Clinician-Reported Impact of Germline Multigene Panel Testing on Cancer Risk Management Recommendations.

Background: With increased adoption of multi-gene panel testing (MGPT) for hereditary cancer, management guidelines now include a wider range of predisposition genes. Yet little is known about whether MGPT results prompt changes to clinicians' risk management recommendations and whether those recommendations adhere to guidelines.

Methods: We assessed cancer risk management recommendations made by clinicians ordering MGPT for hereditary cancer at a diagnostic laboratory using an internet-based survey.

Paired-like homeobox gene (PHOX2B) nonpolyalanine repeat expansion mutations (NPARMs): genotype-phenotype correlation in congenital central hypoventilation syndrome (CCHS).

Purpose: CCHS is an extremely rare congenital disorder requiring artificial ventilation as life support. Typically caused by heterozygous polyalanine repeat expansion mutations (PARMs) in the PHOX2B gene, identification of a relationship between PARM length and phenotype severity has enabled anticipatory management. However, for patients with non-PARMs in PHOX2B (NPARMs, ~10% of CCHS patients), a genotype-phenotype correlation has not been established.

Paired tumor sequencing and germline testing in breast cancer management: An experience of a single academic center.

Background: Genetic testing for cancer predisposition is recommended to women with breast cancer who meet the criteria for such testing. After the FDA approvals of the poly ADP ribose polymerase (PARP) inhibitors, olaparib and talazoparib, for treatment of metastatic breast cancer, carrying germline mutations in BRCA1 and BRCA2 genes, the genetic testing result has become critical in their care. With the recent FDA approval of alpelisib for the treatment of PIK3CA-mutated hormone-receptor positive metastatic breast cancer, tumor molecular profiling to identify somatic mutations and potential molecularly targeted agents is increasingly utilized in the treatment of advanced breast cancer.

Prevalence of pathogenic variants in DNA damage response and repair genes in patients undergoing cancer risk assessment and reporting a personal history of early-onset renal cancer.

Pathogenic variants (PVs) in multiple genes are known to increase the risk of early-onset renal cancer (eoRC). However, many eoRC patients lack PVs in RC-specific genes; thus, their genetic risk remains undefined. Here, we determine if PVs in DNA damage response and repair (DDRR) genes are enriched in eoRC patients undergoing cancer risk assessment.

Estimating the relative frequency of leukodystrophies and recommendations for carrier screening in the era of next-generation sequencing.

Leukodystrophies are a heterogeneous group of heritable disorders characterized by abnormal brain white matter signal on magnetic resonance imaging (MRI) and primary involvement of the cellular components of myelin. Previous estimates suggest the incidence of leukodystrophies as a whole to be 1 in 7,000 individuals, however the frequency of specific diagnoses relative to others has not been described. Next generation sequencing approaches offer the opportunity to redefine our understanding of the relative frequency of different leukodystrophies.

Clinical features and cancer risk in families with pathogenic variants irrespective of clinical criteria.

Background: The clinical phenotype of 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 pathogenic variants not selected by HDGC clinical criteria.

Methods: Patients were all consecutively identified pathogenic variant carriers from a clinical laboratory tested with multigene panel testing and from an academic cancer genetics programme.

Genotype-phenotype associations among panel-based TP53+ subjects.

Purpose: Panel testing has led to the identification of TP53 pathogenic/likely pathogenic (P/LP) variant carriers (TP53+) who exhibit a broad range of phenotypes. We sought to evaluate and compare genotype-phenotype associations among TP53+ panel-ascertained subjects.

Methods: Between 2012 and 2017, 317 TP53+ subjects (279 females and 38 males) identified through panel testing at one testing laboratory were found to have evaluable clinical histories and molecular results.

Family communication and patient distress after germline genetic testing in individuals with pancreatic ductal adenocarcinoma.

Background: Germline genetic testing currently is recommended for patients with pancreatic ductal adenocarcinoma (PDAC). In the current study, the authors assessed how often results are communicated to first-degree relatives within 3 months and the emotional impact of testing on patients.

Methods: A total of 148 patients who were newly diagnosed with PDAC and who had undergone testing of 32 cancer susceptibility genes at 3 academic centers were selected; 71% participated.

Prevalence of germline variants in inflammatory breast cancer.

Background: Inflammatory breast cancer (IBC) is an uncommon and aggressive subtype of breast cancer associated with early disease recurrence and short survival. The prevalence of germline variants in cancer predisposition genes has not been systematically evaluated in women with IBC.

Methods: Among 301 women enrolled in the clinical IBC registry at a single institution between 2010 and 2017, 168 had documented genetic testing.

Prospective study of germline genetic testing in incident cases of pancreatic adenocarcinoma.

Background: The objective of this study was to investigate the prevalence of pathogenic germline variants (PGVs) in 32 cancer susceptibility genes in individuals with newly diagnosed pancreatic ductal adenocarcinoma (PDAC). A key secondary objective was to evaluate how often PGVs would have been undetected with existing genetic testing criteria.

Methods: From May 2016 through May 2017, this multicenter cohort study enrolled consecutive patients aged 18 to 89 years with histologically confirmed PDAC diagnosed within the previous 12 weeks.

Exome sequencing in neonates: diagnostic rates, characteristics, and time to diagnosis.

Purpose: Neonatal patients are particularly appropriate for utilization of diagnostic exome sequencing (DES), as many Mendelian diseases are known to present in this period of life but often with complex, heterogeneous features. We attempted to determine the diagnostic rates and features of neonatal patients undergoing DES.

Methods: The clinical histories and results of 66 neonatal patients undergoing DES were retrospectively reviewed.

Somatic TP53 variants frequently confound germ-line testing results.

Purpose: Blood/saliva DNA is thought to represent the germ line in genetic cancer-risk assessment. Cases with pathogenic TP53 variants detected by multigene panel testing are often discordant with Li-Fraumeni syndrome, raising concern about misinterpretation of acquired aberrant clonal expansions (ACEs) with TP53 variants as germ-line results.

Methods: Pathogenic TP53 variants with abnormal next-generation sequencing metrics (e.

Unexpected Mutations Identified on Multigene Panels Pose Clinical Management Challenges.

Purpose: Mutations in the gene confer up to an 80% lifetime risk of diffuse gastric cancer and up to a 60% lifetime risk of lobular breast cancer. Testing for mutations is recommended for individuals who meet the International Gastric Cancer Linkage Consortium (IGCLC) guidelines. However, the interpretation of unexpected mutations identified in patients who do not meet IGCLC criteria or do not have phenotypes suggestive of hereditary diffuse gastric cancer is clinically challenging.

Utilization of multigene panels in hereditary cancer predisposition testing: analysis of more than 2,000 patients.

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).