Clara Bodelon

PhD

NIH

Staff Scientist

PLCO (Learn more about this study)

2019-1017

Dec 27, 2019

Mutational landscape of in situ breast cancers in relation to invasive breast cancers

Advances in breast cancer screening and treatment have reduced breast cancer mortality in the US over the past 30 years. However, the widespread adoption of screening mammography has been accompanied by dramatic increases in early stage breast cancer diagnoses, including in situ breast cancers. Accumulating evidence suggests that a substantial fraction of these early stage breast cancers would never have emerged clinically if not detected through screening. Ductal carcinoma in situ (DCIS) is considered a non-obligate precursor lesion of invasive ductal carcinoma and it is estimated that only 50% of DCIS may progress to invasion. There is widespread consensus that new approaches are urgently needed to distinguish indolent DCIS cases from those that may become life threatening. Molecular alterations identifying the individuals with high-risk breast lesions that will progress to invasive breast cancer remain to be identified. Identification of such markers could have the potential to prevent overtreatment of low-risk DCIS, as well as to develop strategies for prevention of progression to invasive breast cancer for those at high-risk. Somatic characteristics account for much of the biological diversity and blueprint of human cells and tumors. Point mutations and copy number alterations (CNA) are thought to be early events in breast cancer and they are the imprints of DNA damage and DNA repair processes occurring during tumorigenesis. They are also the source of identifying mutational signatures, which are currently unknown for DCIS. The goal of this proposal is to characterize the mutational landscape based on point mutations and CNAs and compare them to invasive breast cancer to better understand the pathways altered during breast cancer progression. This investigation will use tissues from a well-characterized prospective cohort study, the Prostate, Lung, Colorectal and Ovarian (PLCO) Screening Trial, which collected DCIS and invasive breast cancer tumor tissues. The proposed study will exploit an on-going effort to analyze point mutations and CNAs in invasive breast tumors from PLCO, as part of the international B~CAST initiative within the Breast Cancer Association Consortium (BCAC) (EEMS Project ID 2016-0017). B~CAST has the largest biobank of breast cancer tumor tissues worldwide and has developed extensive experience to work with multiple pathology specimens, including formalin-fixed, paraffin-embedded (FFPE) tissues. We propose to leverage the expertise from B~CAST and perform similar somatic analyses for DCIS tumors within PLCO. In addition to identifying subgroups of DCIS, we will explore the relation of well-known breast cancer risk and clinical factors, genetics and other biomarkers to better understand whether they are related to molecular subgroups of DCIS and how they relate to invasive breast cancer.