September 18, 2018
3 min read

Low-cost genetic test spurs ‘cascade testing’ among relatives

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Nearly half of people closely related to carriers of cancer-associated genes accepted invitations to undergo low-cost genetic testing to assess their own risk, according a retrospective study of an online initiative.

“Testing those diagnosed with a disease is the most efficient way to identify carriers of predisposing germline genetic variants and is consistent with clinical practice guidelines,” Jennifer Caswell-Jin, MD, instructor of medicine at Stanford University School of Medicine, and colleagues wrote. “To achieve the goal of genetically targeted primary disease prevention, testing for an identified familial pathogenic variant must then extend to disease-free relatives in a process known as ‘cascade testing.’”

Researchers analyzed results from an online initiative that offered genetic testing for $50 to carriers of one of 30 cancer-associated genes and their first-degree relatives (ie, mother, father, children or siblings).

An informational email invited relatives. All participants spoke with a genetic counselor by telephone to obtain their test results.

In the first year of the program, 1,101 initiative applicants — including 741 carriers and 360 of their first-degree relatives — invited 2,280 first-degree relatives to undergo genetic testing. Applicants were more often women (78.1% of carriers, 63.9% of first-degree relatives; P < .001).

Median follow-up was 216 days.

Overall, 47.5% (95% CI, 45.5-49.6) of invited relatives underwent testing.

“One unique thing about this study is that it isn't focused on any single gene,” Caswell-Jin said in a press release. “These participants were carriers of mutations in any of 30 different genes, some of which are very strongly associated with the development of specific cancers. Because about half of a patient’s first-degree relatives are also likely carriers of the same mutation, cascade testing has significant public health implications for early cancer detection and even prevention.”

Invited female relatives appeared more likely than male relatives to undergo testing (52.6% vs. 42%; P < .001).

Among the first-degree relatives who underwent testing, 48.1% (95% CI, 45.2-50.8) carried the known familial pathogenic variant.

Researchers did not observe significant differences in rates of testing between participants invited because of well-characterized genes — including BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2, CDH1, CDKN2A, STK11 or TP53 — and participants invited because of less well-characterized genes (48.1% vs. 45.9%).

Among the tested relatives found to have the same mutation as the known carrier, 12% (95% CI, 9.2-14.8) invited additional relatives to undergo testing.

“Although this was potentially lower than we might have expected, in many cases it was due to the fact that there were no more first-degree relatives in the family to test,” Caswell-Jin said.


Among tested relatives, 4.9% (95% CI, 3.8-6.1) carried a different pathogenic variant than the known carrier.

Additionally, 16.8% (95% CI, 14.7-18.8) of relatives had a variant of uncertain significance.

“These pathogenic mutations were totally unexpected and suggest that this may reflect the prevalence in the general population of known cancer-associated mutations,” Allison Kurian, MD, associate professor of medicine and of health research and policy at Stanford University School of Medicine, said in the release. “It addresses a long-standing question in the field about what we might find if we routinely tested everyone.”

Implementing cascade testing for cancer-associated genes remains difficult. The tests are often expensive and not covered by insurance. Due to privacy, clinicians are not able to directly contact a patient’s relatives, leaving the burden on the newly diagnosed patient.

Allowing the laboratory to contact a patient’s relatives through information provided by the patients and offering genetic testing at a lower cost appeared to increase the feasibility of cascade testing.

“We’ve found that this approach has been remarkably successful in overcoming traditional barriers to reaching and testing a patient’s relatives,” Kurian said in the release. “The results have been very striking, as traditional approaches to cascade testing result in only about 30% of relatives undergoing testing.”

The limitations of the study included selection bias and missing information.

“We are very engaged in learning how to most effectively implement genetic testing, particularly in a broad population,” Kurian said. “We are eager to pursue this finding further and to understand how we can improve on this new model of cascade testing.”

The researchers cited extending affordable testing and clinician-aided decision making as future directions for research.

“This is such an exciting era,” Caswell-Jin said. “We expect the proportion of people undergoing genetic testing for disease-associated mutations will continue to increase. We need to make sure they get the support they need to understand their results, and to encourage additional support and follow-up.” – by Cassie Homer

Disclosures: Color Genomics and the BRCA Foundation funded the study. Caswell-Jin reports no relevant financial disclosures. Kurian reports institutional research funding from Myriad Genetics. Please see the study for all other authors’ relevant financial disclosures.