Purpose:The aim of this study was to determine the clinical and molecular characteristics of 2,079 patients who underwent hereditary cancer multigene panel testing.Methods:Panels included comprehensive analysis of 14–22 cancer susceptibility genes (BRCA1 and BRCA2 not included), depending on the panel ordered (BreastNext, OvaNext, ColoNext, or CancerNext). Next-generation sequencing and deletion/duplication analyses were performed for all genes except EPCAM (deletion/duplication analysis only). Clinical histories of ColoNext patients harboring mutations in genes with well-established diagnostic criteria were assessed to determine whether diagnostic/testing criteria were met.Results:Positive rates were defined as the proportion of patients with a pathogenic mutation/likely pathogenic variant(s) and were as follows: 7.4% for BreastNext, 7.2% for OvaNext, 9.2% for ColoNext, and 9.6% for CancerNext. Inconclusive results were found in 19.8% of BreastNext, 25.6% of OvaNext, 15.1% of ColoNext, and 23.5% of CancerNext tests. Based on information submitted by clinicians, 30% of ColoNext patients with mutations in genes with well-established diagnostic criteria did not meet corresponding criteria.Conclusion:Our data point to an important role for targeted multigene panels in diagnosing hereditary cancer predisposition, particularly for patients with clinical histories spanning several possible diagnoses and for patients with suspicious clinical histories not meeting diagnostic criteria for a specific hereditary cancer syndrome.

PurposeBlood/saliva DNA is thought to represent the germline in genetic cancer risk assessment. Cases with pathogenic TP53 variants detected by multi-gene panel tests (MGPT) are often discordant with Li-Fraumeni Syndrome (LFS), raising concern about misinterpretation of acquired aberrant clonal expansions (ACE) with TP53 variants as germline results.MethodsPathogenic TP53 variants with abnormal next-generation sequencing (NGS) metrics (e.g., decreased ratio [<25%] of mutant to wild-type allele, >2 detected alleles) were selected from a CLIA laboratory testing cohort. Alternate tissues and/or close relatives were tested to discern between ACE and germline status. Clinical data and LFS testing criteria were examined.ResultsAmong 114,630 MGPT and 1,454 TP53 gene-specific analyses, abnormal NGS metrics were observed in 20% of 353 TP53 positive results, and ACE was confirmed for 91% of cases with ancillary materials, most due to clonal hematopoiesis. Only four met Chompret criteria. ACE cases were older (50 years vs 33.7; P = 0.02) and were more frequent among MGPT (66/285; 23.2%) vs TP53 gene-specific tests (6/68; 8.8%, P = 0.005).ConclusionACE confounds germline diagnosis, may portend hematologic malignancy, and may result in unwarranted clinical interventions. Ancillary testing to confirm germline status should precede Li-Fraumeni syndrome management.

BackgroundThe clinical phenotype of CDH1 pathogenic variant carriers has mostly been studied in families that fulfil criteria of hereditary diffuse gastric cancer (HDGC). We aimed at determining cancer phenotype and cancer risk estimation among families with CDH1 pathogenic variants not selected by HDGC clinical criteria.MethodsPatients were all consecutively identified CDH1 pathogenic variant carriers from a clinical laboratory tested with multigene panel testing and from an academic cancer genetics programme. Clinical and demographic features, cancer phenotypes and genotype–phenotype correlations were determined among CDH1 families. Age-specific cumulative cancer risks (penetrance) were calculated based on 38 families with available pedigrees.ResultsWithin the 113 CDH1 pathogenic variant probands and 476 relatives, 113 had gastric cancer, 177 breast cancer and 196 other cancers. Mean age at diagnosis was 47 for gastric and 54 for breast cancer. Forty-six per cent fulfilled criteria of HDGC. While 36% of families had both gastric and breast cancers, 36% had breast but no gastric cancers and 16% had gastric but not breast cancers. Cumulative risk of cancer by age 80 was 37.2% for gastric and 42.9% for breast cancer.ConclusionIn unselected CDH1 pathogenic variant carrier families, gastric cancer risks were lower and age at diagnosis higher than previously reported in families pre-selected for HDGC criteria. A substantial proportion of families did not present with any gastric cancers and their cancers were limited to breast. Thus, clinical criteria for CDH1 testing should be widened, including breast cancer families only, and a consideration for delayed prophylactic gastrectomy/surveillance should be evaluated.

These findings support the significant prevalence of PGVs associated with PDAC and the limitations of current paradigms for selecting patients for genetic testing, and they thereby lend support for universal germline multigene genetic testing in this population.

MGPT TP53+ individuals differ in phenotype from those ascertained through SGT and are notably older at cancer diagnosis and less likely to meet LFS clinical criteria. These findings suggest that LFS may have a greater phenotypic spectrum than previously appreciated. This has implications for the counseling of MGPT TP53+ individuals. Prospective follow-up of these individuals and families is needed to re-evaluate cancer risks.