Incidental findings in genomics

Vienna, Austria: While the cost of the genome and exome¹ sequencing falls, its use to characterize rare diseases and personalize the treatment of cancer, for example, is increasingly common. But such analyzes may yield results unrelated to the condition for which they were requested. What to do with these secondary findings (SF) or incidental findings (IF) is problematic. Should they be reported to the patient and under what circumstances? How should clinical geneticists deal with the possibly unnecessary worry they may cause?

At the annual conference of the European Society of Human Genetics today (Saturday), Ms Estela Carrasco, MSc, PhD student and genetic counselor at Vall d’Hebron Hospital, Barcelona, ​​Spain, will describe how she and her colleagues set out to investigate the prevalence of SF/IFs in cancer susceptibility genes (CSGs) in patients who underwent exome sequencing for rare non-cancer diseases, and to identify CSGs with potential clinical actionability that were unrelated to the purpose of the primary analysis. They then assessed the psychological impact of disclosing SF/IF to patients and their relatives compared to a cohort who underwent testing because of their family history of cancer. They analyzed the exomes of 533 patients who were screened for non-cancer indications and followed up by examining the psychological impact of disclosing SF/IF to these patients two to six months after the results were delivered.

“We found pathogenic (potentially pathogenic) SF/IF variants in CSGs in 2% of patients who had undergone exome testing for reasons unrelated to cancer predisposition,” says Ms. Carrasco. “This allowed us to perform predictive tests on 42 relatives, 18 of whom wore CSGs.”

The psychological impact was higher in those where the variant was identified as an incidental finding, but this must be weighed against the benefit of early detection and preventive strategies that could be introduced in families who had no no previous cancer diagnosis, researchers say. “While a 2% rate of SF/FI may not seem like a lot, it is remarkable. And genetic counseling can help both communicate results and help patients and their families cope. to the newly discovered genetic disease,” says Ms. Carrasco.

Researchers intend to continue investigating new ways to provide genetic test results to patients; for example, the impact of separating the timing of primary findings from secondary findings. “We believe that being able to demonstrate the clinical actionability of secondary outcomes is reassuring for patients.”

Of the 29 carriers identified (11 index cases and 18 related), 20 registered for further surveillance. Researchers were able to identify three paragangliomas (a type of neuroendocrine tumor) and early breast cancer in a 74-year-old woman with a BRCA2 variant who had completed population-based breast cancer screening. A BRCA2 relative with metastatic prostate cancer received targeted therapy after his BRCA2 status was revealed.

Particular problems arise, however, in the case of children. “The principle of a child’s autonomy can be lost if disclosure is made before an appropriate age. Health professionals should therefore be cautious when an exome sequencing analysis is requested in minors,” explains Ms. Carrasco. “On the other hand, the disclosure of these results could generate an indirect benefit for these children because it could allow their relatives to join early detection and prevention programs, thus preserving their health. To achieve this, it is important to report only clinically exploitable genes.

“It is important to provide adequate counseling to people undergoing exome sequencing, or in the case of children to their parents or guardians, to ensure that all potential medical applications of genetic testing are understood. And , professionally, in cases where exome sequencing is requested by clinicians with little training in disseminating SF/IF information, genetic counselors and clinical geneticists should be part of the team multidisciplinary care.

Professor Alexandre Reymond, chair of the conference, said: “Unlike radiologists, whose incidental findings mean there is a tumour, geneticists’ incidental findings are often predictive in nature. While this should not prevent us from acting on an actionable discovery, it requires dedicated and specifically trained staff to ensure that all information provided to patients and their families is clear, understandable and understood.