http://hdl.handle.net/10379/1217 2017-10-29T23:46:12Z http://hdl.handle.net/10379/4067 Clinical applications of gene expression in colorectal cancer. Kerin, Michael J. Despite developments in diagnosis and treatment, 20% of colorectal cancer (CRC) patients present with metastatic disease and 30% of cases recur after curative surgery. Furthermore, the molecular factors involved in prognosis and response to therapy in CRC is poorly understood. The aims of this study were to quantitatively examine the expression of target genes in colorectal cancer and to correlate their expression levels with clinico-pathological variables. Journal article 2013-01-01T00:00:00Z http://hdl.handle.net/10379/4000 The KRAS-Variant Is Associated with Risk of Developing Double Primary Breast and Ovarian Cancer Kerin, Michael J.; McVeigh, Terri; Dorairaj, Jemima J.; Heneghan, Helen M.; Miller, Nicola Purpose: A germline microRNA binding site-disrupting variant, the KRAS-variant (rs61764370), is associated with an increased risk of developing several cancers. Because this variant is most strongly associated with ovarian cancer risk in patients from hereditary breast and ovarian families (HBOC), and with the risk of premenopausal triple negative breast cancer, we evaluated the association of the KRAS-variant with women with personal histories of both breast and ovarian cancer, referred to as double primary patients.Experimental Design: Germline DNA from double primary patients was tested for the KRAS-variant (n = 232). Confirmation of pathologic diagnoses, age of diagnoses, interval between ovarian cancer diagnosis and sample collection, additional cancer diagnoses, and family history were obtained when available. All patients were tested for deleterious BRCA mutations.Results: The KRAS-variant was significantly enriched in uninformative (BRCA negative) double primary patients, being found in 39% of patients accrued within two years of their ovarian cancer diagnosis. Furthermore, the KRAS-variant was found in 35% of uninformative double primary patients diagnosed with ovarian cancer post-menopausally, and was significantly associated with uninformative double primary patients with a positive family history. The KRAS-variant was also significantly enriched in uninformative patients who developed more then two primary cancers, being found in 48% of women with two breast primaries plus ovarian cancer or with triple primary cancers.Conclusions: These findings further validate the importance of the KRAS-variant in breast and ovarian cancer risk, and support the association of this variant as a genetic marker for HBOC families previously considered uninformative. 2012-01-01T00:00:00Z http://hdl.handle.net/10379/3883 Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer. Kerin, Michael J.; Miller, Nicola TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ~480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10!-7), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10!-8) and BRCA1 mutation carrier (P = 1.1 × 10!-5) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10!-14), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10!-15) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10!-12) and BRCA1 mutation carrier (P = 1.6 × 10!-14) breast and invasive ovarian (P = 1.3 × 10!-11) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant. Journal article 2013-04-01T00:00:00Z http://hdl.handle.net/10379/3851 Large-scale genotyping identifies 41 new loci associated with breast cancer risk. Kerin, Michael J.; Miller, Nicola Breast cancer is the most common cancer among women. Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ~9% of the familial risk of the disease. We report here a meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping. These SNPs were genotyped in 45,290 cases and 41,880 controls of European ancestry from 41 studies in the Breast Cancer Association Consortium (BCAC). The SNPs were genotyped as part of a collaborative genotyping experiment involving four consortia (Collaborative Oncological Gene-environment Study, COGS) and used a custom Illumina iSelect genotyping array, iCOGS, comprising more than 200,000 SNPs. We identified SNPs at 41 new breast cancer susceptibility loci at genome-wide significance (P < 5 × 10!¿8). Further analyses suggest that more than 1,000 additional loci are involved in breast cancer susceptibility. Journal article 2013-03-27T00:00:00Z