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Abstract HPV-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC) are recognized as distinct entities. There remains uncertainty surrounding the causal effects of smoking and alcohol on the development of these two cancer types. Here we perform multivariable Mendelian randomization (MR) to evaluate the causal effects of smoking and alcohol on the risk of HPV-positive and HPV-negative HNSCC in 3431 cases and 3469 controls. Lifetime smoking exposure, as measured by the Comprehensive Smoking Index (CSI), is associated with increased risk of both HPV-negative HNSCC (OR = 3.03, 95%CI:1.75-5.24, P = 7.00E-05) and HPV-positive HNSCC (OR = 2.73, 95%CI:1.39-5.36, P = 0.003). Drinks Per Week is also linked with increased risk of both HPV-negative HNSCC (OR = 7.72, 95%CI:3.63-16.4, P = 1.00E-07) and HPV-positive HNSCC (OR = 2.66, 95%CI:1.06-6.68, P = 0.038). Smoking and alcohol independently increase the risk of both HPV-positive and HPV-negative HNSCC. These findings have important implications for understanding the modifying risk factors between HNSCC subtypes.

Introduction: SCLC has traditionally been considered to arise from toxic exposure factors, such as smoking. Recent evidence has revealed that germline mutations may also affect the development of SCLC; however, these alterations remain understudied. We sought to identify novel germline mutations in SCLC including germline copy number variations (CNVs) in our cohort of patients. Methods: We designed a custom hybrid-capture gene panel to evaluate germline alterations in 192 cancer-predisposition and frequently mutated genes in SCLC. We applied this panel to germline analysis of a treatment-naive cohort of 67 patients with SCLC at our institution. Subsequently, we annotated the variants using the American College of Medical Genetics criteria and further classified variants of uncertain significance using a set of in silico tools, including DeepMind AlphaMissense, MutationTaster, SIFT, and Polyphen2. Results: We identified American College of Medical Genetics pathogenic or likely pathogenic alterations in seven of 67 patients. Five (71%) were novel alterations (BCORL1, FANCC, ATR, and BBC3) and a novel CNV (SLFN11) with two (29%) previously described mutations (CHEK1 and BRIP1). We also identified 191 variants of uncertain significance in 60 of 67 patients, of which, depending on the in silico tool, 5% to 14% were predicted to be pathogenic. Patients with SCLC with the seven pathogenic alterations were observed to have a numerically longer overall survival (hazard ratio = 0.50) and progression-free survival (hazard ratio = 0.45) though not statistically significant compared with the remaining cohort. Conclusions: Our study identifies novel germline alterations, including a CNV, and provides additional evidence that germline factors could be important contributing factors to the development of SCLC.

Polo-like-kinase-1 (PLK-1) is a serine/threonine kinase that regulates the cell cycle and acts as an oncogene in multiple cancers, including oral squamous cell carcinoma (OSCC). The loss of PLK-1 can inhibit growth and induce apoptosis, making it an attractive therapeutic target in OSCC. We evaluated the efficacy of PLK-1 inhibitors as novel, targeted therapeutics in OSCC. PLK-1 inhibition using BI6727 (volasertib) was found to affect cell death at low nanomolar concentrations in most tested OSCC cell lines, but not in normal oral keratinocytes. In cell lines resistant to volasertib alone, pre-treatment with radiotherapy followed by volasertib reduced cell viability and induced apoptosis. The combinatorial efficacy of volasertib and radiotherapy was replicated in xenograft mouse models. These findings highlight the potential of adding PLK-1 inhibitors to adjuvant therapy regimens in OSCC.