Dissecting the heritable risk of breast cancer: From statistical methods to susceptibility genes

Fanfani, Viola; Zátopková, Martina; Harris, Adrian L.; Stracquadanio, Giovanni

doi:10.1016/j.semcancer.2020.06.001

Cited by 12 publications

(8 citation statements)

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“…Genome-wide estimates were compared with LD score regression (LDsc) results (28). Gold-standard methods require raw data; however, previous studies have shown that LDsc has comparable performance in most scenarios (22). Since LDsc is routinely used to estimate heritability for the traits in the UK BioBank, we retrieved the results for all 38 cancers and compared them to BAGHERA estimates.…”

Section: Comparison With State-of-the-art Methods For Genome-wide and Local Heritability Estimationmentioning

confidence: 99%

“…Heritability analysis provides the statistical framework to estimate the contribution of all common SNPs to cancer risk regardless of their statistical significance and effect size (16). Studying heritability is now becoming a crucial step in cancer GWAS and has provided insights on the risk of developing many malignancies (17), including prostate (18), cervical (19), testicular germ cell tumor (20) and breast cancer (21,22). However, since the functional impact of the SNPs is context-dependent (23), it is important to quantify the amount of heritability explained by genomic regions associated with well-characterized biological functions (24,25).…”

Section: Introductionmentioning

confidence: 99%

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The Landscape of the Heritable Cancer Genome

et al. 2021

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Genome-wide association studies (GWAS) have found hundreds of single nucleotide polymorphisms (SNPs) associated with increased risk of cancer. However, the amount of heritable risk explained by SNPs is limited, leaving most of cancer heritability unexplained. Tumor sequencing projects have shown that causal mutations are enriched in genic regions. We hypothesized that SNPs located in protein coding genes and nearby regulatory regions could explain a significant proportion of the heritable risk of cancer.To perform gene-level heritability analysis, we developed a new method, called Bayesian Gene HERitability Analysis (BAGHERA), to estimate the heritability explained by all genotyped SNPs and by those located in genic regions using GWAS summary statistics. BAGHERA was specifically designed for low heritability traits such as cancer and provides robust heritability estimates under different genetic architectures. BAGHERA-based analysis of 38 cancers reported in the UK Biobank showed that SNPs explain at least 10% of the heritable risk for 14 of them, including late onset malignancies. We then identified 1,146 genes, called cancer heritability genes (CHGs), explaining a significant proportion of cancer heritability. CHGs were involved in hallmark processes controlling the transformation from normal to cancerous cells. Importantly, 60 of them also harbored somatic driver mutations, and 27 are tumor suppressors. Our results suggest that germline and somatic mutation information could be exploited to identify subgroups of individuals at higher risk of cancer in the broader population and could prove useful to establish strategies for early detection and cancer surveillance. SignificanceThis study describes a new statistical method to identify genes associated with cancer heritability in the broader population, creating a map of the heritable cancer genome with gene-level resolution.Research.

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Section: Comparison With State-of-the-art Methods For Genome-wide and Local Heritability Estimationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Landscape of the Heritable Cancer Genome

et al. 2021

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“…SNP refers to the polymorphism of the DNA sequence caused by the variation of a single nucleotide at the genomic level. SNPs are widely found in the human genome and can influence the expression and function of key genes involved in tumorigenesis 11–13 . A study in HNSCC found that SNPs of ADH are associated with tumorigenesis, possibly due to their key role in regulating acetaldehyde formation 14 .…”

Section: Discussionmentioning

confidence: 99%

Association Between Alcohol Dehydrogenase Polymorphisms and the Recurrence of Laryngeal Carcinoma

Huang

Lau

et al. 2022

The Laryngoscope

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Objectives Alcohol consumption is closely associated with prognosis for laryngeal squamous cell carcinoma (LSCC) patients. As key enzymes in ethanol metabolism, proteins in the alcohol dehydrogenase (ADH) family make for valuable targets to establish a novel predictive nomogram model. This study attempts to do so by focusing on the single nucleotide polymorphisms (SNPs) of ADH1B and ADH1C in LSCC. Methods Sixty eight LSCC patients that were followed up for more than 10 years were retrospectively analyzed. Endpoints of the current study included disease‐free survival and overall survival. Survival analyses were performed using the Kaplan–Meier method and evaluated by log‐rank test. The prognostic value of eight ADH1B SNPs and three ADH1C SNPs were evaluated using univariate and multivariate Cox regression analyses. A nomogram model for disease‐free survival was established and evaluated using the receiver operating characteristic curve, the C‐index, and a calibration plot. Results Significant association was exhibited between rs17033 (p < 0.001) and rs1229984 (p = 0.002) with an increase in LSCC recurrence rate on Kaplan–Meier curves. Multivariate logistic regression analysis revealed that the rs17033 polymorphism of ADH1B was independently associated with an increased risk of LSCC recurrence (HR = 3.325, 95% CI = 1.684–6.566, p = 0.001). Based on these findings, a prognostic nomogram of LSCC patients involving ADH1B rs17033 was constructed. Conclusion This study has demonstrated an independent association between ADH1B gene variants and the recurrence of LSCC. A nomogram model based on rs17033 of ADH1B, age, T, and N stages were successfully developed for the first time to predict the probability of recurrence in LSCC patients. Level of Evidence 3 Retrospective cohort study Laryngoscope, 132:2169–2176, 2022

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“…However, these treatments burden patients with side effects that reduce therapy compliance and quality of life. In most patients where BC arises not from single gene mutations (or discrete combinations) [5,6], selective estrogen-receptor modulators (SERMs), e.g., tamoxifen and raloxifene, are approved for both the treatment and prevention of BC and decrease BC risk by about 35% [7]. However, tamoxifen is rarely used in clinics for prevention due to serious side effects such as endometrial cancer [8,9].…”

Section: Introductionmentioning

confidence: 99%

Cumin Prevents 17β-Estradiol-Associated Breast Cancer in ACI Rats

Aqil

Jeyabalan

Munagala

et al. 2021

IJMS

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Breast cancer (BC) is a leading cause of cancer deaths in women in less developed countries and the second leading cause of cancer death in women in the U.S. In this study, we report the inhibition of E2-mediated mammary tumorigenesis by Cuminum cyminum (cumin) administered via the diet as cumin powder, as well as dried ethanolic extract. Groups of female ACI rats were given either an AIN-93M diet or a diet supplemented with cumin powder (5% and 7.5%, w/w) or dried ethanolic cumin extract (1%, w/w), and then challenged with subcutaneous E2 silastic implants (1.2 cm; 9 mg). The first appearance of a palpable mammary tumor was significantly delayed by both the cumin powder and extract. At the end of the study, the tumor incidence was 96% in the control group, whereas only 55% and 45% animals had palpable tumors in the cumin powder and extract groups, respectively. Significant reductions in tumor volume (660 ± 122 vs. 138 ± 49 and 75 ± 46 mm3) and tumor multiplicity (4.21 ± 0.43 vs. 1.16 ± 0.26 and 0.9 ± 0.29 tumors/animal) were also observed by the cumin powder and cumin extract groups, respectively. The cumin powder diet intervention dose- and time-dependently offset E2-related pituitary growth, and reduced the levels of circulating prolactin and the levels of PCNA in the mammary tissues. Mechanistically, the cumin powder diet resulted in a significant reversal of E2-associated modulation in ERα, CYP1A1 and CYP1B1. Further, the cumin powder diet reversed the expression levels of miRNAs (miR-182, miR-375, miR-127 and miR-206) that were highly modulated by E2 treatment. We analyzed the composition of the extract by GC/MS and established cymene and cuminaldehyde as major components, and further detected no signs of gross or systemic toxicity. Thus, cumin bioactives can significantly delay and prevent E2-mediated mammary tumorigenesis in a safe and effective manner, and warrant continued efforts to develop these clinically translatable spice bioactives as chemopreventives and therapeutics against BC.

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Dissecting the heritable risk of breast cancer: From statistical methods to susceptibility genes

Cited by 12 publications

References 93 publications

The Landscape of the Heritable Cancer Genome

The Landscape of the Heritable Cancer Genome

Association Between Alcohol Dehydrogenase Polymorphisms and the Recurrence of Laryngeal Carcinoma

Cumin Prevents 17β-Estradiol-Associated Breast Cancer in ACI Rats

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