Browsing by Subject "Cancer genetics"

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    Bevacizumab-induced hypertension and proteinuria: a genome-wide study of more than 1000 patients
    (Springer Nature, 2022) Quintanilha, Julia C.F.; Wang, Jin; Sibley, Alexander B.; Jiang, Chen; Etheridge, Amy S.; Shen, Fei; Jiang, Guanglong; Mulkey, Flora; Patel, Jai N.; Hertz, Daniel L.; Dees, Elizabeth Claire; McLeod, Howard L.; Bertagnolli, Monica; Rugo, Hope; Kindler, Hedy L.; Kelly, William Kevin; Ratain, Mark J.; Kroetz, Deanna L.; Owzar, Kouros; Schneider, Bryan P.; Lin, Danyu; Innocenti, Federico; Medicine, School of Medicine
    Background: Hypertension and proteinuria are common bevacizumab-induced toxicities. No validated biomarkers are available for identifying patients at risk of these toxicities. Methods: A genome-wide association study (GWAS) meta-analysis was performed in 1039 bevacizumab-treated patients of European ancestry in four clinical trials (CALGB 40502, 40503, 80303, 90401). Grade ≥2 hypertension and proteinuria were recorded (CTCAE v.3.0). Single-nucleotide polymorphism (SNP)-toxicity associations were determined using a cause-specific Cox model adjusting for age and sex. Results: The most significant SNP associated with hypertension with concordant effect in three out of the four studies (p-value <0.05 for each study) was rs6770663 (A > G) in KCNAB1, with the G allele increasing the risk of hypertension (p-value = 4.16 × 10-6). The effect of the G allele was replicated in ECOG-ACRIN E5103 in 582 patients (p-value = 0.005). The meta-analysis of all five studies for rs6770663 led to p-value = 7.73 × 10-8, close to genome-wide significance. The most significant SNP associated with proteinuria was rs339947 (C > A, between DNAH5 and TRIO), with the A allele increasing the risk of proteinuria (p-value = 1.58 × 10-7). Conclusions: The results from the largest study of bevacizumab toxicity provide new markers of drug safety for further evaluations. SNP in KCNAB1 validated in an independent dataset provides evidence toward its clinical applicability to predict bevacizumab-induced hypertension.
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    Cisplatin +/− rucaparib after preoperative chemotherapy in patients with triple-negative or BRCA mutated breast cancer
    (Springer Nature, 2021-03-22) Kalra, Maitri; Tong, Yan; Jones, David R.; Walsh, Tom; Danso, Michael A.; Ma, Cynthia X.; Silverman, Paula; King, Mary-Claire; Badve, Sunil S.; Perkins, Susan M.; Miller, Kathy D.; Biostatistics, School of Public Health
    Patients with triple-negative breast cancer (TNBC) who have residual disease after neoadjuvant therapy have a high risk of recurrence. We tested the impact of DNA-damaging chemotherapy alone or with PARP inhibition in this high-risk population. Patients with TNBC or deleterious BRCA mutation (TNBC/BRCAmut) who had >2 cm of invasive disease in the breast or persistent lymph node (LN) involvement after neoadjuvant therapy were assigned 1:1 to cisplatin alone or with rucaparib. Germline mutations were identified with BROCA analysis. The primary endpoint was 2-year disease-free survival (DFS) with 80% power to detect an HR 0.5. From Feb 2010 to May 2013, 128 patients were enrolled. Median tumor size at surgery was 1.9 cm (0-11.5 cm) with 1 (0-38) involved LN; median Residual Cancer Burden (RCB) score was 2.6. Six patients had known deleterious BRCA1 or BRCA2 mutations at study entry, but BROCA identified deleterious mutations in 22% of patients with available samples. Toxicity was similar in both arms. Despite frequent dose reductions (21% of patients) and delays (43.8% of patients), 73% of patients completed planned cisplatin. Rucaparib exposure was limited with median concentration 275 (82-4694) ng/mL post-infusion on day 3. The addition of rucaparib to cisplatin did not increase 2-year DFS (54.2% cisplatin vs. 64.1% cisplatin + rucaparib; P = 0.29). In the high-risk post preoperative TNBC/BRCAmut setting, the addition of low-dose rucaparib did not improve 2-year DFS or increase the toxicity of cisplatin. Genetic testing was underutilized in this high-risk population.
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    Correction: Bevacizumab-induced hypertension and proteinuria: a genome-wide study of more than 1000 patients
    (Springer Nature, 2022) Quintanilha, Julia C.F.; Wang, Jin; Sibley, Alexander B.; Jiang, Chen; Etheridge, Amy S.; Shen, Fei; Jiang, Guanglong; Mulkey, Flora; Patel, Jai N.; Hertz, Daniel L.; Dees, Elizabeth Claire; McLeod, Howard L.; Bertagnolli, Monica; Rugo, Hope; Kindler, Hedy L.; Kelly, William Kevin; Ratain, Mark J.; Kroetz, Deanna L.; Owzar, Kouros; Schneider, Bryan P.; Lin, Danyu; Innocenti, Federico; Medicine, School of Medicine
    Correction to: British Journal of Cancer 10.1038/s41416-021-01557-w, published online 06 October 2021 The original version of this article unfortunately contained a mistake in an author affiliation. Dr. Kouros Owzar was listed as “Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA”, when it should be “Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA”. The original article has been corrected.
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    Genome-wide meta-analysis identifies eight new susceptibility loci for cutaneous squamous cell carcinoma
    (Nature Research, 2020-02-10) Sarin, Kavita Y.; Lin, Yuan; Daneshjou, Roxana; Ziyatdinov, Andrey; Thorleifsson, Gudmar; Rubin, Adam; Pardo, Luba M.; Wu, Wenting; Khavari, Paul A.; Uitterlinden, Andre; Nijsten, Tamar; Toland, Amanda E.; Olafsson, Jon H.; Sigurgeirsson, Bardur; Thorisdottir, Kristin; Jorgensen, Eric; Whittemore, Alice S.; Kraft, Peter; Stacey, Simon N.; Stefansson, Kari; Asgari, Maryam M.; Han, Jiali; Epidemiology, School of Public Health
    Cutaneous squamous cell carcinoma (SCC) is one of the most common cancers in the United States. Previous genome-wide association studies (GWAS) have identified 14 single nucleotide polymorphisms (SNPs) associated with cutaneous SCC. Here, we report the largest cutaneous SCC meta-analysis to date, representing six international cohorts and totaling 19,149 SCC cases and 680,049 controls. We discover eight novel loci associated with SCC, confirm all previously associated loci, and perform fine mapping of causal variants. The novel SNPs occur within skin-specific regulatory elements and implicate loci involved in cancer development, immune regulation, and keratinocyte differentiation in SCC susceptibility.
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    Identification of germline cancer predisposition variants during clinical ctDNA testing
    (Springer Nature, 2021-07) Stout, Leigh Anne; Kassem, Nawal; Hunter, Cynthia; Philips, Santosh; Radovich, Milan; Schneider, Bryan P.; Medical and Molecular Genetics, School of Medicine
    Next-generation sequencing of circulating tumor DNA (ctDNA) is a non-invasive method to guide therapy selection for cancer patients. ctDNA variant allele frequency (VAF) is commonly reported and may aid in discerning whether a variant is germline or somatic. We report on the fidelity of VAF in ctDNA as a predictor for germline variant carriage. Two patient cohorts were studied. Cohort 1 included patients with known germline variants. Cohort 2 included patients with any variant detected by the ctDNA assay with VAF of 40–60%. In cohort 1, 36 of 91 (40%) known germline variants were identified through ctDNA analysis with a VAF of 39–87.6%. In cohort 2, 111 of 160 (69%) variants identified by ctDNA analysis with a VAF between 40 and 60% were found to be germline. Therefore, variants with a VAF between 40 and 60% should induce suspicion for germline status but should not be used as a replacement for germline testing.
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    Identifying polymorphic cis-regulatory variants as risk markers for lung carcinogenesis and chemotherapy responses in tobacco smokers from eastern India
    (Springer Nature, 2023-03-10) Sengupta, Debmalya; Mukhopadhyay, Pramiti; Banerjee, Souradeep; Ganguly, Kausik; Mascharak, Prateek; Mukherjee, Noyonika; Mitra, Sangeeta; Bhattacharjee, Samsiddhi; Mitra, Ritabrata; Sarkar, Abhijit; Chaudhuri, Tamohan; Bhattacharjee, Gautam; Nath, Somsubhra; Roychoudhury, Susanta; Sengupta, Mainak; Biochemistry and Molecular Biology, School of Medicine
    Aberrant expression of xenobiotic metabolism and DNA repair genes is critical to lung cancer pathogenesis. This study aims to identify the cis-regulatory variants of the genes modulating lung cancer risk among tobacco smokers and altering their chemotherapy responses. From a list of 2984 SNVs, prioritization and functional annotation revealed 22 cis-eQTLs of 14 genes within the gene expression-correlated DNase I hypersensitive sites using lung tissue-specific ENCODE, GTEx, Roadmap Epigenomics, and TCGA datasets. The 22 cis-regulatory variants predictably alter the binding of 44 transcription factors (TFs) expressed in lung tissue. Interestingly, 6 reported lung cancer-associated variants were found in linkage disequilibrium (LD) with 5 prioritized cis-eQTLs from our study. A case–control study with 3 promoter cis-eQTLs (p < 0.01) on 101 lung cancer patients and 401 healthy controls from eastern India with confirmed smoking history revealed an association of rs3764821 (ALDH3B1) (OR = 2.53, 95% CI = 1.57–4.07, p = 0.00014) and rs3748523 (RAD52) (OR = 1.69, 95% CI = 1.17–2.47, p = 0.006) with lung cancer risk. The effect of different chemotherapy regimens on the overall survival of lung cancer patients to the associated variants showed that the risk alleles of both variants significantly decreased (p < 0.05) patient survival.
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    Integrative analysis identifies an older female-linked AML patient group with better risk in ECOG-ACRIN Cancer Research Group's clinical trial E3999
    (Springer Nature, 2022-09-23) Rapaport, Franck; Seier, Kenneth; Neelamraju, Yaseswini; Hassane, Duane; Baslan, Timour; Gildea, Daniel T.; Haddox, Samuel; Lee, Tak; Murdock, H. Moses; Sheridan, Caroline; Thurmond, Alexis; Wang, Ling; Carroll, Martin; Cripe, Larry D.; Fernandez, Hugo; Mason, Christopher E.; Paietta, Elisabeth; Roboz, Gail J.; Sun, Zhuoxin; Tallman, Martin S.; Zhang, Yanming; Gönen, Mithat; Levine, Ross; Melnick, Ari M.; Kleppe, Maria; Garrett-Bakelman, Francine E.; Medicine, School of Medicine
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    Mutational and splicing landscape in a cohort of 43,000 patients tested for hereditary cancer
    (Springer Nature, 2022-08-25) Horton, Carolyn; Cass, Ashley; Conner, Blair R.; Hoang, Lily; Zimmermann, Heather; Abualkheir, Nelly; Burks, David; Qian, Dajun; Molparia, Bhuvan; Vuong, Huy; LaDuca, Holly; Grzybowski, Jessica; Durda, Kate; Pilarski, Robert; Profato, Jessica; Clayback, Katherine; Mahoney, Martin; Schroeder, Courtney; Torres-Martinez, Wilfredo; Elliott, Aaron; Chao, Elizabeth C.; Karam, Rachid; Medical and Molecular Genetics, School of Medicine
    DNA germline genetic testing can identify individuals with cancer susceptibility. However, DNA sequencing alone is limited in its detection and classification of mRNA splicing variants, particularly those located far from coding sequences. Here we address the limitations of splicing variant identification and interpretation by pairing DNA and RNA sequencing and describe the mutational and splicing landscape in a clinical cohort of 43,524 individuals undergoing genetic testing for hereditary cancer predisposition.
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    Prognostic Mutational Signatures of NSCLC Patients treated with chemotherapy, immunotherapy and chemoimmunotherapy
    (Springer Nature, 2023-03-27) Smith, Margaret R.; Wang, Yuezhu; D’Agostino, Ralph, Jr.; Liu, Yin; Ruiz, Jimmy; Lycan, Thomas; Oliver, George; Miller, Lance D.; Topaloglu, Umit; Pinkney, Jireh; Abdulhaleem, Mohammed N.; Chan, Michael D.; Farris, Michael; Su, Jing; Mileham, Kathryn F.; Xing, Fei; Biostatistics and Health Data Science, School of Medicine
    Different types of therapy are currently being used to treat non-small cell lung cancer (NSCLC) depending on the stage of tumor and the presence of potentially druggable mutations. However, few biomarkers are available to guide clinicians in selecting the most effective therapy for all patients with various genetic backgrounds. To examine whether patients' mutation profiles are associated with the response to a specific treatment, we collected comprehensive clinical characteristics and sequencing data from 524 patients with stage III and IV NSCLC treated at Atrium Health Wake Forest Baptist. Overall survival based Cox-proportional hazard regression models were applied to identify mutations that were "beneficial" (HR < 1) or "detrimental" (HR > 1) for patients treated with chemotherapy (chemo), immune checkpoint inhibitor (ICI) and chemo+ICI combination therapy (Chemo+ICI) followed by the generation of mutation composite scores (MCS) for each treatment. We also found that MCS is highly treatment specific that MCS derived from one treatment group failed to predict the response in others. Receiver operating characteristics (ROC) analyses showed a superior predictive power of MCS compared to TMB and PD-L1 status for immune therapy-treated patients. Mutation interaction analysis also identified novel co-occurring and mutually exclusive mutations in each treatment group. Our work highlights how patients' sequencing data facilitates the clinical selection of optimized treatment strategies.
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    Stromal heterogeneity may explain increased incidence of metaplastic breast cancer in women of African descent
    (Springer Nature, 2023-09-14) Kumar, Brijesh; Khatpe, Aditi S.; Guanglong, Jiang; Batic, Katie; Bhat-Nakshatri, Poornima; Granatir, Maggie M.; Addison, Rebekah Joann; Szymanski, Megan; Baldridge, Lee Ann; Temm, Constance J.; Sandusky, George; Althouse, Sandra K.; Cote, Michele L.; Miller, Kathy D.; Storniolo, Anna Maria; Nakshatri, Harikrishna; Surgery, School of Medicine
    The biologic basis of genetic ancestry-dependent variability in disease incidence and outcome is just beginning to be explored. We recently reported enrichment of a population of ZEB1-expressing cells located adjacent to ductal epithelial cells in normal breasts of women of African ancestry compared to those of European ancestry. In this study, we demonstrate that these cells have properties of fibroadipogenic/mesenchymal stromal cells that express PROCR and PDGFRα and transdifferentiate into adipogenic and osteogenic lineages. PROCR + /ZEB1 + /PDGFRα+ (PZP) cells are enriched in normal breast tissues of women of African compared to European ancestry. PZP: epithelial cell communication results in luminal epithelial cells acquiring basal cell characteristics and IL-6-dependent increase in STAT3 phosphorylation. Furthermore, level of phospho-STAT3 is higher in normal and cancerous breast tissues of women of African ancestry. PZP cells transformed with HRasG12V ± SV40-T/t antigens generate metaplastic carcinoma suggesting that these cells are one of the cells-of-origin of metaplastic breast cancers.