Cancer Susceptibility
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Saman Sargazi ◽  
Armin Zahedi Abghari ◽  
Hosna Sarani ◽  
Roghayeh Sheervalilou ◽  
Shekoufeh Mirinejad ◽  

2021 ◽  
Leila Dorling ◽  
Sara Carvalho ◽  
Jamie Allen ◽  
Michael Parsons ◽  
Cristina Fortuno ◽  

BACKGROUND Protein truncating variants in ATM, BRCA1, BRCA2, CHEK2 and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain. METHODS Combining 59,639 breast cancer cases and 53,165 controls, we sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1,146 training variants), BRCA1 (644), BRCA2 (1,425), CHEK2 (325) and PALB2 (472). We evaluated breast cancer risks according to five in-silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated. RESULTS The most predictive in-silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1 and BRCA2, data were compatible with small subsets (approximately 7%, 2% and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47-2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best fitting models were well calibrated in the validation set. CONCLUSIONS These results will inform risk prediction models and the selection of candidate variants for functional assays, and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility.

2021 ◽  
Natascia Marino ◽  
Rana German ◽  
Ram Podicheti ◽  
Douglas B. Rusch ◽  
Pam Rockey ◽  

Background: Genome-wide association studies have identified several breast cancer susceptibility loci. However, biomarkers for risk assessment are still missing. Here, we investigated cancer-related molecular changes detected in tissues from women at high risk for breast cancer prior to disease manifestation. Disease-free breast tissue cores donated by healthy women (N=146, median age=39 years) were processed for both methylome (MethylCap) and transcriptome (Illumina HiSeq4000) sequencing. Analysis of tissue microarray and primary breast epithelial cells was used to confirm gene expression dysregulation. Results: Transcriptomic analysis identified 69 differentially expressed genes between women at either high and those at average risk of breast cancer (Tyrer-Cuzick model) at FDR<0.05 and fold change≥2. The majority of the identified genes were involved in DNA damage checkpoint, cell cycle, and cell adhesion. Two genes, FAM83A and NEK2, were overexpressed in tissue sections (FDR<0.01) and primary epithelial cells (p<0.05) from high-risk breasts. Moreover, 1698 DNA methylation aberrations were identified in high-risk breast tissues (FDR<0.05), partially overlapped with cancer-related signatures, and correlated with transcriptional changes (p<0.05, r≤0.5). Finally, among the participants, 35 women donated breast biopsies at two time points, and age-related molecular alterations enhanced in high-risk subjects were identified. Conclusions: Normal breast tissue from women at high risk of breast cancer bears molecular aberrations that may contribute to breast cancer susceptibility. This study is the first molecular characterization of the true normal breast tissues and provides an opportunity to investigate molecular markers of breast cancer risk, which may lead to new preventive approaches.

Anna Hohneck ◽  
Florian Custodis ◽  
Stephanie Rosenkaimer ◽  
Ralf Hofheinz ◽  
Sandra Maier ◽  

Abstract Background Cardiooncology is a relatively new subspeciality, investigating the side effects of cytoreductive therapies on the cardiovascular (CV) system. Gender differences are well known in oncological and CV diseases, but are less elucidated in cardiooncological collectives. Methods Five hundred and fifty-one patients (278 male, 273 female) with diagnosed cancer who underwent regular cardiological surveillance were enrolled in the ‘MAnnheim Registry for CardioOncology’ and followed over a median of 41 (95% confidence interval: 40–43) months. Results Female patients were younger at the time of first cancer diagnosis [median 60 (range 50–70) vs. 66 (55–75), P = 0.0004], while the most common tumour was breast cancer (49.8%). Hyperlipidaemia was more often present in female patients (37% vs. 25%, P = 0.001). Male patients had a higher cancer susceptibility than female patients. They suffered more often from hypertension (51% vs. 67%, P = 0.0002) or diabetes (14% vs. 21%, P = 0.02) and revealed more often vitamin D deficiency [(U/l) median 26.0 (range 17–38) vs. 16 (9–25), P = 0.002] and anaemia [(g/dl) median 11.8 (range 10.4–12.9) vs. 11.7 (9.6–13.6), P = 0.51]. During follow-up, 140 patients died (male 77, female 63; P = 0.21). An increased mortality rate was observed in male patients (11.4% vs. 14%, P = 0.89), with even higher mortality rates of up to 18.9% vs. 7.7% (P = 0.02) considering tumours that can affect both sexes compared. Conclusions Although female patients were younger at the time of first cancer diagnosis, male patients had both higher cancer susceptibility and an increased mortality risk. Concomitant CV diseases were more common in male patients.

2021 ◽  
Vol 12 (1) ◽  
Wanqing Wen ◽  
Zhishan Chen ◽  
Jiandong Bao ◽  
Quan Long ◽  
Xiao-ou Shu ◽  

AbstractIdentifying transcription factors (TFs) whose DNA bindings are altered by genetic variants that regulate susceptibility genes is imperative to understand transcriptional dysregulation in disease etiology. Here, we develop a statistical framework to analyze extensive ChIP-seq and GWAS data and identify 22 breast cancer risk-associated TFs. We find that, by analyzing genetic variations of TF-DNA bindings, the interaction of FOXA1 with co-factors such as ESR1 and E2F1, and the interaction of TFs with chromatin features (i.e., enhancers) play a key role in breast cancer susceptibility. Using genetic variants occupied by the 22 TFs, transcriptome-wide association analyses identify 52 previously unreported breast cancer susceptibility genes, including seven with evidence of essentiality from functional screens in breast relevant cell lines. We show that FOXA1 and co-factors form a core TF-transcriptional network regulating the susceptibility genes. Our findings provide additional insights into genetic variations of TF-DNA bindings (particularly for FOXA1) underlying breast cancer susceptibility.

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Aga Syed Sameer ◽  
Saniya Nissar

Toll-like receptors (TLRs) are the important mediators of inflammatory pathways in the gut which play a major role in mediating the immune responses towards a wide variety of pathogen-derived ligands and link adaptive immunity with the innate immunity. Numerous studies in different populations across the continents have reported on the significant roles of TLR gene polymorphisms in modulating the risk of colorectal cancer (CRC). CRC is one of the major malignancies affecting the worldwide population and is currently ranking the third most common cancer in the world. In this review, we have attempted to discuss the structure, functions, and signaling of TLRs in comprehensive detail together with the role played by various TLR gene SNPs in CRC susceptibility.

2021 ◽  
Jiayao Fan ◽  
Huiqing Xu ◽  
Bing Liu ◽  
Fangyuan Jing ◽  
Qingfang He ◽  

Genes ◽  
2021 ◽  
Vol 12 (9) ◽  
pp. 1371
Elizabeth R. Berger ◽  
Mehra Golshan

The identification that breast cancer is hereditary was first described in the nineteenth century. With the identification of the BRCA1 and BRCA 2 breast/ovarian cancer susceptibility genes in the mid-1990s and the introduction of genetic testing, significant advancements have been made in tailoring surveillance, guiding decisions on medical or surgical risk reduction and cancer treatments for genetic variant carriers. This review discusses various medical and surgical management options for hereditary breast cancers.

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