||5U01CA260352-03 Interpret this number
||Weill Medical Coll Of Cornell Univ
||Prediagnostic Exposures, Germline Genetics, and Triple Negative Breast Cancer Mutational and Immune Profiles
Triple negative breast cancer (TNBC) are typically aggressive cancers with shorter median time to relapse and
death than other breast cancers. Because these cancers are defined by the absence of a target, identification
of tailored therapies has been challenging. However, immune therapy shows important promise in TNBC,
including the first FDA approval for immunotherapy in breast cancer and favorable response data for the
addition of immunotherapy to neoadjuvant chemotherapy. Recent evidence suggests that tumor molecular
characteristics may provide clues to both the different etiology and prognoses for TNBCs. Gene expression
studies revealed that TNBCs are heterogeneous and composed of finer subtypes, defined in part by immune
response signatures. It has been hypothesized that the patients’ immune response plays an important role in
determining tumor progression. Further, sequencing studies have identified a set of genes that are frequently
mutated in breast tumors and several mutational signatures that reflect distinct mutagenic processes, and may
have etiologic implications. The mutational signatures that have been identified in TNBCs are distinct from the
more common luminal breast cancers, highlighting the need for research specific to this subtype.
We propose to perform whole exome sequencing (WES) of matched tumor and germline DNA samples
from 400 TNBC patients from four prospective cohort studies, the Nurses’ Health Study, Nurses’ Health Study
II, Cancer Prevention Study II, and Cancer Prevention Study 3. In combination with our existing rich database
of germline GWAS, breast cancer risk factors, and tumor immune signatures, we are well positioned to better
understand how genetic and nongenetic risk factors influence breast tumor mutational signatures, immune
response and prognosis. We will assess the association of genetic and nongenetic risk factors with tumor
mutational profiles (Aim 1), and tumor immune profiles (Aim 2). We will also examine the association between
immune response signatures and tumor mutation profiles (Aim 3). In exploratory analyses, we will evaluate
whether a possible joint effect of somatic mutational signatures and immune response signatures are
associated with breast cancer-specific survival (Aim 4). Knowledge from this study will be extremely valuable in
developing prevention strategies and treatment targets for these aggressive tumors.
To complete these aims, we have assembled a multidisciplinary team of experts in breast cancer
epidemiology, genetic epidemiology, statistical genetics, bioinformatics, immuno-oncology, and tumor
genomics. The Principal Investigators have extensive experience with the cohort resources and have worked
collaboratively for over thirteen years. We have also partnered with the B-CAST and AMBER consortia to
create a large and diverse repository of WES data from TNBCs, which will enable us to both replicate our
results and compare mutational profiles and their associations with prediagnostic and clinical factors in
European-ancestry and African American women.
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, Kraft P.
Cancer research, 2023-04-14; 83(8), p. 1191-1202.
Association of body mass index and inflammatory dietary pattern with breast cancer pathologic and genomic immunophenotype in the nurses' health study.
, Damicis A.
, Heng Y.J.
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, Collier K.A.
, Adams E.J.
, Kensler K.H.
, Baker G.M.
, Wesolowski R.
, Sardesai S.
, et al.
Breast cancer research : BCR, 2022-11-14; 24(1), p. 78.
Somatic mutational profiles and germline polygenic risk scores in human cancer.
, Gusev A.
, Heng Y.J.
, Alexandrov L.B.
, Kraft P.
Genome medicine, 2022-02-11; 14(1), p. 14.