Citations

Key PointsCandidate SNP associations with survival outcomes after URD transplant are most likely false-positive findings. Over 85% of candidate SNPs are not linked to a biochemical function; of those that are, about half are not linked to the candidate gene.

Abstract Background: Accumulating epidemiological studies positively associate healthy body mass index (BMI) and higher physical activity with lowered risk of postmenopausal breast cancer. Many of the proposed biomarkers underlying these associations, such as insulin, inflammatory markers, steroid hormones, and adipokines, are produced or regulated by adipose tissue. However, the biological impact of lifestyle factors at the level of the breast tissue, particularly adipose tissue in the breast, is unclear and may play a role in the etiology of breast cancer. Methods: Using a cross-sectional design, we examined the impact of demographic and lifestyle factors on histological features of breast adipose tissue. Women (age) undergoing reduction mammoplasty surgery were consented to collection of their cancer-free breast tissue at the time of surgery. An adipose rich section of the sample was dissected under sterile conditions and formalin fixed. Samples were sectioned at 7 µm thickness and stained with hematoxylin and eosin. The stained sections were imaged and mean adipocyte size was determined as diameter (µm) from 3 randomly selected areas at 10X magnification and each sample was scored by two independent assessors using Image J software. BMI status documented at the time of surgery was abstracted form medical records. A subset of women completed an additional visit where percent total body fat was measured by air displacement plethysmography and aerobic fitness (VO2peak) was measured by a maximal graded exercise test with expired gas collection. The association between adipocyte size and demographic/lifestyle factors was examined using multivariate linear regression adjusted for age and menopausal status. Results: Participants (n=42) were primarily Caucasian (77%) and pre/peri-menopausal (62%), with a mean age of 44.6±12.9 years (range 19-70) and mean BMI of 27.7±5.1 kg/m2 (range 19.1-37.4). Adipocyte size was associated with BMI (per 5 kg/m2 increase, β = 5.6±2.15, p=0.01) and number of pregnancies (β = 6.04±2.34, p=0.02), but not age (β = 0.1±0.3, p=0.81). In the subset of participants who completed an additional study visit (n=9), there was a trend towards an inverse association between adipocyte size and aerobic fitness (per 2 ml/kg/min of O2 consumption, β = -3.54±1.52, p=0.07) and percent body fat (per 2% increase, β = 1.94±1.28, p=0.17) in unadjusted analyses. Conclusion: Higher BMI is associated with larger adipocyte size in adipose tissue taken from the breast, suggesting a biological role for body composition in influencing gross histological features of adipocytes and its behavior that would impact the health of the mammary gland. A better understanding of the biological mechanisms underlying the observed epidemiological associations are needed to guide the development of intervention strategies and the most effective public health messages for breast cancer prevention. Citation Format: Kristin L. Campbell, Nagarajan Kannan, Sarah E. Neil-Sztramko, Connie J. Eaves, Jonathan P. Little, Ilona Csizmadi, David Zhu, Sarah Sayyari, Kelcey Bland, James D. Johnson. Influence of lifestyle factors on adipocyte size in human breast tissue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4258. doi:10.1158/1538-7445.AM2017-4258

Abstract The Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) in collaboration with the Colorectal Cancer Family Registry (CCFR) aims to identify genetic variants and environmental risk factors that impact colorectal cancer (CRC). Over 30 studies from North America, Europe, and Australia participate in GECCO. These studies have collected clinical, epidemiological, and survival data, as well as blood and tumor biospecimens, for over 80,000 CRC cases and controls. The current study aims to conduct targeted deep sequencing of tumors and matching normal DNA to identify recurrent and novel somatic and germline variants in 4,200 CRC cases. To achieve this goal, an AmpliSeq targeted sequencing panel of 1.12 Mbp was constructed to sequence the coding regions of 190 significantly mutated genes identified from whole exome sequencing datasets generated by the Nurses’ Health Study and Health Professional’s Follow-up Study, and The Cancer Genome Atlas. The panel also covers coding regions of 15 genes with germline high penetrance mutations in CRC, 54 regions to detect CRC-related copy number alterations (CNAs), and microsatellite and homopolymer repeat regions to identify defective DNA mismatch repair. Primers were also included to detect Fusobacterium nucleatum DNA in tumor biopsies, as F. nucleatum is thought to promote CRC carcinogenesis. Sequencing of the DNA libraries on Illumina HiSeq 2500 produced a mean coverage of greater than 500X for tumor DNA and 100X for normal DNA, with >85% of the bases covered at the target at 50x. So far, targeted sequencing of >1,500 DNA samples from CRC tumors and normal tissues has identified recurrent and novel somatic mutations, germline genetic variants, and hypermutation status of the tumors due to defective DNA mismatch repair or pathogenic mutations in the POLE gene. Targeted sequencing has also allowed quantification of the F. nucleatum DNA in tumor biopsies; the results were validated by a multiplex QPCR assay. At the AACR annual meeting, we will present targeted sequencing results generated from the first two GECCO-participating studies (n=1,300 cases). These data will be valuable for future association testing of somatic mutations, CNAs, hypermutation status, and F. nucleatum with germline genetic variants, lifestyle, and environmental risk factors and survival. This large study will allow development of better strategies for diagnosis, treatment, and prevention of CRC. Citation Format: Syed H. Zaidi, Wei Sun, Jeroen Huyghe, Catherine S. Grasso, Quang Trinh, Charles Connolly, Amy French, Jasmine Mu, Marios Giannakis, Eve Shinbrot, Ivan Borozan, Michael J. Quist, Hermann Brenner, Daniel Buchanan, Peter Campbell, Andrew Chan, Jenny Chang-Claude, Vincent Ferretti, Charles Fuchs, Andrea Gsur, Marc Gunter, Tabitha Harrison, Michael Hoffmeister, Wen-Yi Huang, Paul Krzyzanowski, Stephen Lee, Mathieu Lemire, Jessica Miller, Danielle Pasternack, Cherie Teney, Elaine Mardis, Polly Newcomb, Lincoln Stein, Lee Timms, David Wheeler, Christina Yung, Niha Zubair, Levi Garraway, Shuji Ogino, Li Hsu, Steven Gallinger, Stephen Thibodeau, Thomas Hudson, Ulrike Peters. Targeted deep sequencing of colorectal tumor tissues to study associations of tumor subtypes with germline genetic, lifestyle, and environmental risk factors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1286. doi:10.1158/1538-7445.AM2017-1286

Staff from the Mayo Clinic in the US and the Karolinska Institute in Sweden describe a joint transatlantic course intended to broaden the horizons of the next generation of researchers in the field of regenerative medicine.