH1, MSH2, MSH6, PMS2, and EPCAM genes are associated with LS. In addition to colon cancer, LS places individuals at increased risk for a variety of other cancers. The lifetime CRC risk up to age 70 years varies, depending on the gene harboring the mutation and ranges from approximately 10% to 85%. Guidelines were recently modified to recommend colonoscopy at the same age and same interval, regardless of which genetic mutation is involved. Colonoscopy should begin between age 20 and 25 years, or 2 to 5 years before the earliest CRC diagnosis in the family if that cancer was diagnosed in someone younger than 25 years. Colonoscopy should be repeated every 1 to 2 years.
NCCN Updates for Other Genes Conferring Increased Risk for CRC
Recent updates suggest that individuals with the APC I1307K variant, single mutation carriers in the BLM or MUTYH genes, or mutation carriers in CHEK2 or GALNT12 should undergo colonoscopy at a younger age, and at increased intervals.
For carriers with a first-degree relative (ie, parent, sibling, child) with CRC, colonoscopy should begin at age 40 years, or 10 years before the earliest CRC diagnosis, and be repeated at least every 5 years. For patients without a first-degree relative with CRC, colonoscopy should begin at age 40 years and be repeated at least every 5 years.
APC I1307K variant. Mutations in the APC gene are typically associated with attenuated familial adenomatous polyposis or familial adenomatous polyposis. Both syndromes are characterized by a high polyp burden, typically more than 10, and with familial adenomatous polyposis often more than 100. However, the I1307K variant is unique in that its presentation is not classic and polyps are not always seen. This variant confers an increased risk for CRC and is typically seen in individuals of Ashkenazi Jewish descent. For carriers with a first-degree relative with CRC, colonoscopy should begin at age 40 years, or 10 years before the earliest CRC diagnosis, and be repeated at least every 5 years. For patients without a first-degree relative with CRC, colonoscopy should begin at age 40 years and be repeated at least every 5 years.
BLM: single carrier/1 mutation. Individuals who carry a mutation in the 2 BLM genes have Bloom syndrome, which is characterized by short stature, increased sensitivity to light, immune deficiency, and an increased risk for cancer. Data are beginning to suggest that individuals carrying 1 mutation have an increased risk for CRC.
CHEK2. Mutations in the CHEK2 gene are associated with an increased risk for CRC and several other cancers.
GALNT12. Mutations in GALNT12 appear to be associated with an increased risk for CRC, although it is unclear if the risk is low or moderate.
MUTYH: single carrier/1 mutation. Individuals who carry a mutation in the 2 MUTYH genes have MAP (MUTYH-associated polyposis) syndrome and a high risk for CRC. Recent data suggest that individuals carrying a mutation in only 1 MUTYH gene may also have an increased risk for CRC, although not as high as in bi-allelic carriers.
NCCN Updates for Genes Associated with Lynch Syndrome
In addition, the updated NCCN guidelines combined CRC surveillance recommendations for individuals who carry a mutation in any of the 5 genes associated with LS. Previously, the CRC screening recommendations were different for carriers of MLH1, MSH2, or EPCAM mutations (which have the highest lifetime colon cancer risks) versus carriers of MSH6 and PMS2 mutations (which have lower lifetime colon cancer risks).
It is now recommended that colon cancer surveillance begin at the same age and at the same interval, regardless of the genetic mutation.1 This is an important update for individuals with LS to share with their at-risk family members, because this adjustment may help to inform the age at which relatives may consider predictive testing for a known mutation in the family.
It is important to keep in mind that as our knowledge about many of the inherited genes associated with cancer risk continues to evolve, risk estimates and management guidelines will likely continue to undergo updates. Many genes are included on available clinical tests that do not yet have precise lifetime cancer risk estimates or corresponding practice guidelines; and this makes these test results challenging for healthcare providers. Staying abreast of any updates to cancer risk estimates and guidelines will enable clinicians to offer additional genetic testing options that may be appropriate for patients who previously underwent genetic testing, and to modify their medical management of patients who previously tested positive for a genetic mutation.
1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Genetic/Familial High-Risk Assessment: Colorectal. Version 1.2016. July 11, 2016. www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf. Accessed September 21, 2016.