Our inaugural PEER awardees were honored for their work in cutting-edge approaches to detection in early stage cancer on February 5, 2020 at the second annual Zhu Center Symposium- Novel Diagnostics for Early Cancer Detection. Read more about our symposium here.
Transformational Methods for Early Cancer Detection Using Cell-Free DNA
Jeffrey Miller, Assistant Professor of Biostatistics, Harvard T.H. Chan School of Public Health
If detected early, many cancers can be successfully treated, leading to a high rate of survival. Unfortunately, cancer is often detected at late stages since current screening technologies have insufficient sensitivity and specificity at low tumor fractions. Cell-free DNA (cfDNA) sequencing presents an exciting possibility for highly accurate, non-invasive cancer screening. When cells die, they often release small fragments of their DNA into the bloodstream. Thus, when cancer is present, plasma from routine blood draws contains DNA from cancer cells. By performing genome sequencing on this plasma cfDNA, it is possible to non-invasively detect and analyze cancers. However, advanced statistical methods are needed to extract the signal from the noise. The fraction of tumor-derived cfDNA fragments is very small, on the order of 1/1000 or less for early stage cancers. The objective of this project is to develop a flexible suite of statistical methods for cancer detection and analysis using cfDNA sequencing data at low tumor fractions. (Aim1) Develop robust nonparametric Poisson regression framework, applied to mutational signatures. (Aim 2) Develop grammar-based methods for complex models of sequential data, applied to copy number alterations. (Aim 3) Develop integrated Bayesian framework for robust cancer detection from cfDNA sequencing.
Pre-diagnostic Tissue Biomarkers and Prostate Cancer Risk in a Population Based Cohort
Lorelei Mucci, Associate Professor, Department of Epidemiology, Harvard T.H. Chan School of Public Health
One million US men undergo a prostate biopsy annually, resulting in 164,000 diagnosed prostate cancers. Only a fraction of men with an initial negative biopsy will ultimately be diagnosed with prostate cancer. As such hundreds of thousands undergo unnecessary biopsies, which carry risk of infection, sepsis, and cost. Identifying predictors at time of negative biopsy that appropriately identify men as high or low risk of developing prostate cancer, particularly aggressive forms of disease, would be clinically significant and allow a tailored follow-up strategy that would improve outcomes. Our scientific premise is that tissue biomarkers in negative prostate biopsies hold translational potential to improve classification of patients at low and high-risk of prostate cancer. We will develop a novel repository of negative prostate biopsies within the Health Professionals Follow-up Study to identify early-detection biomarkers. We will sample 500 men from 9,600 who have had a negative prostate biopsy, of whom 250 ultimately were diagnosed with cancer during a median 14.5-years follow-up and 250 cancerfree controls. Specifically, we will: Aim 1: Examine histologic biomarkers of inflammation and future prostate cancer risk. Aim 2: Use RNAseq to identify genes and pathways in prostate epithelial and stromal tissue associated with future cancer risk.
Early Detection of Non-viral Hepatocellular Carcinoma: A Proteomics Study
Xuehong Zhang, Assistant Professor, Department of Nutrition, Harvard T. H. Chan School of Public Health; Assistant Professor in Medicine, Harvard Medical School; Associate Epidemiologist, Brigham and Women’s Hospital
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide, and its incidence has tripled in the US since the 1980s. Most HCCs are diagnosed at a late—and thus, less treatable—stage. Patients with cirrhosis are at high risk for HCC; however, biomarkers suitable for screening and early diagnosis of HCC are lacking. HCC also exhibits racial disparities, as there is a higher prevalence of HCC in racial minorities in the US, and black patients typically present with a more advanced stage of HCC. The objective of this proposed PEER research is to use novel technologies to identify new plasma protein biomarkers for non-viral HCC that can advance understanding of disease etiology, enable early HCC detection in cirrhosis patients, and assess racial or ethnic differences in biology. We propose leveraging a prospective cohort of cirrhosis patients and three Harvard cohorts from the general population. This PEER award provides an excellent opportunity for the PI to extend a career in early diagnosis and detection of HCC and lay the groundwork for larger external collaborative grant applications.