Which hereditary syndromes are associated with colorectal cancer, and when is genetic testing for these syndromes recommended?
Approximately one-fifth of colorectal cancers (CRCs) are related to a hereditary syndrome.
Lynch syndrome (LS), or hereditary nonpolyposis colorectal cancer (HNPCC), accounts for 2-4% of colorectal cancer cases in the United States.
Given the frequency of LS, multiple
institutions have endorsed immunohistochemistry (IHC) and, in some
cases, microsatellite instability (MSI) testing in all colorectal and
endometrial cancers to determine which patients should receive germline
genetic testing.
Other less common syndromes associated with CRC include familial adenomatous polyposis (FAP), MUTYH (MYH)-associated
polyposis (MAP), Peutz-Jeghers syndrome (PJS), juvenile polyposis
syndrome (JPS), hereditary diffuse gastric cancer, serrated polyposis
syndrome, Cowden syndrome, and Li-Fraumeni syndrome.
If a familial syndrome is suspected,
germline genetic testing, such as a hereditary cancer multigene panel,
single gene testing, or familial mutation testing, may be appropriate.
Should vitamin D testing be performed in colorectal cancer?
Multiple studies have suggested that a lack of vitamin D is associated
with poorer outcomes in colorectal cancer (CRC); however, other studies
have indicated no cancer-specific benefit from vitamin D
supplementation. Studies are ongoing, but the National Comprehensive
Cancer Network (NCCN) does not currently recommend routine vitamin D
testing in patients with CRC.
Which Test to Use?
Regarding their performance as a screening tool for Lynch syndrome, both
IHC and molecular MSI testing are considered quite sensitive and
produce concordant results.
Although the sensitivity of molecular MSI testing has been reported to
be as low as 58%, partially owing to the ineffectiveness of detecting
MSH6 mutation carriers, more recent studies using mononucleotide markers
show the high sensitivities, reaching up to 100%, with increased
detection of MSH6 mutation carriers.
Although very sensitive, both IHC and molecular MSI testing have their
limitations; therefore, if questionable results are obtained by either
method, they should be confirmed with alternative tests.
Molecular Testing
Tissue from a primary, recurrent, or metastatic colorectal tumor is
acceptable for somatic molecular testing because results are similar for
these specimen types.
Formalin-fixed, paraffin-embedded tissue should be used.
Germline
genetic testing for hereditary CRC syndromes should be based on
clinical presentation and family history, and should be performed in
conjunction with genetic consultation.
A
hereditary cancer multigene panel, single gene testing, or familial
mutation testing may be appropriate if a hereditary cancer is suspected.
Microsatellite Instability and Mismatch Repair Somatic Testing
Testing for MSI via polymerase chain reaction (PCR), or for mismatch
repair (MMR) protein status via immunohistochemistry (IHC), is
recommended in all patients with a history of CRC to evaluate for LS
risk. MSI (either low or high) or MMR deficiency identifies patients at
high risk.
MSI testing is also useful to determine whether to use adjuvant
chemotherapy in stage II disease, and both MSI and MMR testing are
useful in treatment selection in stage IV disease.
High
MSI and MMR deficiency are both associated with a more favorable
prognosis in stage II disease and decreased likelihood of metastases.
Extended RAS Somatic Testing
Extended RAS gene testing, specifically KRAS (codons 12 and 13 of exon 2; codons 59 and 61 of exon 3; and codons 117 and 146 of exon 4) and NRAS (codons
12 and 13 of exon 2; codons 59 and 61 of exon 3; and codons 117 and 146
of exon 4), is recommended in all patients with CRC at the diagnosis of
stage IV disease or being considered for anti-EGFR therapy. Patients with any known KRAS variant in exons 2, 3, or 4 or NRAS variant in exons 2, 3, or 4 should not receive cetuximab or panitumumab.
No specific methodology is recommended for
RAS testing.
Wild-type
KRAS is associated with improved prognosis and increased lymph node retrieval.
BRAF Somatic Testing
BRAF testing is recommended in all patients with metastatic
CRC at the diagnosis of stage IV disease and should be considered in
patients with wild-type KRAS/NRAS metastatic colon cancer.
Wild-type
BRAF is associated with improved prognosis and increased lymph node retrieval.
Presence of the
BRAF V600E variant in patients with MMR-deficient CRC tumors with loss of
MLH1 suggests sporadic CRC, although it does not rule out Lynch syndrome. Presence of the
BRAF V600E
variant also decreases the probability that treatment with panitumumab
or cetuximab therapy will be effective without anti-BRAF therapy (eg,
vemurafenib); combination therapy is recommended.
Pharmacogenetics
Fluorouracil Drugs
MSI-low (MSI-L) or microsatellite stable (MSS) tumors are associated
with improved outcomes with 5-fluorouracil (5-FU) adjuvant therapy.
Patients with low-risk stage II MSI-high (MSI-H) tumors should not be given 5-FU adjuvant therapy.
Irinotecan
Decreased UGT1A1 gene expression may lead to drug toxicity, including development of severe neutropenia, from irinotecan.
The
UGT1A1*28 allele is associated with an increased risk of toxicity.
Patients who are heterozygous or homozygous for the
*28 allele should receive a reduced starting dose of irinotecan
and be treated with caution.Pretreatment testing for
UGT1A1*28 should be considered, although guidelines have yet to be established.
Fluoropyrimidine
MSI-H status and MMR deficiency are associated with a decreased
benefit from fluoropyrimidine adjuvant therapy in stage II disease.
Certain variants in the dihydropyrimidine dehydrogenase gene (
DYPD) are associated with life-threatening toxicity from fluoropyrimidine.
These
variants are thought to occur in 1-2% of the population; however,
universal testing for these variants before fluoropyrimidine treatment
is not currently recommended.
Anti-EGFR Therapy
As mentioned above, patients with any known KRAS variant in exon 2, 3, or 4 or NRAS variant in exon 2, 3, or 4 should not receive cetuximab or panitumumab, and presence of the BRAF V600E variant also decreases the probability that treatment with these drugs will be effective without anti-BRAF therapy.
HER2 overexpression may also predict resistance to anti-EGFR treatment.
However,
HER2 testing is not currently recommended for treatment planning.