Project 1 PI, R.C. Lindsley DFCI (Cancer Genetics, Leukemia). Allogeneic
hematopoietic stem cell transplantation is the only potentially curative treatment for patients with myelodysplastic syndrome (MDS), but long-term survival is limited by the risk of transplant-related complications. Short telomere length, mediated by inherited or acquired factors, impairs cellular response to genotoxic and replicative stress and could identify patients at higher risk for toxicity after transplantation. The objective of this study was to measure relative telomere length in pre-transplant MDS patients and evaluate the association of telomere length with MDS disease characteristics and transplantation outcomes.
These investigators found that shorter telomere length was significantly associated with older age, male sex, somatic mutations that impair the DNA damage response, and more severe pre-transplant cytopenias, but not with bone marrow blast count, MDS treatment history, or history of prior cancer therapy. Among 1267 patients ≥40 years old, telomere length in the shortest quartile was associated with inferior survival (p<0.001) due to a high risk of non-relapse mortality (p=0.001) after adjusting for significant clinical and genetic variables.
This research was supported by National Institutes of Health grants NIH 5P30CA006516-54 K08CA204734, and 5P30 CA006516. The core performed DNA extraction of 1514 MDS patient blood samples and telomere length analysis on 1514 samples. A publication resulted from this work: Short Telomere Length Predicts Non-Relapse Mortality after Stem Cell Transplantation for Myelodysplastic Syndrome. Myllymäki M, Redd R, Reilly C, Saber W, Spellman S, Gibson C, Hu Z Wang T, Orr E, Grenier J, Chen M, Steensma D, Cutler CDFCI, De Vivo IBWH, Antin JHDFCI, Neuberg DSDFCI, Agarwal S, Lindsley RCDFCI. Blood 2020 Aug 17
Project 2 PI, Brian Wolpin DFCI (Cancer Epidemiology, Cancer Risk Prevention, Gastrointestinal Malignancies).
The identification of biomarkers of pancreatic cancer survival are urgently needed given the high fatality of this disease. While leukocyte telomere length has been associated with risk of subsequent pancreatic cancer, few prospective studies have evaluated the association of prediagnostic leukocyte telomere length with pancreatic cancer survival. The Core completed the telomere assays among 423 participants diagnosed with pancreatic adenocarcinoma.The objective of this study was to examine the association between prediagnostic telomere length with the overall survival. These investigators found that shorter prediagnostic leukocycte telomere length was associated with worse clinical outcome in patients with pancreatic cancer from four large DF/HCC-based cancer epidemiology cohort studies. This study suggests an important role of telomere shortening in patient survival after clinical diagnosis of pancreatic cancer.
This research was supported by National Institutes of Health grants, R01 CA205406, NIH R35 CA197735, NIH/NCI U01 CA210171, NIH/NCI P50 CA127003, Department of Defense CA13028. The core performed DNA extraction and Whole Genome Amplification of 423 participants and Telomere Length Analysis of 423 participants. A publication resulted from this work: Prediagnostic Leukocyte Telomere Length and Pancreatic Cancer Survival. Hamada T, Yuan C, Bao Y, Zhang M, Khalaf N, Babic A, Morales-Oyarvide V, Chochrane B, Gaziano J, Giovannucci EHSPH, Kraft PHSPH, Manson JBWH, Ng KDFCI, Nowak J, Rowan T, Sesso H, Stampfer MHSPH, Amundadottir L, Fuchs C, De Vivo IBWH, Ogino SDFCI, Wolpin BDFCI Cancer Epidemiol Biomarkers Prev. 2019 Nov;28(11):1868-1875.
Project 3 PI, Rulla Tamimi BWH (Cancer Epidemiology and Co-Leader, Breast Program)
Cumulative epidemiologic evidence has shown that early-life adiposity is strongly inversely associated with breast cancer risk throughout life, independent of adult obesity. However, the molecular mechanisms remain poorly understood. We assessed the association of early-life adiposity with the transcriptome of breast tumor in the Nurses’ Health Studies, conducting multivariable linear regression analysis to identify differentially expressed genes in tumor and tumor-adjacent tissue. Molecular pathway analysis was also performed. No gene was statistically significantly differentially expressed by early-life body size after multiple comparison adjustment. However, pathway analysis revealed several statistically significantly up or down regulated gene sets. Larger body size during ages 10-20 years was associated with decreased cellular proliferation pathways, including MYC target genes, in both ER+ and ER- tumors. These findings provide new insights into the biological and pathological underpinnings of the early-life adiposity and breast cancer association.
This work has been funded by the following grants: Komen Foundation Grant SAC110014 and the NIH/NCI U19/GAME-ON DRIVE (CA148065) initiative, UM1CA186107, P01 CA87969, UM1 CA176726, U01 CA176726 and R01 CA166666. The Core extracted RNA from 835 women with breast cancer and tumor-adjacent histologically-normal tissue
A publication resulted from this work: Early-Life Body Adiposity and the Breast Tumor Transcriptome Wang J, Peng C, Askew C, Heng YJ, Baker GM, Rubadue CA, Glass K, Eliassen AHBWH, Tamimi RMBWH, Polyak KDFCI, Hankinson S. J Natl Cancer Inst 2020 Nov 2;djaa169. doi: 10.1093/jnci/djaa169. Online ahead of print. PMID: 33136151 DOI: 10.1093/jnci/djaa169
PUBLICATION ACKNOWLEDGEMENT:
If research supported by this core facility results in publication, please acknowledge this support by including the following in your publication(s):
“We thank Dana-Farber/Harvard Cancer Center in Boston, MA, for the use of the Population Sciences Laboratory Support Core. Dana-Farber/Harvard Cancer Center is supported in part by an NCI Cancer Center Support Grant # NIH 5 P30 CA06516.”
