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Autophagy is a housekeeping mechanism tasked with eliminating misfolded proteins and damaged organelles to maintain cellular homeostasis. Autophagy deficiency results in increased oxidative stress, DNA damage and chronic cellular injury. Among the core genes in the autophagy machinery, ATG7 is required for autophagy initiation and autophagosome formation. Based on the analysis of an extended pedigree of familial cholangiocarcinoma, we determined that all affected family members had a novel germline mutation (c.2000C>T p.Arg659* (p.R659*)) in ATG7. Somatic deletions of ATG7 were identified in the tumors of affected individuals. We applied linked-read sequencing to one tumor sample and demonstrated that the ATG7 somatic deletion and germline mutation were located on distinct alleles, resulting in two hits to ATG7. From a parallel population genetic study, we identified a germline polymorphism of ATG7 (c.1591C>G p.Asp522Glu (p.D522E)) associated with increased risk of cholangiocarcinoma. To characterize the impact of these germline ATG7 variants on autophagy activity, we developed an ATG7-null cell line derived from the human bile duct. The mutant p.R659* ATG7 protein lacked the ability to lipidate its LC3 substrate, leading to complete loss of autophagy and increased p62 levels. Our findings indicate that germline ATG7 variants have the potential to impact autophagy function with implications for cholangiocarcinoma development., (© 2022. The Author(s).)

Purpose: To accurately ascertain the frequency of pathogenic germline variants (PGVs) in a pan-cancer patient population with universal genetic testing and to assess the economic impact of receiving genetic testing on healthcare costs., Methods: In this prospective study, germline genetic testing using a 105-gene panel was administered to an unselected pan-cancer patient population irrespective of eligibility by current guidelines. Financial records of subjects were analyzed to assess the effect of PGV detection on cost of care one year from the date of testing., Results: A total of 284 patients participated in this study, of which 44 patients (15%) tested positive for a PGV in 14 different cancer types. Of the patients with PGVs, 23 patients (52%) were ineligible for testing by current guidelines. Identification of a PGV did not increase cost of care., Conclusion: Implementation of universal genetic testing for cancer patients in the clinic, beyond that specified by current guidelines, is necessary to accurately assess and treat hereditary cancer syndromes and does not increase healthcare costs.

Systemic inflammation is present during and serves as a diagnostic tool for cancer-associated cachexia and is detrimental to serum 25-hydroxyvitamin D (25(OH)D) concentrations in non-cancer conditions. The neutrophil-to-lymphocyte ratio (NLR) is a desirable measure of systemic inflammation because it is easily calculated from a routine complete blood cell count with differentials. We sought to determine if an elevation in the NLR associates with greater weight loss, cachexia, and lower serum 25-hydroxyvitamin D (25(OH)D) concentrations in patients with advanced cancer. Advanced colon, lung, and prostate cancer patients (stages III/IV; n = 50) were retrospectively studied and separated into one of two groups: 1) Above (n = 25) or 2) Below (n = 25) the median NLR of 3.15 determined at diagnosis. Around the time of diagnosis, serum 25(OH)D and body weight were assessed, while body weight was assessed again at a later date. Weight loss and cachexia were significantly (both p < 0.05) greater and there was a trend (p < 0.10) for lower serum 25(OH)D concentrations in the Above group. We conclude that an elevation in the NLR associates with greater weight loss and cachexia, and potentially, a lower serum 25(OH)D concentration in patients with advanced colon, lung, or prostate cancer.

DNA copy number aberrations (CNA) are frequently observed in colorectal cancers (CRC). There is an urgent need for CNA-based biomarkers in clinics,. n For Stage III CRC, if combined with imaging or pathologic evidence, these markers promise more precise care. We conducted this Stage III specific biomarker discovery with a cohort of 134 CRCs, and with a newly developed high-efficiency CNA profiling protocol. Specifically, we developed the profiling protocol for tumor-normal matched tissue samples based on low-coverage clinical whole-genome sequencing (WGS). We demonstrated the protocol's accuracy and robustness by a systematic benchmark with microarray, high-coverage whole-exome and -genome approaches, where the low-coverage WGS-derived CNA segments were highly accordant (PCC >0.95) with those derived from microarray, and they were substantially less variable if compared to exome-derived segments. A lasso-based model and multivariate cox regression analysis identified a chromosome 17p loss, containing the TP53 tumor suppressor gene, that was significantly associated with reduced survival (P = 0.0139, HR = 1.688, 95% CI = [1.112-2.562]), which was validated by an independent cohort of 187 Stage III CRCs. In summary, this low-coverage WGS protocol has high sensitivity, high resolution and low cost and the identified 17p-loss is an effective poor prognosis marker for Stage III patients.

The impact of precision oncology on guiding treatment decisions of late-stage cancer patients was previously studied in a retrospective analysis. However, the overall survival and costs were not previously evaluated. We report the overall survival and healthcare costs associated with precision oncology in these patients with advanced cancer. Building on a matched cohort study of 44 patients with metastatic cancer who received all of their care within a single institution, we evaluated the overall survival and healthcare costs for each patient. We analyzed the outcomes of 22 patients who received genomic testing and targeted therapy (precision oncology) between July 1, 2013 and January 31, 2015, and compared to 22 historically controlled patients (control) who received standard chemotherapy ( N = 17) or best supportive care ( N = 5). The median overall survival was 51.7 weeks for the targeted treatment group and 25.8 weeks for the control group ( P = 0.008) when matching on age, gender, histological diagnosis and previous treatment lines. Average costs over the entire period were $2,720 per week for the targeted treatment group and $3,453 per week for the control group, ( P = 0.036). A separate analysis of 1,814 patients with late-stage cancer diagnoses found that those who received a targeted cancer treatment ( N = 93) had 6.9% lower costs in the last 3 months of life compared with those who did not. These findings suggest that precision oncology may improve overall survival for refractory cancer patients while lowering average per-week healthcare costs, resource utilization and end-of-life costs., Competing Interests: CONFLICTS OF INTEREST None.