Germline variants of ATG7 in familial cholangiocarcinoma alter autophagy and p62.

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.

Universal Germline Testing of Unselected Cancer Patients Detects Pathogenic Variants Missed by Standard Guidelines without Increasing Healthcare Costs.

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.

Familial Clustering of Erosive Hand Osteoarthritis in a Large Statewide Cohort.

OBJECTIVE: Erosive hand osteoarthritis (OA) is a severe and rapidly progressing subset of hand OA. Its etiology remains largely unknown, which has hindered development of successful treatments. This study was undertaken to test the hypothesis that erosive hand OA demonstrates familial clustering in a large statewide population linked to genealogical records, and to determine the association of potential risk factors with erosive hand OA. METHODS: Patients diagnosed as having erosive hand OA were identified by searching 4,741,840 unique medical records from a comprehensive statewide database, the Utah Population Database (UPDB). Affected individuals were mapped to pedigrees to identify high-risk families with excess clustering of erosive hand OA as defined by a familial standardized incidence ratio (FSIR) of ≥2.0. The magnitude of familial risk of erosive hand OA in related individuals was calculated using Cox regression models. Association of potential erosive hand OA risk factors was analyzed using multivariate conditional logistic regression and logistic regression models. RESULTS: We identified 703 affected individuals linked to 240 unrelated high-risk pedigrees with excess clustering of erosive hand OA (FSIR ≥2.0, P < 0.05). The relative risk of developing erosive hand OA was significantly elevated in first-degree relatives (P < 0.001). There were significant associations between a diagnosis of erosive hand OA and age, sex, diabetes, and obesity (all P < 0.05). CONCLUSION: Familial clustering of erosive hand OA observed in a statewide database indicates a potential genetic contribution to the etiology of the disease. Age, sex, diabetes, and obesity are risk factors for erosive hand OA. Identification of causal gene variants in these high-risk families may provide insight into the genes and pathways that contribute to erosive hand OA onset and progression.

An elevated neutrophil-to-lymphocyte ratio associates with weight loss and cachexia in cancer.

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.

Whole genome analysis identifies the association of TP53 genomic deletions with lower survival in Stage III colorectal 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.

Precision oncology in advanced cancer patients improves overall survival with lower weekly healthcare costs.

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.

A Retrospective Analysis of Precision Medicine Outcomes in Patients With Advanced Cancer Reveals Improved Progression-Free Survival Without Increased Health Care Costs.

PURPOSE: The advent of genomic diagnostic technologies such as next-generation sequencing has recently enabled the use of genomic information to guide targeted treatment in patients with cancer, an approach known as precision medicine. However, clinical outcomes, including survival and the cost of health care associated with precision cancer medicine, have been challenging to measure and remain largely unreported. PATIENTS AND METHODS: We conducted a matched cohort study of 72 patients with metastatic cancer of diverse subtypes in the setting of a large, integrated health care delivery system. We analyzed the outcomes of 36 patients who received genomic testing and targeted therapy (precision cancer medicine) between July 1, 2013, and January 31, 2015, compared with 36 historical control patients who received standard chemotherapy (n = 29) or best supportive care (n = 7). RESULTS: The average progression-free survival was 22.9 weeks for the precision medicine group and 12.0 weeks for the control group ( P = .002) with a hazard ratio of 0.47 (95% CI, 0.29 to 0.75) when matching on age, sex, histologic diagnosis, and previous lines of treatment. In a subset analysis of patients who received all care within the Intermountain Healthcare system (n = 44), per patient charges per week were $4,665 in the precision treatment group and $5,000 in the control group ( P = .126). CONCLUSION: These findings suggest that precision cancer medicine may improve survival for patients with refractory cancer without increasing health care costs. Although the results of this study warrant further validation, this precision medicine approach may be a viable option for patients with advanced cancer.