Analyzing Copy Number Alterations in Preinvasive Disease of High-Grade Serous Ovarian Cancer to Build the Basis for Early Detection
Abstract
Rationale and Objective: Ovarian cancer progresses fast with only vague symptoms, typically resulting in late diagnosis and making ovarian cancer one of the most deadly types of cancer in women. Early detection of the tumor, however, leads to a significant difference, increasing the fraction of women who survive for more than 5 years from 28% to 90%. The ability to identify cells that are likely to turn into cancer, while being still curable, is key for early detection. New research now suggests that the most fatal subtype of ovarian cancer (high-grade serous ovarian cancer) originates from the fallopian tube since non-invasive lesions, which are molecularly comparable to full-blown ovarian cancer, were identified in the part of the fallopian tube that is close to the ovary. From there, they reach the surface of the ovary, where they progress and ultimately create a cancer that gives the impression to be of an ovarian origin. Damage to DNA is known to cause and drive malignancy and, thus, DNA alterations occurring early during tumorigenesis can be tracked and used for preventive medicine. In the last years, sophisticated novel sequencing techniques have been established and can now generate reliable data from very small amounts of DNA. Critical Problem Addressed: Until now, early detection approaches in ovarian cancer screened for invasive disease confined to the ovaries. However, these studies did not prove efficient in prolonging survival. Focusing on non-invasive and thus curable lesions appears to be a more rational way to tackle early detection. A key technological limitation, which previously hampered such an approach, is the small amount of DNA available from the limited tumor content of non-invasive disease, an amount insufficient for traditional sequencing methods. New Paradigms, Insights, Technologies, Applications Provided: We build our approach upon the outstanding sequencing technology and cancer genome analysis in the Getz lab and the wealth of knowledge and experience in the field of ovarian cancer in the Birrer lab. We are now able to sequence and analyze genomic alterations from as little as 1 ng of DNA with high sensitivity and specificity. By applying this cutting-edge technology to non-invasive high-grade serous ovarian cancer, we aim to (i) characterize genomic alterations in curable lesions of the fallopian tube; (ii) gain radical new insights into ovarian cancer tumorigenesis; (iii) advance preventive medicine by further applying our tools to DNA derived from vaginal fluids of high-risk patients; and (iv) promote technology advancement for the field of cancer genomics. Relevance According to the Vision and Mission of the Ovarian Cancer Research Program (OCRP): Early diagnosis of ovarian cancer by detecting precursor lesions appears to be the most promising way to reduce high-grade serous ovarian cancer mortality. By using novel next-generation sequencing methods as well as innovative analytical tools, our study will build the basis for a future screening method. Due to its cost-effectiveness and non-invasiveness, our envisioned preventive approach can be implemented in routine practice, thereby leading to a significant improvement in health care. Our proposed pioneering development of screening and the deeper understanding of pre-invasive disease and tumor development targets two of the critical needs addressed by the OCRP (understanding precursor lesions; developing performance and reliability of screening) and is of key interest to all professionals who care for women and their families.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710084
Entities
People
- Gad Getz
Organizations
- Massachusetts General Hospital
- United States Army