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    Awarded Grants
    Molecular Epidemiology of Secondary Lung Cancer in Breast Cancer Patients

    Scientific Abstract:
    Background: Several studies indicate that breast cancer patients who undergo radiotherapy have an increased risk of lung cancer, also known as secondary lung cancer. Study of the adverse effects of breast cancer treatment has become increasingly important in light of the earlier detection and prolonged survival of breast cancer patients. Also, the occurrence of two primary cancers in one’s life is unusual, and so women who suffer both breast and secondary lung cancer are likely a unique and genetic subgroup of women. Indeed, these women may harbor the phenotype of a “moderately” penetrant gene. Dr. Peter Shields (mentor) has been recently funded by National Institute of Health to study 777 breast cancer patients with secondary lung cancer (cases) and 777 breast cancer patients without lung cancer (controls) diagnosed from 1958-1997 in Sweden. That grant proposal focuses on determining the effect of smoking and radiation therapy on secondary lung cancer risk in breast cancer patients by gathering reliable smoking and radiation dosage, and relating this to p53 mutations and loss of heterozygosity, thereby relating these to etiological pathways. I plan to also utilize these tissues for a separate study of hypermethylation in breast and secondary lung cancer, and the genetic susceptibility for this. Both lung cancer and breast cancer have been linked to altered one carbon metabolism (folate deficient diets, abnormal hypermethylation in breast and lung cancers, and normal tissues from these organs). Additionally, genetic polymorphisms of key enzymes in the methylation process have been discovered. Hypothesis: Herein I propose a study to determine if there is a particular susceptibility for hypermethylation in women who suffer two primary cancers in their life. I also hypothesize that altered one carbon metabolism (hypermethylation of gene promoters and /or genetic polymorphism of methylation) will predict the risk of secondary lung cancer among breast cancer patients. Specific Aims: (1) To determine the frequency of hypermethylation in breast and secondary lung cancers from the same women, and the association for such (case-only approach), along with the prevalence in breast cancers for cases compared with controls (case-control approach). (2) To determine whether genetic polymorphisms in methylenetetrahydrofolate reductase (MTHFR), cystathione b-synthase (CBS), methionine synthase (MS) and DNA methyltransferase-3b (DNMT-3b) genes will predict primary breast cancer and secondary lung cancer. Study Design: We are currently collecting medical record, next-of-kin data and tissue blocks (breast and lung tumors) from 777 cases and 777 matched controls, identified by the Swedish Cancer Registry. Lab assays, which include extraction of DNA, methylation specific PCR and genetic polymorphism analyses, will be performed by me at Shields lab. Statistical analysis will be performed by myself through a collaboration with Karolinska Institute under their mentorship. As collection of medical record data and tissue blocks are covered by the NIH grant, this parallel proposal offers a unique opportunity to test additional hypothesis with a significant saving at cost. Potential outcomes and Benefits of the Research: Through the study, I hope to identify genetic markers that make some women more susceptible to breast cancer in general, and to secondary lung cancer in particular. This genetic information will be critical for a breast cancer patient to make informed decision whether to elicit radiotherapy and will give added incentive for a woman to stop smoking. The “moderately” penetrant genes identified here may be relevant not only to secondary lung cancer risk, but to sporadic breast cancer too. This study will add to literature significantly as the first study to identify molecular markers (genetic polymorphism for methylation and the hypermethylation of gene promoters) for secondary lung cancer among breast cancer patients. This study is large, population-based and will also yield important mechanistic information about carcinogenesis among patients who suffer multiple cancers. It is also hoped that this postdoc training project will help me become an independent molecular epidemiologist and contribute to the improvement of breast cancer prevention and treatment.

    Lay Abstract:
    More and more breast cancer patients are receiving radiation therapy after surgery. Radiation improves disease free survival for certain women. However, several studies indicate that breast cancer patients who undergo radiotherapy have an increased risk of lung cancer, also known as secondary lung cancer. The risk is similar, for example, as that for endometrial cancer in women taking tamoxifen. Thus, it is important to understand the magnitude of the risk for secondary lung cancer, the biology behind it, and to identify who is at most risk. Also, the occurrence of two primary cancers in one’s life is unusual, and so women who suffer both breast and secondary lung cancer are likely a unique and genetic subgroup of women. Study of these women may shed light on cancer susceptibility genes. Dr. Peter Shields (mentor) has been recently funded by National Institute of Health to study 777 breast cancer patients with secondary lung cancer (cases) and 777 breast cancer patients without lung cancer (controls) diagnosed from 1958-1997 in Sweden. That grant proposal focuses on determining the effect of smoking and radiation therapy on secondary lung cancer risk in breast cancer patients by studying the tumors for DNA damage related to the P53 tumor suppressor gene to see if there is a fingerprint for carcinogen exposure. Here I propose a parallel study to see if we can identify a genetic susceptibility marker for this, and also for women who have an altered process called methylation. Methylation of a specific gene will reduce the expression, and so this is an important method of inactivating tumor suppressor genes that does not involve mutations. Depending on the gene, more than 60% of breast and lung cancers can be methylated, and so the concurrent study of breast cancer and secondary lung cancer, using both tumors from the same women, might identify who are susceptible. Thus, for the present study we hypothesize that altered methylation of genes will predict the risk of secondary lung cancer among breast cancer patients. This will be a large-scale study of 777 women with secondary lung cancer and 777 controls. Our collaborators at Karolinska Institute in Sweden will collect medical records and tissue blocks for these women, where tumor tissues are available through the Swedish Cancer Registry dating back to 1958. Samples will be shipped to Shields’ lab and I will conduct the assays. I will first extract DNA from samples, then methylation specific PCR assay will be performed. All the involved assays are readily available in the lab. Statistical analysis will be performed by myself through a collaboration with the Swedish team. As collection of medical record data and tissue blocks are covered by the NIH grant, this parallel proposal offers a unique opportunity to test additional hypothesis with a significant saving at cost. I received a Ph.D. in tumor biology in the Department of Oncology at Georgetown University. It is hoped that this postdoc training project will help me make the transition from a molecular researcher in breast cancer to an epidemiologist in breast cancer research. Through the study proposed herein, I will learn the concepts and techniques to conduct an international epidemiological study, develop and validate biomarker assays, as well as perform statistical analyses and interpretation of data. There is an insufficient number of molecular epidemiologists in breast cancer research. I plan to pursue a career of cancer epidemiology and contribute to the improvement of breast cancer prevention and treatment. Through the study, we hope to identify genetic markers that made certain breast cancer patients more susceptible in general, and to secondary lung cancer in particular. This genetic information will be critical for a breast cancer patient to make informed decision whether to elicit radiotherapy and will give added incentive for a woman to stop smoking. This study will be the first to search for methylation-related molecular markers for secondary lung cancer among breast cancer patients. This study is large, population-based and will also yield important mechanistic information about carcinogenesis among patients who suffer multiple cancers