Cystic fibrosis (CF) is a lethal genetic disorder that affects many organ systems of the body, including various endocrine and exocrine tissues. Health and survival positively associate with body mass and as a consequence, CF clinical care includes high-fat, high-calorie diets to maintain and increase adipose tissue stores. Such strategies have been implemented without a clear understanding of the cause and effect relationship between body mass and patients' health. Here, we use CF mouse models, which display small adipose stores, to begin examining body fat as a prelude into mechanistic studies of low body growth in CF, so that optimal therapeutic strategies can be developed. We reasoned that low adiposity must result from reduced number and/or volume of adipocytes. To determine relative contribution of either mechanism, we quantified volume of intraperitoneal and subcutaneous adipocytes. We found smaller, but not fewer, adipocytes in CF compared to wildtype (WT) animals. Specifically, intraperitoneal CF adipocytes were half the volume of WT cells, whereas subcutaneous cells were less affected by the Cftr genotype. No differences were found in cell types between CF and WT adipose tissues. Adipose tissue CFTR mRNA was detected and we found greater CFTR expression in intraperitoneal depots as compared with subcutaneous samples. RNA sequencing revealed that CF adipose tissue exhibited lower expression of several key genes of adipocyte function (Lep, Pck1, Fas, Jun), consistent with low triglyceride storage. The data indicate that CF adipocytes contain less triglycerides than WT cells and a role for CFTR in these cells is proposed.
Purpose Single nucleotide polymorphisms in angiotensinogen at positions -20 and -6 are associated with increased severity and progression of various fibrotic diseases. Our earlier work demonstrated that the progression of Idiopathic Pulmonary Fibrosis was associated with the A-6 allele. This study examined the hypothesis that the homozygous CC genotype at -20 and the AA genotype at -6 would confer worse measures of pulmonary function (measured by pulmonary function tests) in Idiopathic Pulmonary Fibrosis. Method Multiple logistic regression analysis was applied to a NIH Lung Tissue Research Consortium cohort and Spanish cohort, while also adjusting for covariates to determine the effects of these SNPs on measures of pulmonary function. Results Analysis demonstrated that the CC genotype at -20 was strongly associated with reduced diffusing capacity in males in both cohorts (p = 0.0028 for LTRC and p = 0.017). In females, the AA genotype was significantly associated with lower FVC (p = 0.0082) and Valv (p = 0.022). In males, the haplotype CA at -20 and -6 in AGT was also strongly associated with reduced diffusing capacity in both cohorts. Conclusions This study is the first to demonstrate an association of angiotensinogen polymorphisms (-20A>C and -6G>A) with lower measures of pulmonary function in Idiopathic Pulmonary Fibrosis. It is also the first to relate the effect of gender in lung fibrosis with polymorphisms in angiotensinogen.
1537 Background: Heterozygous germline ATM mutation carriers have an increased risk of developing breast, pancreas, and other cancers. The clinical and pathologic characteristics of ATM-associated breast cancers have not been well defined. Methods: Patients who underwent multigene panel testing (MGPT) between 2013-2019 and identified to harbor ATM mutations were included in the study. We evaluated demographics, pathology, and surgical management of our ATM mutation carriers with breast cancer. Results: At total of 319 individuals were identified to have variants in ATM, of which 114 were pathogenic/likely pathogenic. The majority of patients were female (82%) and Caucasian (88%). A total of 56 patients (49%) had a personal cancer diagnosis, the most common of which was breast cancer (n = 39). Nine individuals had more than one primary malignancy. The mean age at breast cancer diagnosis was 52, with a range of 25-82. The majority of patients had invasive ductal carcinoma (74%), grade 2 or 3 (90%), and ER and /or PR positive (87%). Of those with known HER2 status, 24% were positive. Thirty-nine percent of patients were lymph node positive, and 42% had lymphovascular invasion. The most common stage at diagnosis was 2 (53%). Of the 39 mutation carriers with breast cancer, 16 (42%) received radiation therapy, and 16 underwent bilateral mastectomy. Of 114 ATM positive patients, there were 55 distinct variants. Sixteen (14%) individuals had a mutation in additional cancer predisposition genes. One variant, c.5015delG, was identified in ten patients in a large, consanguineous Iraqi family with an extensive history of pancreatic and other cancers. Eight individuals were identified to have the known high-penetrance variant, c.7271T > G. Conclusions: Our study describes the clinical and pathological characteristics of ATM mutations carriers with breast cancer. The majority of patients had intermediate to high grade disease, hormone receptor positive, with a suggestion of a higher rate of HER2 positivity and lymph node involvement. Additional studies are needed to elucidate the unique characteristics of ATM-associated breast cancer, which may have implications for personalized management.
1529 Background: Multigene panel testing (MGT) is commonly utilized in patients with a personal or family history of cancer. One of the more common gene mutations identified is in the ATM gene, associated with a moderately increased risk of breast and other cancers. There are reports of an association with pancreatic cancer, however the exact risks are unclear. The aim of this study is to describe the family history of pancreatic cancer in a cohort of ATM mutation carriers, and to evaluate possible genotype/phenotype correlation. Methods: Patients who underwent MGT, between ‘13 and ‘19, and tested positive for a pathogenic/likely pathogenic ATM mutation were included in this study. Family history, with a focus on pancreatic cancer, and genetic testing results were analyzed. Results: A total of 114 patients were identified to carry an ATM mutation. Twenty-two (19.3%) individuals had a family history of pancreatic cancer in a close relative, and of those, 13 (11.4%) had an affected first degree relative, and 11 (9.6%) had an affected second degree relative. Among the families with pancreatic cancer, 20 close relatives had a personal history of pancreatic cancer, with the youngest diagnosed at age 40, the oldest diagnosed at age 91, and a mean age of diagnosis of 66.5 years. Thirteen unique variants were identified: 4 splice site, 3 missense, 3 frameshift, 1 nonsense, and 1 silent. Two families had the known high-penetrance ATM mutation, c.7271T > C (p.V2424G). Conclusions: This study describes the association of pancreatic cancer in individuals found to carry pathogenic ATM mutations. A significant proportion (19.3%) of patients had a family history of pancreatic cancer in a close relative, diagnosed as young as age 40. The mean age of diagnosis was slightly younger than the average age in the general population (age 70). As pancreatic cancer screening continues to improve, this information will be an important component to help guide cancer risk assessment and future screening recommendations for ATM mutation carriers. Additional larger studies are needed to further characterize pancreatic cancer risks in patients with ATM gene mutations.
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