Somatic variants in hereditary cancer (hCa) risk genes are frequently identified in tumors and represent an opportunity to diagnose hCa. We implemented a universal hCa somatic screening program in a large HMO to identify patients with hCa and determine if this approach augmented existing genetic counseling approaches. An automated “somatic safety net” process offered germline testing (gDNAt) to patients with advanced cancer harboring somatic variants in ATM, BRCA1, BRCA2, MLH1, MSH2, MSH6, PALB2, and/or PMS2 who had not previously undergone gDNAt. Patients previously completing gDNAt via “traditional genetic counseling” and “somatic safety net” were compared for demographics, tumor type, presence of germline pathogenic/likely pathogenic (gP/LP) variant, and whether NCCN criteria were met for hCa genetic testing. A total of 584 unique somatic variants were identified in the gene list of interest (ATM, BRCA1, BRCA2, MLH1, MSH1, MSH6, PALB2 and PMS2) from 503 unique tumor samples/patients during the study period. 111 patients had previously undergone gDNAt prior to completing their somatic tumor DNA test and were considered part of the “traditional genetic counseling” group (where a patient was referred for genetic counseling and gDNAt due to personal/family history criteria and/or cascade testing). Among the 392 patients who had not undergone gDNAt at the time of their somatic tumor testing: 1) 52.6% (206/392) patients never completed gDNAt (they were deceased, declined gDNAt or could not be contacted), 2) 14.0% (55/392) patients completed gDNAt concurrently/after their somatic tumor test for a personal/family history indication unrelated to the somatic tumor testing results (this group also comprised part of the “traditional genetic counseling” group), and 3) 131/392 (33.4%) patients completed gDNAt specifically due to their somatic result or “somatic safety net” searches of the somatic tumor database resulting in direct outreach by the genetics department and gDNAt. In the “traditional genetic counseling” group that completed gDNAt, 54% (89/166) of patients harbored a pathogenic or likely pathogenic (P/LP) germline variant in at least one of the genes of interest, while 46% (77/166) had a germline test that was negative/normal or contained one or more variants of uncertain clinical significance (negative/VUS). In the “somatic safety net” group that completed gDNAt, 29% (38/131) of patients had at least one germline P/LP variant, while 71% (93/131) of patients had a normal/VUS result on gDNAt. Among patients with a germline P/LP variant, significantly more patients met criteria under NCCN breast/colon guidelines for gDNAt in the “traditional genetic counseling” group (99%; 88/89) compared to the “somatic safety net” group (34%; 13/38) with p < 0.001 (Fisher’s exact test). For all patients who completed gDNAt, we also determined the percentage of P/LP somatic variants that were germline for each of the 8 genes. For genes where at least 20 somatic variants were identified in the tumor data set (ATM, BRCA1/2, MSH2, MSH6) between 20-50% of these somatic variants were also germline. Genes with fewer than 10 somatic variants identified (MLH1, PALB2, PMS2) had more variable frequencies of being germline (likely due to low n value for each of these genes), but collectively they had a similar percentage of being germline when combined as a single group (40%). Across all genes, 36% (127/357) of the P/LP somatic variants identified were present in the patient’s germline. We also determined the primary tumor type for all patients who underwent gDNAt and the likelihood for a germline variant to be present in different primary tumors with a somatic variant. Collectively, 43% (127/297) of all tumors with a somatic variant in the gene list of interest also harbored a germline variant. The most frequent primary tumors containing a somatic variant (in decreasing order) were breast, pancreatic, ovarian, colorectal, lung, and prostate. Other tumor types (eg, melanoma, bladder, hepatobiliary, sarcoma) represented a smaller proportion of the overall tumor group, but these tumors contained a collectively similar frequency of germline variants to more common tumors analyzed. Patients who received gDNAt through the “traditional genetic counseling” were more likely to have cardinal hereditary tumors than the “somatic safety net” group. A universal “somatic safety net” screen is a successful strategy to diagnose hCa and augments traditional strategies based on personal/family history. We argue that this approach should be more widely applied and will complement existing universal tumor screening strategies such as MMR-immunohistochemistry for HNPCC.
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Oct 15, 2024
J F M Middeldorp + 4
Open Access