Biology subjects

Weitzel, J. N.

Publications and source records attributed to Weitzel, J. N..

3 recordsLinked to original sources

bioRxiv2022

Profile of the somatic mutational landscape in breast tumors from Hispanic/Latina women

Breast cancer causes the most cancer deaths among Hispanic/Latinas (H/L). However, limited tumor-sequencing data from H/L are available to guide treatment. To address this gap, we performed whole-exome sequencing of DNA from 140 HL germline and 146 matched breast tumors and RNA-seq for the tumors. We generated somatic-mutation profiles, identified copy-number alterations (CNAs), and compared results to non-Hispanic White (White) women in The Cancer Genome Atlas. Similar to Whites, PIK3CA and TP53 were the most commonly mutated genes in breast tumors from H/L. We found 4 common COSMIC mutation signatures (1, 2, 3, 13) and signature 16 not previously reported in other breast-cancer datasets. We observed recurrent amplifications in breast-cancer drivers including MYC, FGFR1, CCND1, and ERBB2, and a recurrent amplification on 17q11.2 associated with high KIAA0100 gene expression, implicated in breast-cancer aggressiveness. Expanded research is required to determine how these characteristics of H/L tumors impact treatment response and survival.

cancer biology↗

bioRxiv2022

Variable Number Tandem Repeats (VNTRs) as modifiers of breast cancer risk in carriers of BRCA1 185delAG

Despite substantial efforts in identifying both rare and common variants affecting disease risk, in the majority of diseases, a large proportion of unexplained genetic risk remains. We propose that variable number tandem repeats (VNTRs) may explain a proportion of the missing genetic risk. Herein, we tested whether VNTRs are causal modifiers of breast cancer risk in 347 female carriers of BRCA1 185delAG, an important group given their high risk of developing breast cancer. We performed targeted-capture to sequence VNTRs, called genotypes with adVNTR, and tested the association of VNTRs and breast cancer risk using Cox regression models. Of 303 VNTRs that passed quality control checks, 4 VNTRs were significantly associated with risk to develop breast cancer at false discovery rate [FDR] < 0.05 and an additional 4 VNTRs had FDR < 0.25. After determining the specific risk alleles, there was a significantly earlier age at development of breast cancer in carriers of the risk genotypes compared to those without the risk genotypes for seven of eight VNTRs. Results from this first systematic study of VNTRs demonstrate that VNTRs may explain a proportion of the unexplained genetic risk for disease and have larger effects than SNPs.

cancer biology↗

bioRxiv2019

A polygenic risk score for breast cancer in U.S. Latinas and Latin-American women

BackgroundOver 180 single nucleotide polymorphisms (SNPs) associated with breast cancer susceptibility have been identified; these SNPs can be combined into polygenic risk scores (PRS) to predict breast cancer risk. Since most SNPs were identified in predominantly European populations, little is known about the performance of PRS in non-Europeans. We tested the performance of a 180-SNP PRS in Latinas, a large ethnic group with variable levels of Indigenous American, European, and African ancestry.\n\nMethodsWe conducted a pooled case-control analysis of U.S. Latinas and Latin-American women (4,658 cases, 7,622 controls). We constructed a 180-SNP PRS consisting of SNPs associated with breast cancer risk (p < 5 x 10-8). We evaluated the association between the PRS and breast cancer risk using multivariable logistic regression and assessed discrimination using area under the receiver operating characteristic curve (AUROC). We also assessed PRS performance across quartiles of Indigenous American genetic ancestry.\n\nResultsOf 180 SNPs tested, 142 showed directionally consistent associations compared with European populations, and 39 were nominally significant (p < 0.05). The PRS was associated with breast cancer risk, with an odds ratio (OR) per standard deviation increment of 1.58 (95% CI 1.52 to 1.64) and AUCROC of 0.63 (95% CI 0.62 to 0.64). The discrimination of the PRS was similar between the top and bottom quartiles of Indigenous American ancestry.\n\nConclusionsThe 180-SNP PRS predicts breast cancer risk in Latinas, with similar performance as reported for Europeans. The performance of the PRS did not vary substantially according to Indigenous American ancestry.

epidemiology↗