Jenny Chang-Claude

Evaluation of linkage of breast cancer to the putative BRCA3 locus on chromosome 13q21 in 128 multiple case families from the Breast Cancer Linkage Consortium

The known susceptibility genes for breast cancer, including BRCA1 and BRCA2, only account for a minority of the familial aggregation of the disease. A recent study of 77 multiple case breast cancer families from Scandinavia found evidence of linkage between the disease and polymorphic markers on chromosome 13q21. We have evaluated the contribution of this candidate “BRCA3” locus to breast cancer susceptibility in 128 high-risk breast cancer families of Western European ancestry with no identified BRCA1 or BRCA2 mutations. No evidence of linkage was found. The estimated proportion (α) of families linked to a susceptibility locus at D13S1308, the location estimated by Kainu et al. [(2000) Proc. Natl. Acad. Sci. USA 97, 9603–9608], was 0 (upper 95% confidence limit 0.13). Adjustment for possible bias due to selection of families on the basis of linkage evidence at BRCA2 did not materially alter this result (α = 0, upper 95% confidence limit 0.18). The proportion of linked families reported by Kainu et al. (0.65) is excluded with a high degree of confidence in our dataset [heterogeneity logarithm of odds (HLOD) at α = 0.65 was −11.0]. We conclude that, if a susceptibility gene does exist at this locus, it can only account for a small proportion of non-BRCA1/2 families with multiple cases of early-onset breast cancer.

Common Breast Cancer Susceptibility Loci Are Associated with Triple-Negative Breast Cancer

Triple-negative breast cancers are an aggressive subtype of breast cancer with poor survival, but there remains little known about the etiologic factors that promote its initiation and development. Commonly inherited breast cancer risk factors identified through genome-wide association studies display heterogeneity of effect among breast cancer subtypes as defined by the status of estrogen and progesterone receptors. In the Triple Negative Breast Cancer Consortium (TNBCC), 22 common breast cancer susceptibility variants were investigated in 2,980 Caucasian women with triple-negative breast cancer and 4,978 healthy controls. We identified six single-nucleotide polymorphisms, including rs2046210 (ESR1), rs12662670 (ESR1), rs3803662 (TOX3), rs999737 (RAD51L1), rs8170 (19p13.1), and rs8100241 (19p13.1), significantly associated with the risk of triple-negative breast cancer. Together, our results provide convincing evidence of genetic susceptibility for triple-negative breast cancer.

Potential for Colorectal Cancer Prevention of Sigmoidoscopy Versus Colonoscopy: Population-Based Case Control Study

We aimed to estimate the proportions of colorectal cancer cases that might be prevented by sigmoidoscopy compared with colonoscopy among women and men. In a population-based case control study conducted in Germany, 540 cases with a first diagnosis of primary colorectal cancer and 614 controls matched for age, sex, and county of residence were recruited. A detailed lifetime history of endoscopic examinations of the large bowel was obtained by standardized personal interviews, validated by medical records, and compared between cases and controls, paying particular attention to location of colorectal cancer and sex differences. Overall, 39%, 77%, and 64% of proximal, distal, and total colorectal cancer cases were estimated to be preventable by colonoscopy. The estimated proportion of total colorectal cancer cases preventable by sigmoidoscopy was 45% among both women and men, assuming that sigmoidoscopy reaches the junction of the descending and sigmoid colon only and findings of distal polyps are not followed by colonoscopy. Assuming that sigmoidoscopy reaches the splenic flexure and colonoscopy is done after detection of distal polyps, estimated proportions of total colorectal cancer preventable by sigmoidoscopy increase to 50% and 55% (73% and 91% of total colorectal cancer preventable by primary colonoscopy) among women and men, respectively. We conclude that colonoscopy provides strong protection against colorectal cancer among both women and men. The proportion of this protection achieved by sigmoidoscopy with follow-up colonoscopy in case of distal polyps may be larger than anticipated. Among men, this regimen may be almost as effective as colonoscopy, at least at previous performance levels of colonoscopy. (Cancer Epidemiol Biomarkers Prev 2007;16(3):494–9)

Estimating the heritability of colorectal cancer

A sizable fraction of colorectal cancer (CRC) is expected to be explained by heritable factors, with heritability estimates ranging from 12 to 35% twin and family studies. Genome-wide association studies (GWAS) have successfully identified a number of common single-nucleotide polymorphisms (SNPs) associated with CRC risk. Although it has been shown that these CRC susceptibility SNPs only explain a small proportion of the genetic risk, it is not clear how much of the heritability these SNPs explain and how much is left to be detected by other, yet to be identified, common SNPs. Therefore, we estimated the heritability of CRC under different scenarios using Genome-Wide Complex Trait Analysis in the Genetics and Epidemiology of Colorectal Cancer Consortium including 8025 cases and 10 814 controls. We estimated that the heritability explained by known common CRC SNPs identified in GWAS was 0.65% (95% CI:0.3-1%; P = 1.11 × 10-16), whereas the heritability explained by all common SNPs was at least 7.42% (95% CI: 4.71-10.12%; P = 8.13 × 10(-8)), suggesting that many common variants associated with CRC risk remain to be detected. Comparing the heritability explained by the common variants with that from twin and family studies, a fraction of the heritability may be explained by other genetic variants, such as rare variants. In addition, our analysis showed that the gene × smoking interaction explained a significant proportion of the CRC variance (P = 1.26 × 10(-2)). In summary, our results suggest that known CRC SNPs only explain a small proportion of the heritability and more common SNPs have yet to be identified.

Association Between a Germline OCA2 Polymorphism at Chromosome 15q13.1 and Estrogen Receptor–Negative Breast Cancer Survival

BACKGROUNDnTraditional prognostic factors for survival and treatment response of patients with breast cancer do not fully account for observed survival variation. We used available genotype data from a previously conducted two-stage, breast cancer susceptibility genome-wide association study (ie, Studies of Epidemiology and Risk factors in Cancer Heredity [SEARCH]) to investigate associations between variation in germline DNA and overall survival.nnnMETHODSnWe evaluated possible associations between overall survival after a breast cancer diagnosis and 10 621 germline single-nucleotide polymorphisms (SNPs) from up to 3761 patients with invasive breast cancer (including 647 deaths and 26 978 person-years at risk) that were genotyped previously in the SEARCH study with high-density oligonucleotide microarrays (ie, hypothesis-generating set). Associations with all-cause mortality were assessed for each SNP by use of Cox regression analysis, generating a per rare allele hazard ratio (HR). To validate putative associations, we used patient genotype information that had been obtained with 5 nuclease assay or mass spectrometry and overall survival information for up to 14 096 patients with invasive breast cancer (including 2303 deaths and 70 019 person-years at risk) from 15 international case-control studies (ie, validation set). Fixed-effects meta-analysis was used to generate an overall effect estimate in the validation dataset and in combined SEARCH and validation datasets. All statistical tests were two-sided.nnnRESULTSnIn the hypothesis-generating dataset, SNP rs4778137 (C>G) of the OCA2 gene at 15q13.1 was statistically significantly associated with overall survival among patients with estrogen receptor-negative tumors, with the rare G allele being associated with increased overall survival (HR of death per rare allele carried = 0.56, 95% confidence interval [CI] = 0.41 to 0.75, P = 9.2 x 10(-5)). This association was also observed in the validation dataset (HR of death per rare allele carried = 0.88, 95% CI = 0.78 to 0.99, P = .03) and in the combined dataset (HR of death per rare allele carried = 0.82, 95% CI = 0.73 to 0.92, P = 5 x 10(-4)).nnnCONCLUSIONnThe rare G allele of the OCA2 polymorphism, rs4778137, may be associated with improved overall survival among patients with estrogen receptor-negative breast cancer.

Genetic variants in the glutathione S-transferase genes and survival in colorectal cancer patients after chemotherapy and differences according to treatment with oxaliplatin.

Introduction The glutathione S-transferase (GST) enzymes are involved in the detoxification of a range of carcinogenic compounds as well as chemotherapeutic agents. Therefore, genetic variants in the GST genes could influence survival in patients with colorectal cancer (CRC). Results from previous studies have been inconsistent and therefore we investigated the association between the GSTP1 ile105val polymorphism and the copy number variants of the GSTM1 and GSTT1 genes and survival in CRC patients treated with adjuvant/palliative chemotherapy. Patients and methods We included 755 CRC patients with stage II–IV disease from two population-based studies carried out in Germany. Genotyping of the GSTP1 polymorphism was carried out using fluorescence-based melting curve analysis and copy number variants were determined using a multiplex PCR. Survival analysis was carried out using the Cox regression model, adjusting for age, sex, UICC stage, cancer site, and radiation therapy. Results Compared with noncarriers, CRC patients who were homozygote carriers of GSTM1 had significantly poorer survival after treatment with oxaliplatin [hazard ratio (HR) 2.25, 95% confidence interval (CI) 0.93–5.44] than those not treated with oxaliplatin (HR 0.64, 95% CI 0.30–1.34; P for heterogeneity=0.031). The association was significant in metastatic CRC patients treated with oxaliplatin (HR 3.59, 95% CI 1.29–10.03). Neither the GSTP1 105val allele nor the GSTT1 deletion was significantly associated with CRC survival. Conclusion Our data suggest that GSTM1 may be a predictive marker for oxaliplatin therapy; however, independent large studies are warranted to confirm these results.

No evidence of gene-calcium interactions from genome-wide analysis of colorectal cancer risk

Background: Calcium intake may reduce risk of colorectal cancer, but the mechanisms remain unclear. Studies of interaction between calcium intake and SNPs in calcium-related pathways have yielded inconsistent results. Methods: To identify gene–calcium interactions, we tested interactions between approximately 2.7 million SNPs across the genome with self-reported calcium intake (from dietary or supplemental sources) in 9,006 colorectal cancer cases and 9,503 controls of European ancestry. To test for multiplicative interactions, we used multivariable logistic regression and defined statistical significance using the conventional genome-wide α = 5E−08. Results: After accounting for multiple comparisons, there were no statistically significant SNP interactions with total, dietary, or supplemental calcium intake. Conclusions: We found no evidence of SNP interactions with calcium intake for colorectal cancer risk in a large population of 18,509 individuals. Impact: These results suggest that in genome-wide analysis common genetic variants do not strongly modify the association between calcium intake and colorectal cancer in European populations. Cancer Epidemiol Biomarkers Prev; 23(12); 2971–6. ©2014 AACR.

Pathway analysis of genetic variants in folate-mediated one-carbon metabolism-related genes and survival in a prospectively followed cohort of colorectal cancer patients

Folate‐mediated one‐carbon metabolism (FOCM) is a key pathway essential for nucleotide synthesis, DNA methylation, and repair. This pathway is a critical target for 5‐fluorouracil (5‐FU), which is predominantly used for colorectal cancer (CRC) treatment. A comprehensive assessment of polymorphisms in FOCM‐related genes and their association with prognosis has not yet been performed. Within 1,739 CRC cases aged ≥30 years diagnosed from 2003 to 2007 (DACHS study), we investigated 397 single nucleotide polymorphisms (SNPs) and 50 candidates in 48 FOCM‐related genes for associations with overall‐ (OS) and disease‐free survival (DFS) using multiple Cox regression (adjusted for age, sex, stage, grade, BMI, and alcohol). We investigated effect modification by 5‐FU‐based chemotherapy and assessed pathway‐specific effects. Correction for multiple testing was performed using false discovery rates (FDR). After a median follow‐up time of 5.0 years, 585 patients were deceased. For one candidate SNP in MTHFR and two in TYMS, we observed significant inverse associations with OS (MTHFR: rs1801133, C677T: HRhet = 0.81, 95% CI: 0.67–0.97; TYMS: rs1001761: HRhet = 0.82, 95% CI: 0.68–0.99 and rs2847149: HRhet = 0.82, 95% CI: 0.68–0.99). After FDR correction, one polymorphism in paraoxonase 1 (PON1; rs3917538) was significantly associated with OS (HRhet = 1.28, 95% CI: 1.07–1.53; HRhzv = 2.02, 95% CI:1.46–2.80; HRlogAdd = 1.31, pFDR = 0.01). Adjusted pathway analyses showed significant associations for pyrimidine biosynthesis (P = 0.04) and fluorouracil drug metabolism (P < 0.01) with significant gene–chemotherapy interactions, including PON1 rs3917538. This study supports the concept that FOCM‐related genes could be associated with CRC survival and may modify effects of 5‐FU‐based chemotherapy in genes in pyrimidine and fluorouracil metabolism, which are relevant targets for therapeutic response and prognosis in CRC. These results require confirmation in additional clinical studies.

Association between menopausal estrogen-only therapy and ovarian carcinoma risk

2 Alice W. Lee MPH, Roberta B. Ness MD, MPH, Lynda D. Roman MD, Kathryn L. Terry 3 ScD, Joellen M. Schildkraut PhD, Jenny Chang-Claude PhD, Jennifer A. Doherty PhD, 4 Usha Menon MD, Daniel W. Cramer MD, ScD, Simon A. Gayther PhD, Harvey Risch 5 MD, PhD, Aleksandra Gentry-Maharaj PhD, Marc T. Goodman PhD, Francesmary 6 Modugno PhD, Ursula Eilber, Kirsten B. Moysich PhD, Andrew Berchuck MD, Mary 7 Anne Rossing DVM, PhD, Allan Jensen PhD, Kristine G. Wicklund PhD, Kara L. 8 Cushing-Haugen MS, Estrid Hogdall PhD, DMSc, Anja Rudolph PhD, Pamela J. 9 Thompson MPH, Lynne R. Wilkens DrPH, Susanne K. Kjaer MD, DMSc, Michael E. 10 Carney MD, Daniel O. Stram PhD, Susan J. Ramus PhD, Anna H. Wu PhD, Malcolm C. 11 Pike PhD, Celeste Leigh Pearce PhD, MPH on behalf of the Ovarian Cancer Association 12