Germline Analysis Increases Identification Of Clinically Actionable Cancer Susceptibility Mutations

A universal approach to genetic analysis may detect a greater number of clinically significant heritable mutations than screening based on current clinical guidelines

medwireNews: US research suggests that almost one in five patients with advanced cancer carry a clinically actionable cancer susceptibility mutation, but that one in 10 of these aberrations would go undetected under current clinical guidelines.

“Knowledge of these additional mutations can help guide therapeutic and preventive interventions, but whether all of these interventions would improve outcomes for patients with cancer or their family members requires further study”, say Kenneth Offit, from the Memorial Sloan Kettering Cancer Center in New York, and co-workers.

Tumour and germline sequencing using a 410-gene panel, including 76 hereditary cancer genes, was conducted on 1040 patients with advanced solid tumours who attended the Memorial Sloan Kettering Cancer Center between 2014 and 2016.

Overall, 19.7% of patients had pathogenic gene variants associated with an increased risk of cancer detected by germline analysis. And 182 of these 205 patients had clinically actionable mutations with high (n=97), moderate (n=52) or low (n=33) penetrance, most commonly BRCA1, BRCA2, PALB2, MSH2, ATM, CHEK2 and APC.

The rate of mutations varied from 56.3% of 16 patients with bladder cancer to 25.0% of 176 patients with pancreatic cancer to 19.6% of 362 prostate cancer patients, 16.4% of 140 renal cancer patients and 9.2% of 65 colon cancer patients.

But 101 (9.7%) of the study population had mutations that would not have been detected under current clinical guidelines, including 65 of those with moderate-to-high penetrance mutations, the researchers report in JAMA.

On the basis of the germline mutation results, 38 (3.7%) patients discussed or initiated a change in treatment to targeted therapy, a PARP inhibitor or platinum-based chemotherapy. And the families of 13 (1.3%) patients underwent genetic testing for cancer susceptibility genes, including relatives of six patients who would not have been recommended for testing under current guidelines.

Writing in a linked editorial, Eliezer Van Allen, from the Dana-Farber Cancer Institute in Boston, Massachusetts, USA, explains that the study authors now propose patients should be screened using a universal panel consisting of phenotype-recommended genes, DNA repair genes and selected founder mutations in APC and MUTYH.

While this strategy could capture more than 90% of germline events, he acknowledges that the current study’s population was significantly enriched for ancestral background and cancer type and may not be generalisable to widespread use.

“[T]he clinical utility of gene-panel germline analysis in expanded and heterogeneous clinical settings should be tested in prospective clinical studies to determine the relative effects of these tests compared with standard-of-care guideline-driven clinical genetics on patient outcomes”, the editorialist recommends.

“Overall, this approach is likely to have major implications for integration of the germline genome in prospective molecular testing and to provide a pathway for comprehensive precision cancer medicine.”

References

Mandelker D, Zhang L, Kemel Y, et al. Mutation detection in patients with advanced cancer by universal sequencing of cancer-related genes in tumor and normal DNA vs guideline-based germline testing. JAMA; 318: 825–835, Advance online publication 5 September 2017. doi:10.1001/jama.2017.11137

Van Allen EM. The potential and challenges of expanded germline testing in clinical oncology. JAMA; 318: 801–803, Advance online publication 5 September 2017. doi:10.1001/jama.2017.11022

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