Germline Genetic Testing in Unselected Squamous and Non-Squamous Head and Neck Cancers.

OBJECTIVE: This study describes the prevalence of pathogenic germline variants (PGVs) in head and neck cancer patients, the incremental yield compared to a guideline-based approach to genetic evaluation, and the uptake of family variant testing. STUDY DESIGN: Prospective cohort study. SETTING: Three tertiary academic medical centers. METHODS: Germline sequencing using an 84-gene screening platform among unselected head and neck cancer patients who received care at Mayo Clinic Cancer Centers between April 2018 and March 2020. RESULTS: Amongst 200 patients, the median age was 62.0 years (Q1, Q3: 55, 71), 23.0% were female, 89.0% white/non-Hispanic, 5.0% Hispanic/Latinx, 6% of another race, and 42.0% had prognostic stage IV disease. The most common subsites were the oropharyngeal (45.0%) and salivary glands (12.0%). The most common histology was squamous cell carcinoma (74.5%). Twenty-one patients (10.5%) had a total of 22 PGVs; 20 of the 21 patients (95.2%) did not meet criteria for testing by current guidelines. Regarding penetrance of the 22 PGVs, 11 were high or moderate (most common PMS2 or HOXB13), and 11 were low or recessive (most common MUTYH, WNR, or RECQL4). One patient had a change in care based on an identified PGV. Family variant testing was completed at a rate of 4.8%. CONCLUSIONS: Universal gene panel testing identified a PGV in 10.5% of head and neck cancer patients; almost all would have been missed by current guideline-based testing. One of 21 patients had a treatment change due to their PGV, indicating that head and neck cancer treatment decisions are not yet widely informed by germline alterations. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:3378-3388, 2023.

Universal Genetic Testing vs. Guideline-Directed Testing for Hereditary Cancer Syndromes Among Traditionally Underrepresented Patients in a Community Oncology Program.

Background Detection of pathogenic germline variants (PGVs) has implications for cancer screening, prognosis, treatment selection, clinical trial enrollment, and family testing. Published guidelines provide indications for PGV testing, determined by clinical and demographic factors, but their applicability in an ethnically and racially diverse community hospital population is unknown. This study describes the diagnostic and incremental yield of universal multi-gene panel testing in a diverse population in a community cancer practice. Methods We completed a prospective study of proactive germline genetic sequencing among patients with solid tumor malignancies at a community-based oncology practice in downtown Jacksonville, FL, between June 2020 and September 2021. The patients were unselected for cancer type, stage, family history, race/ethnicity, and age. PGVs identified using an 84-gene next-generation sequencing (NGS) tumor genomic testing platform were stratified by penetrance. National Comprehensive Cancer Networks (NCCN) guidelines determined incremental PGV rates. Results Two hundred twenty-three patients were enrolled, with a median age of 63 years, 78.5% female. 32.7% were Black/African American, and 5.4% were Hispanic. 39.9% of patients were commercially insured, Medicare/Medicaid insured 52.5%, and 2.7% were uninsured. The most common cancers in this cohort were breast (61.9%), lung (10.3%), and colorectal (7.2%). Twenty-three patients (10.3%) carried one or more PGVs, and 50.2% carried a variant of uncertain significance (VUS). Though there was no significant difference in the rate of PGVs based on race/ethnicity, African Americans were numerically more likely to have a VUS reported than whites (P=0.059). Eighteen (8.1%) patients had incremental clinically actionable findings that practice guidelines would not have detected, which was higher in non-whites. Conclusions In this racially/ethnically and socioeconomically diverse cohort, universal multi-gene panel testing (MGPT) increased diagnostic yield over targeted guideline-informed testing. Rates of VUS and incremental PGV were higher in non-white populations.

Somatic tumor testing implications for Lynch syndrome germline genetic testing.

Clinicians involved in cancer treatment often utilize somatic tumor sequencing to help tailor chemotherapy and immunotherapy. However, somatic tumor sequencing can also identify patients at risk for germline pathogenic variants causing cancer predisposition syndromes like Lynch syndrome. The extent to which clinicians realize this implication of tumor sequencing is currently unclear. We performed a retrospective chart review of Stanford Health Care patients who had somatic variant(s) in the Lynch syndrome genes or microsatellite instability identified on tumor sequencing to determine the proportion of patients who were referred to genetics. Among 6,556 patients who had tumor testing, 90 (1.37%) had findings compatible with Lynch syndrome. Of the 62 patients who had not already seen genetics, 47/62 (75.8%) were not referred to genetics for germline testing. Additionally, 26/47 (55.3%) of these individuals had a tumor type within the Lynch syndrome spectrum. Of the 10 patients who did elect germline testing after tumor sequencing, 3/10 were positive for Lynch syndrome. Our study highlights the need for specific guidelines to inform clinician referral practices on germline follow-up of somatic tumor testing and demonstrates the importance of continued research on the relationship between somatic tumor variants and germline variants to inform such guidelines.

Germline Cancer Susceptibility Gene Testing in Unselected Patients with Hepatobiliary Cancers: A Multi-Center Prospective Study.

Data from germline testing in unselected patients with hepatobiliary cancers are limited. Identification of germline predisposition can have important implications on cancer treatment and family counseling. To determine prevalence of pathogenic germline variants (PGV) in patients with hepatobiliary cancer, we undertook a prospective multi-site study of germline sequencing using a >80-gene next-generation sequencing platform among patients with hepatobiliary cancers receiving care at Mayo Clinic Cancer Centers between April 1, 2018 and March 31, 2020. Patients were not selected on the basis of stage, family cancer history, ethnicity, or age. Family cascade testing was offered at no cost. Of 205 patients, the median age was 65 years, 58.5% were male, 81% were White, and 64.4% had cholangiocarcinoma, 21.5% hepatocellular carcinoma, 7.8% gallbladder cancer, and 4.3% carcinoma of ampulla of Vater. PGV were found in 15.6% (n = 32) of patients, including 23 (71%) in moderate and high penetrance cancer susceptibility genes. A total of 75% of patients with a positive result would not have been detected using guidelines for genetic evaluation. Prevalence of PGV was 15.7% in intrahepatic cholangiocarcinoma, 17% in extrahepatic cholangiocarcinoma, 15.9% in hepatocellular cancer, and 33% in carcinoma of ampulla of Vater. On the basis of these genetic findings, 55% were potentially eligible for approved precision therapy and/or clinical treatment trials. Universal multi-gene panel testing in hepatobiliary cancers was associated with detection of heritable mutations in over 15% of patients most of whom would not have been tested using current guidelines. Germline testing should be considered in all patients with hepatobiliary cancers. PREVENTION RELEVANCE: Universal multi-gene testing in hepatobiliary cancers was associated with heritable mutations in over 15% of patients, most of whom would not have been tested using current guidelines. 55% were potentially eligible for approved precision therapy and/or clinical treatment trials. Germline testing should be considered in all patients with hepatobiliary cancers.

The expanding spectrum of NFIB-associated phenotypes in a diverse patient population-A report of two new patients.

NFIB (Nuclear Factor I B) haploinsufficiency has recently been identified as a cause of intellectual disability and macrocephaly. Here we describe two patients with pathogenic variants in NFIB. The first is a 6-year-old Latino male with developmental delays, mild hypotonia, facial anomalies, and brain magnetic resonance imaging findings comprising mild thinning of the corpus callosum, with more marked thinning of the splenium and blunting of the rostrum and cavum septum pellucidum. Exome sequencing identified a previously described de novo variant in NFIB, c.265C>T, predicting p.Arg89Ter. The second is a 5-year-old Latino male with developmental delays, hypotonia, dysmorphic features, a preauricular tag and pit, a small ventricular septal defect, and brain magnetic resonance imaging findings including a dysmorphic corpus callosum and a small posterior fossa. A single nucleotide polymorphism microarray identified a 92 kb interstitial deletion at 9p23 including several exons of NFIB and no other known genes. Our two patients add to the knowledge of this rare condition through our addition of new brain MRI findings and dysmorphic features. Additionally, these are the first known Latino patients to be described with NFIB haploinsufficiency, expanding our understanding of the associated facial features in diverse populations. Further data are needed to determine genotype-phenotype relationships for NFIB.