Multigene panel testing should be considered for all patients with colorectal cancer (CRC) who are diagnosed younger than age 50 years, new findings suggest.
Among 450 patients with early-onset CRC, 16% had a pathogenic mutation, and testing with a multigene panel identified mutations that might have been otherwise missed.
A third of these patients harbored pathogenic mutations that did not meet National Comprehensive Cancer Network (NCCN) Guidelines for at least one of the genes in which they were found to have a mutation.
"Genetic counseling and testing with a broad multigene panel should be considered for all patients with early-onset CRC due to their high prevalence of hereditary cancer syndrome," the authors conclude.
The study was published online December 15 in JAMA Oncology.
Early-onset cancer is a hallmark of inherited cancer predisposition, but genetic testing is still not yet universal. "Tumor screening for Lynch syndrome is being done at many — but not all — hospitals for all colorectal cancer patients, and patients with abnormal tumor screening are referred to cancer genetics to consider genetic testing for Lynch syndrome," said lead author Heather Hampel, MS, CGC, associate director, Division of Human Genetics, Ohio State University Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus.
"Patients with normal tumor screening are generally only referred to cancer genetics if they have a strong family history or polyposis," she told Medscape Medical News. "What our study has found is that all of the colorectal cancer patients diagnosed under age 50 should be referred to cancer genetics for consideration of a multigene panel test of hereditary cancer susceptibility genes, including more than just testing for Lynch syndrome. I would guess that the majority of these patients are not being seen in cancer genetics currently."
Beyond Lynch Syndrome
CRC is typically a disease that occurs in older adults, with only 10% of patients diagnosed before age 50 years.
Hereditary cancer syndromes are implicated in approximately 5% of all CRC cases, the authors note in their paper. Although the prevalence of genetic predisposition is likely higher among individuals who develop cancers at an early age, younger patients with CRC are significantly less likely than their counterparts with young-onset breast cancer to undergo genetic evaluation.
The most common hereditary cause of CRC is Lynch syndrome, which is caused by germline mutations in the DNA mismatch repair (MMR) deficiency genes MLH1, MSH2, MSH6, and PMS2, or EPCAM. Lynch syndrome accounts for about 4% to 13.5% of patients with early-onset disease.
NCCN guidelines suggest that all patients with CRC diagnosed at age younger than 50 years consider genetic testing for Lynch syndrome.
However, the prevalence of other hereditary cancer syndromes among younger patients is relatively unknown because of limited studies, which have also generally been confined to select populations, the authors note.
Pathogenic Mutations Revealed
In the current study, Hampel and colleagues sought to determine the prevalence and spectrum of germline mutations in 25 genes associated with various hereditary cancer syndromes by using a multigene panel.
Among the 450 patients in the cohort, the mean age at cancer diagnosis was 42.5 years, and 8.2% of patients (n = 37) had an additional malignancy.
Nearly one fifth (19.1%) reported having at least 1 first-degree relative with colon cancer, and a family history of other cancers, including cancer of the endometrium, breast, ovary, and/or pancreas, was also reported.
Most patients (n = 402 [89.3%]) had MMR-proficient tumors, with 10.7% (n = 48) harboring tumors that were MMR deficient.
Mulitigene testing also revealed 75 pathogenic or gene mutations that were likely to be pathogenic in 72 patients (16%). There were 36 patients (8%) with Lynch syndrome only, while 2 (0.4%) had Lynch syndrome along with another hereditary cancer syndrome.
In addition, 34 patients (7.6%) had a different hereditary cancer syndrome.
A total of 61 patients (13.6%) had mutations in high- or moderate-penetrance genes, and 11 (2.4%) had mutations in low-penetrance genes.
The authors also found that patients with pathogenic mutations were more likely to have a family history of colon cancer (45.8% vs 14%; P < .001) and endometrial cancer (11.1% vs 2.9%; P = .005) when compared with patients lacking mutations.
Patients with Lynch syndrome also tended to be diagnosed at earlier stages compared with those who had a different type of hereditary cancer syndrome (51.4% vs 25.7%; P = .047).
Even though many of the detected mutations were in genes that have already been linked to CRC risk, the authors point out that 18.1% of patients had mutations in genes that are not generally associated with CRC.
Testing Family Members Important
Hampel also pointed out that most patients do have access to multigene testing. "There are multiple laboratories providing this type of genetic testing and the cost has decreased significantly over the past few years so it is much more accessible," she said. "Most insurers will cover genetic testing for individuals with early-onset CRC, and most of the laboratories even have financial hardship programs that cover the costs of testing completely for uninsured or underinsured patients who meet certain criteria."
If a patient is positive for pathogenic mutations, it is essential that family members be tested as well.
"Cascade testing is when we follow the mutation through the family, testing at-risk relatives like siblings, children, parents, aunts/uncles, and cousins who are over age 18," Hampel explained. "It is a critical component of the study, so we are actively trying to provide genetic counseling and testing to as many relatives as possible."
Many of them have not developed cancer yet, so this testing can save their lives by identifying who is at increased risk and needs intensive cancer surveillance and prevention options," she added.
Proceed With Caution
In an accompanying editorial, Eduardo Vilar, MD, PhD, from the University of Texas MD Anderson Cancer Center in Houston, and Elena M. Stoffel, MD, from the University of Michigan, Ann Arbor, reiterate that the current findings show the benefit of incorporating multigene panel genetic testing.
Use of such a panel will "increase the diagnosis of individuals with genetic predisposition to cancer and will expand current knowledge regarding the associated phenotypes, further supporting the cost-effectiveness of testing that can guide management for patients with cancer and their at-risk relatives," they write.
However, they caution that important questions remain. For example, variants of uncertain significance are common and are identified in nearly 1 in 3 of these patients, thus leaving both patients and healthcare professionals with "uncertain" results.
Another question concerns the actual risk associated with the genes. "What is the relative (and absolute) increase in CRC risk associated with mutations in the 'other' cancer genes not previously associated with CRC, and how should this information influence recommendations for colonic and extracolonic screening and surveillance?" the editorialists ask.
Because most younger patients with CRC lacked a pathogenic mutation in any of the 25 cancer genes on the panel, this raises the issue of other novel cancer genes, or combinations of genes, or gene-environment interactions that might explain the increase in incidence of CRC in those under the age of 50 years, they note.
"We are entering a 'brave new world' of research aimed at clarifying the functional significance of germline variants in high- and moderate-risk genes and how these interact with exposures and lifestyle factors," Dr Vilar and Dr Stoffel conclude.