Serie, Daniel

Abstract Background: Colorectal cancer (CRC) in densely affected families without Lynch Syndrome may be due to mutations in undiscovered genetic loci. Familial linkage analyses have yielded disparate results; the use of exome sequencing in coding regions may identify novel segregating variants. Methods: We completed exome sequencing on 40 affected cases from 16 multicase pedigrees to identify novel loci. Variants shared among all sequenced cases within each family were identified and filtered to exclude common variants and single-nucleotide variants (SNV) predicted to be benign. Results: We identified 32 nonsense or splice-site SNVs, 375 missense SNVs, 1,394 synonymous or noncoding SNVs, and 50 indels in the 16 families. Of particular interest are two validated and replicated missense variants in CENPE and KIF23, which are both located within previously reported CRC linkage regions, on chromosomes 1 and 15, respectively. Conclusions: Whole-exome sequencing identified DNA variants in multiple genes. Additional sequencing of these genes in additional samples will further elucidate the role of variants in these regions in CRC susceptibility. Impact: Exome sequencing of familial CRC cases can identify novel rare variants that may influence disease risk. Cancer Epidemiol Biomarkers Prev; 22(7); 1239–51. ©2013 AACR.

Summary A recent meta‐analysis of three genome‐wide association studies of chronic lymphocytic leukaemia ( CLL ) identified two common variants at the 6p21.31 locus that are associated with CLL risk. To verify and further explore the association of these variants with other non‐ H odgkin lymphoma ( NHL ) subtypes, we genotyped 1196 CLL cases, 1699 NHL cases, and 2410 controls. We found significant associations between the 6p21.31 variants and CLL risk (rs210134: P = 0·01; rs210142: P = 6·8 × 10 −3 ). These variants also showed a trend towards association with some of the other NHL subtypes. Our results validate the prior work and support specific genetic pathways for risk among NHL subtypes.

Abstract A substantial proportion of familial colorectal cancer (CRC) is not a consequence of known susceptibility loci, such as mismatch repair (MMR) genes, supporting the existence of additional loci. To identify novel CRC loci, we conducted a genome-wide linkage scan in 356 white families with no evidence of defective MMR (i.e., no tumors with loss of expression of MMR proteins; no microsatellite instability (MSI)-high tumors, and no evidence of linkage to MMR genes). This represents the largest linkage analysis of proficient MMR (pMMR) familial CRC to date. Families were ascertained via the NCI-supported Colon Cancer Family Registry multi-site (Colon CFR) consortium, the City of Hope, and Memorial University of Newfoundland. A total of 1,612 individuals (average 5.0 per family, range 2-10 with an average of 2.2 affected and 2.8 unaffected individuals) were genotyped using genome-wide single nucleotide polymorphism linkage arrays; parametric and non-parametric linkage analysis used MERLIN in a priori-defined family groups. Five lod scores greater than 3.0 were observed, accounting for heterogeneity, in four chromosomal regions. The greatest lod scores were at 4q21.1 among families with mean age of diagnosis less than 50 years (dominant HLOD=4.51, α=0.84, 145.40 cM, rs10518142) and at 12q24.32 among all families (dominant HLOD=3.60, α=0.48, 285.15 cM, rs952093). Among families with four or more affected individuals and among clinic-based families, a common peak was observed at 15q22.31 (101.40 cM, rs1477798; dominant HLOD=3.07, α=0.29; dominant HLOD=3.03, α=0.32, respectively). Analysis of families with only two affected individuals yielded a peak at 8q13.2 (recessive HLOD=3.02, α=0.51, 132.52 cM, rs1319036). These linkage regions comprise previously unreported loci, supporting the hypothesis that novel loci contribute to CRC in familial pMMR cases. These loci are also largely distinct from those identified in case-control GWAS. To follow up on these findings, a custom Agilent Sure Select Target Enrichment panel has been designed for genes in three of these regions, in order to sequence probands using an Illumina HiSeq 2000. This study demonstrates the utility of family-based data and provides evidence for additional alleles for familial CRC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2930. doi:1538-7445.AM2012-2930

Abstract INTRODUCTION: Mammographic breast density is a strong risk factor for breast cancer (BC). We established the Mayo Mammography Health Study (MMHS) cohort study at the Mayo Clinic in Rochester, Minnesota (MN) to examine the association of breast density with BC. We evaluated the influence of the image acquisition technique on the density and BC association. METHODS: From October 2003 to September 2006, all women scheduled for screening mammography at the Mayo Clinic were invited to participate. Eligible women were residents of MN, Iowa (IA) or Wisconsin (WI); age 35+; and had no personal history of BC. A risk factor questionnaire, consent form and permission to link to tumor registries were obtained. Incident BC was identified through 2009 by linkage to the Mayo and state cancer registries. A case-cohort of all incident BCs and 2300 randomly selected women (the subcohort) were used to examine the association of breast density and BC using digitized film mammograms at the time of enrollment while controlling for the influence of the acquisition parameters (peak kilovoltage, milliampere-second, and compressed breast thickness). Two density measures were considered: a quantitative percent density (PD) measure estimated using the computer-assisted thresholding program, Cumulus (University of Toronto), and the 4-category clinical BI-RADS measure. Proportional hazards regression was used to calculate hazards ratios (HR) and 95% confidence intervals (CI) for BC associated with quartiles of PD (0-6.2%,6.3-14.9%, 15.0-25.7% and 25.8%+) and BI-RADS categories 1-4 (almost entirely fatty to extremely dense). All models included age, postmenopausal hormone use (PMH), BMI, and menopausal status. The influence of acquisition parameters was evaluated by examining models with and without their inclusion. RESULTS: A total of 20,982 (50%) women participated in MMHS; 1058 (5%) with a prior history of BC were excluded, for a total cohort of 19,924. Compared to nonresponders, responders were younger (57.5 vs. 58.4 yrs), more likely to have ever used PMH (45% vs. 33%), and more likely to have a BC family history (19% vs 16%). The case-cohort consisted of 317 incident cases and 2300 women in the subcohort. Women were excluded from the current analysis if PD could not be estimated or if acquisition parameters were not available, leaving 249 cases and 1937 in the subcohort. As expected, PD was associated with BC [HR (95% CI): 1.0 (REF), 2.1 (1.4-3.1), 3.0 (2.0-4.5), and 4.6 (3.0-7.0) for quartiles; p-trend<0.001]. Controlling for acquisition parameters attenuated the association [HR (95% CI): 1.0 (REF), 2.3 (1.5-3.4), 2.4 (1.6-3.7), and 3.0 (1.8-5.0) for quartiles; p-trend<0.001]. Results for BI-RADS density were similar to those for PD. CONCLUSION: This study confirms that breast density is a significant risk factor for BC and demonstrates that the acquisition technique confounds the density and BC risk association. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3716. doi:10.1158/1538-7445.AM2011-3716

Abstract We performed a meta-analysis of 3 genome-wide association studies to identify additional common variants influencing chronic lymphocytic leukemia (CLL) risk. The discovery phase was composed of genome-wide association study data from 1121 cases and 3745 controls. Replication analysis was performed in 861 cases and 2033 controls. We identified a novel CLL risk locus at 6p21.33 (rs210142; intronic to the BAK1 gene, BCL2 antagonist killer 1; P = 9.47 × 10−16). A strong relationship between risk genotype and reduced BAK1 expression was shown in lymphoblastoid cell lines. This finding provides additional support for polygenic inheritance to CLL and provides further insight into the biologic basis of disease development.

Abstract Introduction: Mammographic breast density is one of the strongest risk factors for breast cancer and appears to be modifiable. However, whether longitudinal changes in density are associated with breast cancer risk is unknown. We hypothesize that decreases in breast density are associated with reduced breast cancer risk. Methods: The Mayo Mammography Health Study cohort enrolled 19,924 women having a screening mammogram (mgm) at the Mayo Clinic, Rochester, between 2003 and 2006. Participants were 35 years and older, had no prior breast cancer and lived in the tri-state area (MN, IA and WI). Risk factor data were collected through self-administered questionnaire and clinic databases. Incident breast cancers were identified through tumor registries (Mayo Clinic, MN, IA, WI). The BI-RADS, 4-category clinical density measure (fatty, scattered density, heterogeneous density and extreme density) was available on all mgms performed after 1996. A case-cohort design consisting of incident cases (n=241) and a random selection of the cohort (n=2300, 28 developed cancer) was used to examine the association between change in BI-RADS density and breast cancer. BI-RADS densities measured from the earliest available, and enrollment mgms (average 6 years apart) were used to assess density change. Proportional hazards regression was performed to estimate the hazard ratio (HR) associated with a change in one or more BI-RADS density categories over time, relative to staying within the same category. Age was used as the time scale, and the subcohort was weighted by the inverse of the sampling proportion. Analyses were adjusted for age, years between mgms, BI-RADS density at earliest mgm, and changes in BMI, postmenopausal hormone use, and menopausal status. Results: Longitudinal analyses were conducted on the 219 cases and 1900 non-cases in the subcohort with at least one mgm available prior to enrollment mgm. Compared to the subcohort, cases were older (56.8 vs. 52.9 years), more likely postmenopausal (73.4% vs. 61.6%), had higher BMI (29.0 vs 28.1) and were more frequently screened (8.0 vs. 6.9 pre-enrollment mgms). As expected, cases were more likely to have extreme density (BI-RADS=4) at earliest mgm than non-cases (16.2% vs 14.3%). Cases were less likely than non-cases to experience a reduction of one density category or more (37.0% vs 38.6%) following earliest mgm. Adjusting for potential confounders, women who decreased one BI-RADS category or more over an average 6 years were at reduced risk of breast cancer (HR=0.72, 95%CI: 0.50-0.99) compared to those whose density was unchanged. However, women who increased one or more BI-RADS categories had suggestion of increased risk (HR=1.52, 95%CI: 0.97-2.4). Conclusion: Women with a decrease in BI-RADS density category over 6 years may have decreased breast cancer risk relative to women whose breast density category remains stable. Two measures of breast density may inform women's risk beyond a measure at one point in time. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4828.