Abstract
Ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS) are clinically undetectable forms of non-invasive breast cancer. DCIS is considered a non-obligate precursor of invasive ductal carcinoma (IDC). LCIS shares many of the same genetic aberrations as invasive lobular breast cancer (ILC), which accounts for 10-15% of all invasive breast cancer. With the advent of screening mammography, the diagnosis of pure DCIS (with no invasive component) and LCIS has become more common, and approximately 20% of screen detected tumours are pure DCIS.The aim of this project is to test the hypothesis that breast cancer is a heterogeneous disease and that by focusing on specific histological subtypes we can increase the power to detect genetic variants that predispose to DCIS/LCIS/ILC. We also exploited the extreme phenotype hypothesis, having focused on cases with a severe phenotype such as early-onset or bilateral disease.
During this PhD we assessed the role of rare coding variants using next generation sequencing approaches. We also interrogated data on 211,000 SNPs, genotyped on the iCOGS platform in 3,000 DCIS cases 2500 LCIS/ILC and 5000 controls, to evaluate common variants that predispose to these subtypes of breast cancer.
Some of the key findings include the excess of CDH1 protein truncating variants in cases with bilateral lobular lesions (8%), and the identification of a novel lobular specific locus on 7q34. We were also able to estimate the prevalence of rare variants predisposing to breast cancer in the context of sporadic cases with DCIS/LCIS/ILC. Further analyses and validation is required in order to assess any of the novel putative genes can be linked with ILC development.
Once such variants have been validated they can be used to predict which women are at high risk of developing DCIS/LCIS/ILC and such women can be offered intensive screening or chemoprevention.
| Date of Award | 2018 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Michael Simpson (Supervisor) & Elinor Sawyer (Supervisor) |