Use of SSRIs is associated with increased risk of fracture. The SSRIs may exert an increased risk of fracture independent of depression and bone mineral density.
Depression is associated with low BMD, with a substantially greater BMD decrease in depressed women and in cases of clinical depression. Depression should be considered as an important risk factor for osteoporosis.
Lung cancer (LC) is the most common cause of cancer mortality and the third most common cancer by incidence in the United States. While environmental factors play an important role in its development, LC risk also exhibits a high degree of heritability. Linkage analyses and genome-wide association studies have identified multiple loci associated with increased LC risk; however, much of the heritability has yet to be explained by these loci. Structural mutations, including copy number variations (CNVs), contribute to phenotypic diversity through dosage and/or cis-regulatory effects. Unbiased CNV mapping is only possible with the use of high-depth, short-read sequencing and remains much more complicated and prone to false positives than SNP detection. As the tools necessary for CNV detection have improved, both somatic and germline CNVs have been shown to play an important role in disease, especially cancer, and often they account for a significant proportion of pathogenic variants. Little has been done to understand the role of germline CNVs in the biological pathways of hereditary lung cancer (HLC). The goal of the current project is to utilize the whole exome sequencing (WES) data in identifying the CNVs in the HLC families (≥3 LC/family) recruited by the Genetic Epidemiology of Lung Cancer Consortium (GELCC). This work uses germline WES data from 203 individuals (60 with a LC diagnosis) from 25 HLC families (≥3 LC affected/family). We limited our investigation to CNVs called by two independent tools using read depth to infer copy number changes and genomic breakpoints: GATK 4 (https://gatk.broadinstitute.org) and XHMM (https://atgu.mgh.harvard.edu/xhmm/). We have identified CNVs (deletions) in the following protein coding genes: KIR2DL1 (19q13.42; OR=1.77), DMBT1 (10q26.13; OR=1.56), SIBPB1 (20p13; OR=1.53), LILRA6 (20p13; OR=1.53), and HLA-DRB5 (6p21.32; OR=1.64) in ≥3 families in at least two individuals/family. All of these genes with the exception of HLA-DRB5 were previously reported in LC studies; HLA-DRB5 was reported in other cancer studies. DMBT1 was reported to be a candidate tumor suppressor gene and frequent loss of heterozygosity (LOH) was observed in several human tumors. It is highly expressed in lung and loss of expression was reported in LC cell lines. All CNVs identified in our study are consistent with Mendelian expectations and appear to be uncommon in the general population. CNVs in these genes may contribute to the lung cancer risk in the HLC families. Further validation of the identified variants is ongoing. We will consider overall CNV burden and disease association with identified deletions and duplications. The enrichment of rare variants in oncogenically associated genes that co-segregate with LC provides specific mutations for future work and improves our understanding of the inheritance and pathogenesis of LC. Citation Format: John Waldron, Kirsten W. Termine, Anthony M. Musolf, Mariza de Andrade, Colette Gaba, Ramaswamy Govindan, Ping Yang, Ming You, Ellen Jaeger, Angelle F. Bencaz, Marshall W. Anderson, Ann G. Schwartz, Susan M. Pinney, Christopher I. Amos, Joan E. Bailey-Wilson, Diptasri M. Mandal. Analyses of whole exome sequencing (WES) data of hereditary lung cancer families identify germline copy number variations (CNVs) in multiple genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1452.
Lung cancer (LC) is by far the leading cause of cancer-related deaths worldwide. LC survival has only improved marginally over the last decades with the five-year survival rate for LC being lower than most other leading cancer sites. African Americans (AAs) have a higher incidence rate and lower survival rate for LC in comparison to all other racial and ethnic groups in the United States. In addition, incidence rates among AAs and European Americans (EAs) vary with histology of LC. Although tobacco smoking has been identified as the major risk factor for LC, studies have shown there is a genetic component involved in the development of the disease. About 25% of LC cases have at least one first- or second-degree relative, indicating that family history is a relevant risk factor. The goal of this study is to characterize genetic, clinical, and environmental risk factors among individuals of EA and AA ancestry from the high-risk families with LC that could hold important clinical value to address LC disease disparity. Study participants with LC were recruited from a network of 30 hospitals from Louisiana along with multiple states across the country. Study participants with at least two confirmed cases of primary LC within the family were eligible. Participants were divided into two subgroups: Familial (≥2 LC cases/family) and Hereditary LC (HLC families) (≥3 affected LC cases/family). Medical and pathology reports were obtained from hospitals along with demographic and environmental data from the families. A total of 192 study participants (157 EA and 35 AA) from both familial and HLC families from the years 1992 through 2021 were used in this study. Data abstracted from the pathology, clinical reports, and study questionnaire was entered into spreadsheets and analyzed. Histology of LC diagnosis and clinical reports on mutation analysis were documented. The preliminary analyses of results have found that the average age of onset for AAs is significantly lower than in EA (P value < 0.0001). Additionally, while smoking is commonly referred to as a major contributor to LC disparities, AAs were found to have significantly lower pack years of cigarette use than EAs (P value < 0.05). The average age the AA participants ‘begin to smoke' was also found to be significantly lower than EAs (P value < 0.05). The majority of the study participants with LC were diagnosed with adenocarcinoma irrespective of the number of pack-years for cigarette use. Mutation analysis in the clinical report for a small number of study participants in the EA families provided limited information. Additional analysis is ongoing. Clinical and pathological characterization in association with risk factors from high-risk families with EA and AA ancestry will provide us with a better understanding behind the disproportionate distribution of incidence and survival for LC in the AA population. Citation Format: Grace L. Brandhurst, Angelle Bencaz, Sarah North, Ellen Jaeger, Diptasri Mandal, Joan Bailey-Wilson. Health disparities in high-risk lung cancer families and their association with smoking, environmental exposures, and other etiological factors [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-190.
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