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Comprehensive Genetic Testing in Patients With Multiple Tumors Detects Additional Risk Variants

NEW YORK (GenomeWeb) – Comprehensive analysis of cancer-predisposing genes can uncover deleterious germline variants in patients with multiple primary tumors, even if they have already undergone narrower molecular testing.

In a new study that appeared in the American Journal of Human Genetics yesterday, researchers from the University of Cambridge and elsewhere sequenced the genomes of 460 individuals with multiple primary tumors (MPTs), a sign that they may have a genetic susceptibility to cancer. In their analysis, the researchers found that even though previous molecular investigations were not able to link a variant to the patients' condition, they were able to identify pathogenic variants in cancer-predisposing genes (CPGs) in about 15 percent of cases. These variants were often in genes associated with the type of tumor the patients had, though in some cases they were not.

"[T]he application of comprehensive CPG testing to a cohort of previously investigated MPT-affected individuals resulted in the detection of multiple pathogenic variants with relevance to the management of those individuals and their relatives," Cambridge's Eamonn Maher, the senior author of the study, and his colleagues wrote.

The researchers sequenced the genomes of 460 individuals from 440 families who were suspected to have a cancer-predisposition syndrome but had no genetic diagnosis. Of these individuals, 435 had developed MPTs and the other 25 had a single primary tumor but a family history of MPTs. The research participants were recruited largely from clinical genetics services in the UK, but also from Greece, Hong Kong, Israel, the US, and Ireland. The most common tumor type among them was breast cancer, followed by colorectal cancer.

Blood samples from all participants were used for whole-genome sequencing on the Illumina HiSeq 2500 and 411 samples were also analyzed using Illumina's TruSight cancer panel.

The researchers uncovered 63 variants in 17 genes in 61 individuals through their single nucleotide variant and indel analysis, while their structural variant analysis using the panel test uncovered six potentially pathogenic variants. When combined, they found a pathogenic or likely pathogenic variant in 67 probands, or 15.2 percent of their cohort.

Thirty-eight of those individuals had previously been diagnosed with a tumor that is typically associated with their cancer risk gene and another eight had a related variant of uncertain significance, the researchers noted. This indicated to them that their results could have clinical utility for patients and their family members.

Others, though, had a pathogenic or likely pathogenic variant in a cancer predisposition gene but an atypical tumor phenotype. This could be a challenge for clinicians to interpret, the researchers noted, as the relevance of the variant to cancer risk is not as clear. It could be, they added, that the tumor phenotype associated with that variant is broader than currently thought or that the tumor and variant are coincidental.

Previously, Maher and his colleagues found that 20.7 percent of MPT individuals referred to a clinical genetic testing service were given a molecular diagnosis upon routine genetic testing. Combining that data and their new findings, they estimated that comprehensive genetic testing would detect a pathogenic or likely pathogenic variant in about a third of the individuals referred.

Based on this, they suggested that patients with multiple primary tumors who are referred to a genetics clinic should be considered for whole-genome sequencing as a first-line test, adding that a large proportion of them "would not have a family history of cancer in a first-degree relative."