Germline cancer susceptibility in individuals with melanoma.

BACKGROUND: Prior studies have estimated a small number of individuals with melanoma (2%-2.5%) have germline cancer predisposition, yet a recent twin study suggested melanoma has the highest hereditability among cancers. OBJECTIVE: To determine the incidence of hereditary melanoma and characterize the spectrum of cancer predisposition genes that may increase the risk of melanoma. METHODS: Four hundred individuals with melanoma and personal or family history of cancers underwent germline testing of >80 cancer predisposition genes. Comparative analysis of germline data was performed on 3 additional oncologic and dermatologic data sets. RESULTS: Germline pathogenic/likely pathogenic (P/LP) variants were identified in 15.3% (61) individuals with melanoma. Most variants (41, 67%) involved genes considered unrelated to melanoma (BLM, BRIP1, CHEK2, MLH1, MSH2, PMS2, RAD51C). A third (20, 33%) were in genes previously associated with familial melanoma (BAP1, BRCA2, CDKN2A, MITF, TP53). Nearly half (30, 46.9%) of P/LP variants were in homologous repair deficiency genes. Validation cohorts demonstrated P/LP rates of 10.6% from an unselected oncologic cohort, 15.8% from a selected commercial testing cohort, and 14.5% from a highly selected dermatologic study. LIMITATIONS: Cohorts with varying degrees of selection, some retrospective. CONCLUSION: Germline predisposition in individuals with melanoma is common, with clinically actionable findings diagnosed in 10.6% to 15.8%.

The safety of Bruton's tyrosine kinase inhibitors in B-cell malignancies: A systematic review.

B-cell malignancies, most notably lymphomas, make up most of the non-Hodgkin lymphomas in the United States. There are limited randomized data comparing first- and second-generation Bruton tyrosine kinase (BTK) inhibitors. Our aim was to compare the safety profiles of first versus second-generation BTK inhibitors. A systematic search was performed from database inception to January 13, 2020. Studies with BTK inhibitor monotherapy for the treatment of B-cell malignancies in the adult population (>18 years old) were utilized and the adverse events (AEs) were extracted. Fifty-five studies that met the inclusion criteria were included in the systematic review with 41 studies with first generation and 14 studies with second generation. The review included both clinical trials and retrospective studies with average time of follow-up of 2 years for the first-generation group and 18 months for the second-generation group. We found that the incidence of cardiovascular AEs was significantly higher in the first-generation group (20.8%) as compared to the second-generation group (6.3%). However, there was a higher incidence of hematologic/oncologic and gastrointestinal side effects in the second-generation group compared to the first (62.3% compared to 39.2% and 36.9% compared to 28.9%). The number of Grade 5 cardiovascular events (death) was same in the first-generation group compared to the second generation. Further research is needed to develop highly selective BTK inhibitors to avoid unwanted AEs by minimizing off-targets.

Clinical and Immunologic Features of Germline Pathogenic Variant-Positive Patients with Melanoma.

PURPOSE: Malignant melanoma represents the most lethal skin cancer with germline predispositions thought to comprise 10% to 15% of all melanoma cases. No studies to date examine the immunologic features that may differentiate survival differences between germline pathogenic variant (gPV)-positive patients with melanoma from gPV-negative patients with melanoma. EXPERIMENTAL DESIGN: Adult patients with melanoma and clinical characteristics suggesting hereditary predisposition to cancer were prospectively recruited to undergo germline testing and flow cytometric analysis of peripheral immune suppressor cells. RESULTS: In this cohort, gPV-positive patients (n = 72) had a significantly improved melanoma-specific survival (MSS) compared with gPV-negative patients (n = 411; HRadj, 0.32; 95% CI, 0.13-0.82; P = 0.01). These survival improvements among gPV-positive patients were most apparent among cutaneous melanoma subtypes (HRadj, 0.12; 95% CI, 0.016-0.86; P = 0.03) and numerically improved in later-stage (IIB-IV) patients (HRadj, 0.34; 95% CI, 0.10-1.11; P = 0.06). Further, gPV-positive patients had a significantly lower level of total circulating PMN-MDSC compared with gPV-negative patients (P = 0.01), which was most apparent in those diagnosed with later stages (IIB-IV) of melanoma (P = 0.009). Finally, a significant upregulation of inflammatory transcriptome signatures in later-stage gPV-positive patients (n = 21) was observed in comparison with gPV-negative patients (n = 173) in the cutaneous melanoma cohort (SKCM) of The Cancer Genome Atlas (TCGA). CONCLUSIONS: gPV-positive patients with melanoma exhibit improved MSS in addition to reduced peripheral PMN-MDSC and an enhanced inflammatory microenvironment.

Better prediction of stroke in atrial fibrillation with incorporation of cancer in CHA2DS2VASC score: CCHA2DS2VASC score.

Introduction: Atrial fibrillation (AF) is associated with an increased risk of stroke. Despite evidence linking cancer and thrombosis, cancer is not part of the CHA2DS2VASc score. Hypothesis: Cancer is an independent risk factor for thromboembolic stroke in patients with AF. Method: The SEER database was utilized to identify patients with lung, colon, breast, and prostate cancers with AF and no prior diagnosis of stroke and. compared to controls within the dataset. The primary endpoint was rates of stroke per 100 person-years. Cox regression modeling and a nested model comparing CHA2DS2VASc score (Model 1) with a complete model including cancer diagnosis (Model 2) were performed. Models were compared using Akaike Information Criterion (AIC) and Net Reclassification Index (NRI). A propensity-matched cohort with equivalent CHA2DS2VASc scores determining stroke-free survival was also performed. Results: A total of 101,185 patients were included in the analysis, with 48,242 in the Cancer and 52,943 in the Non-cancer Group. Stroke rate per 100 person-years was significantly higher in the Cancer Group. The CHA2DS2VASc model (Model 1) was compared against a model including cancer (Model 2) showing improved predictability as assessed by both NRI and AIC. Cox regression analysis calculated a hazard ratio of 1.085 for Cancer, which was comparable to age >75, female sex, and diabetes. Propensity matched Kaplan-Meier curve demonstrated a decreased probability of stroke-free survival in the Cancer Group. Conclusion: Cancers increase the risk of stroke in patients with AF. Consideration should be given to the addition of cancer to the clinical scoring system.

Radiation induced cardiovascular disease: An odyssey of bedside-bench-bedside approach.

The journey to Mars will be an ambitious, yet arduous task as it will entail culmination of all the information we have gathered over many decades. While the mission is of utmost importance, preservation of astronaut's well-being is paramount also. To that end, mitigation of radiation risk especially afflicting cardiovascular disease (CVD) is of great interest and challenge. Current data from astronauts on low earth orbit and Apollo missions provides insight on the risk of CVD from radiation exposure. However, data is limited given the small cohort size of astronauts who embarked on just nine prolonged missions. Therefore, a cerebral approach to understanding and mitigating risks are essential. This paper discusses the need for a predictive preclinical model to help understand and mitigate the effects of radiation on astronauts. We will discuss strengths and limitations of preclinical models and the methods of validating and constructing a model to predict human clinical outcomes. Our bedside-bench-bedside approach focuses on adapting the preclinical model through common investigative tools used between humans and animals. The result will be an optimization of preclinical model to a point of being a surrogate clinical model capable of predicting CVD outcomes in astronauts exposed to radiation.

Primer on Hereditary Cancer Predisposition Genes Included Within Somatic Next-Generation Sequencing Panels.

PURPOSE: It has been estimated that 5% to 10% of cancers are due to hereditary causes. Recent data sets indicate that the incidence of hereditary cancer may be as high as 17.5% in patients with cancer, and a notable subset is missed if screening is solely by family history and current syndrome-based testing guidelines. Identification of germline variants has implications for both patients and their families. There is currently no comprehensive overview of cancer susceptibility genes or inclusion of these genes in commercially available somatic testing. We aimed to summarize genes linked to hereditary cancer and the somatic and germline panels that include such genes. METHODS: Germline predisposition genes were chosen if commercially available for testing. Penetrance was defined as low, moderate, or high according to whether the gene conferred a 0% to 20%, 20% to 50%, or 50% to 100% lifetime risk of developing the cancer or, when percentages were not available, was estimated on the basis of existing literature descriptions. RESULTS: We identified a total of 89 genes linked to hereditary cancer predisposition, and we summarized these genes alphabetically and by organ system. We considered four germline and six somatic commercially available panel tests and quantified the coverage of germline genes across them. Comparison between the number of genes that had germline importance and the number of genes included in somatic testing showed that many but not all germline genes are tested by frequently used somatic panels. CONCLUSION: The inclusion of cancer-predisposing genes in somatic variant testing panels makes incidental germline findings likely. Although somatic testing can be used to screen for germline variants, this strategy is inadequate for comprehensive screening. Access to genetic counseling is essential for interpretation of germline implications of somatic testing and implementation of appropriate screening and follow-up.