Thesis

Paired tumor and germline molecular profiling: germline findings and their clinical impact

Targeted next-generation DNA sequencing of paired tumor and germline DNA samples allows for detection of treatment-relevant variants in tumors with greater accuracy than tumor-only sequencing. In addition, this approach allows for the identification of cancer predisposition pathogenic variants in a patient’s germline DNA. A records review was used to determine the rate of positive germline findings, and their clinical follow-up, in 600 consecutive pediatric and adult patients who underwent paired molecular profiling using the UCSF500 assay. The assay sequences the coding regions of ~500 targeted cancer-related genes. One hundred positive germline findings were flagged in 90 of 600 patients (15%). There were 38 types of positive findings, with sequence changes in MUTYH (n = 15), CHEK2 (n = 11), BRCA2 (n = 10), BRCA1 (n = 5), and TP53 (n = 5) occurring most frequently. In 67 (74%) of the cases, positive germline findings were previously unknown and genetic counseling was recommended. Of the 41 patients who have been seen by a genetic counselor at UCSF, 34 (83%) had their findings interpreted as autosomal dominant clinically actionable cancer risk variants. Patient family members in 10 of these cases had germline testing for the autosomal dominant findings; 8 individuals were found to have the familial risk variant and 13 had true negative results. The data reveals that paired tumor and germline DNA analysis uncovers actionable heritable traits in a significant fraction of cancer patients and represents the preferred approach to analyzing malignancies in children and adults.

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