In the Journals

Young-onset colon cancers often genetic despite no family history

Elena M. Stoffel, MD, MPH
Elena M. Stoffel

One in five patients diagnosed with colorectal cancer younger than age 50 showed an inherited genetic predisposition to the disease, yet more than half of these patients lacked a clinical or family history that would typically indicate the need for genetic testing, according to new research.

“Usually when someone is diagnosed with cancer, if there’s no family history of cancer we think the likelihood of an inherited factor is small,” Elena M. Stoffel, MD, MPH, assistant professor of internal medicine at the University of Michigan Medical School and director of the Cancer Genetics Clinic at the University of Michigan Comprehensive Cancer Center, said in a press release. “But our study suggests that even in the absence of a family history of cancer, the prevalence of inherited factors is so high in young colorectal cancer patients that it makes sense to test everyone, as these heritable alterations can impact their care as well as the care of their family members.”

To determine the proportion of young CRCs that have a genetic link, Stoffel and colleagues reviewed data on 430 patients diagnosed with CRC younger than age 50 at the University of Michigan Comprehensive Cancer Center between 1998 and 2015. Overall, 26% had a first-degree relative with CRC, and 10% had tumors with histologic evidence of mismatch repair deficiency.

Further, 73% of the patients underwent clinical germline sequencing, and a quarter of them (18% of total cohort) showed mutations linked to a hereditary cancer syndrome, while 6.7% showed variants of uncertain significance.

Thirteen percent of the entire cohort and 71% of all germline mutations were in DNA mismatch repair genes associated with Lynch syndrome, and 2.3% of the entire cohort and 13% of all germline mutations were in the APC tumor suppressor gene associated with familial adenomatous polyposis.

Thirteen additional patients showed mutations in other cancer-associated genes, most of which were in MUTYH (1.9% of total cohort, 10% of all germline mutations), followed by SMAD4, BRCA1, TP53, and CHEK2.

Additionally, 117 patients who had “negative” clinical genetic evaluations underwent next-generation targeted sequencing using multigene panels, of which 5% showed likely germline variants associated with hereditary cancer syndromes.

Finally, of the 85 total patients who showed germline mutations associated with a hereditary cancer syndrome, only 51% reported a CRC diagnosis in a first-degree relative.

Barriers to genetic testing

According to Stoffel, these results highlight the limitations of algorithms used to identify individuals who should undergo genetic testing.

“I think what we’re finding is the people we used to test in the past were probably the tip of the iceberg,” she said in the press release. “And that there are many other people who may not meet those strict criteria, who are actually at high risk.”

She added that an additional barrier is the strict criteria insurance companies have regarding who qualifies for genetic testing, which often require multiple relatives over two generations who were diagnosed with CRC.

“Requiring those criteria in young people means that you’re going to miss people,” she said in the press release. “Missing inherited alterations in young people arguably has a larger impact because of the opportunity to prevent cancers in their at-risk relatives.”

She said another problem is that new multigene panel testing technology, though more effective for genetic screening, is costlier and often not covered by insurers, costing patients between $300 and $2,000 out-of-pocket.

“We’re caught in that time frame between where the technology has advanced to the certain point where our tests are now better than they used to be,” she said in the press release. “The insurers are not covering the new technology because they consider it experimental.”

Additional research is required to satisfy payers that the new screening methods are superior, and to show their effects on morbidity and mortality, she added.

“I think whenever we see a patient with colorectal cancer we should be asking why did this person develop cancer,” she said in the press release. “We know that in most cases it’s just plain bad luck, but we always need to look at a patient’s family history, and in young people, consideration of the possibility of an inherited condition should always be there even if there is no family history of cancer. With early intervention, we can prevent future cancers in these patients as well as cancers in their relatives.” – by Adam Leitenberger

Disclosures: The authors report no relevant financial disclosures.

Elena M. Stoffel, MD, MPH
Elena M. Stoffel

One in five patients diagnosed with colorectal cancer younger than age 50 showed an inherited genetic predisposition to the disease, yet more than half of these patients lacked a clinical or family history that would typically indicate the need for genetic testing, according to new research.

“Usually when someone is diagnosed with cancer, if there’s no family history of cancer we think the likelihood of an inherited factor is small,” Elena M. Stoffel, MD, MPH, assistant professor of internal medicine at the University of Michigan Medical School and director of the Cancer Genetics Clinic at the University of Michigan Comprehensive Cancer Center, said in a press release. “But our study suggests that even in the absence of a family history of cancer, the prevalence of inherited factors is so high in young colorectal cancer patients that it makes sense to test everyone, as these heritable alterations can impact their care as well as the care of their family members.”

To determine the proportion of young CRCs that have a genetic link, Stoffel and colleagues reviewed data on 430 patients diagnosed with CRC younger than age 50 at the University of Michigan Comprehensive Cancer Center between 1998 and 2015. Overall, 26% had a first-degree relative with CRC, and 10% had tumors with histologic evidence of mismatch repair deficiency.

Further, 73% of the patients underwent clinical germline sequencing, and a quarter of them (18% of total cohort) showed mutations linked to a hereditary cancer syndrome, while 6.7% showed variants of uncertain significance.

Thirteen percent of the entire cohort and 71% of all germline mutations were in DNA mismatch repair genes associated with Lynch syndrome, and 2.3% of the entire cohort and 13% of all germline mutations were in the APC tumor suppressor gene associated with familial adenomatous polyposis.

Thirteen additional patients showed mutations in other cancer-associated genes, most of which were in MUTYH (1.9% of total cohort, 10% of all germline mutations), followed by SMAD4, BRCA1, TP53, and CHEK2.

Additionally, 117 patients who had “negative” clinical genetic evaluations underwent next-generation targeted sequencing using multigene panels, of which 5% showed likely germline variants associated with hereditary cancer syndromes.

Finally, of the 85 total patients who showed germline mutations associated with a hereditary cancer syndrome, only 51% reported a CRC diagnosis in a first-degree relative.

Barriers to genetic testing

According to Stoffel, these results highlight the limitations of algorithms used to identify individuals who should undergo genetic testing.

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“I think what we’re finding is the people we used to test in the past were probably the tip of the iceberg,” she said in the press release. “And that there are many other people who may not meet those strict criteria, who are actually at high risk.”

She added that an additional barrier is the strict criteria insurance companies have regarding who qualifies for genetic testing, which often require multiple relatives over two generations who were diagnosed with CRC.

“Requiring those criteria in young people means that you’re going to miss people,” she said in the press release. “Missing inherited alterations in young people arguably has a larger impact because of the opportunity to prevent cancers in their at-risk relatives.”

She said another problem is that new multigene panel testing technology, though more effective for genetic screening, is costlier and often not covered by insurers, costing patients between $300 and $2,000 out-of-pocket.

“We’re caught in that time frame between where the technology has advanced to the certain point where our tests are now better than they used to be,” she said in the press release. “The insurers are not covering the new technology because they consider it experimental.”

Additional research is required to satisfy payers that the new screening methods are superior, and to show their effects on morbidity and mortality, she added.

“I think whenever we see a patient with colorectal cancer we should be asking why did this person develop cancer,” she said in the press release. “We know that in most cases it’s just plain bad luck, but we always need to look at a patient’s family history, and in young people, consideration of the possibility of an inherited condition should always be there even if there is no family history of cancer. With early intervention, we can prevent future cancers in these patients as well as cancers in their relatives.” – by Adam Leitenberger

Disclosures: The authors report no relevant financial disclosures.