||1R37CA275914-01A1 Interpret this number
||Massachusetts General Hospital
||Etiologic Heterogeneity Between Molecular Subtypes of Prostate Cancer
This proposed project investigates the hypothesis that risk factors for prostate cancer differ by molecular
subtype of the tumor. It addresses the conundrum that prostate cancer has fewer established risk factors than
other cancer types, despite its high incidence and mortality. By credentialing risk factors, this project lays the
ground for primary prevention efforts and for mechanistic research. Notably, few studies have investigated
etiologic differences based on molecular subtypes of prostate cancer.
In this project, we will molecularly profile 3,373 prostate tumors diagnosed among 107,313 men (23% of
whom are African-American) who participate in the Health Professionals Follow-up Study (HPFS), the
Physicians’ Health Study (PHS), or the Southern Community Cohort Study (SCCS) and on whom we have
collected decades of prospective risk factor data prior to cancer diagnosis. The project builds on our previous
work demonstrating that potential prostate cancer risk factors such as obesity, height, and some inherited
genetic variants may specifically be associated with tumors with the common TMPRSS2:ERG fusion. To
assess the most common molecular subtypes with different mechanisms of carcinogenesis, we will apply
cutting-edge, in-situ pathology methods for (1) gene fusions from the ETS family (TMPRSS2:ERG, ETV1,
ETV4, ETV5), (2) loss of the tumor suppressor PTEN, and (3) gain of the oncogene MYC.
In Aim 1, we will generate population-based data on the prevalence of the common tumor alterations by
age at diagnosis and assess the co-occurrence of molecular phenotypes at the cellular level with integrated
single-cell data. In Aim 2, we will assess risk factors for molecular subtypes of prostate cancer. We will
characterize which molecular subtypes are associated with non-modifiable risk factors (family history, attained
height, and inherited risk as measured by the polygenic risk score for prostate cancer), modifiable risk factors
with substantial prior evidence (adult-age adiposity and smoking), and novel risk factors for specific subtypes
(physical activity and insulinemic dietary patterns). In Aim 3, we will tailor the cBioPortal, the most widely used
cancer genomics portal, for accessible data-sharing in molecular cancer epidemiology.
The impact of this project will be the generation of the first population-based, age-specific prevalence data
on molecular subtypes and their co-occurrence; the connection between etiology and molecular heterogeneity;
and the availability of high-quality original data from decades of follow-up for the research community.
Importantly, a nuanced understanding of the etiology of prostate cancer is indispensable to reducing its
mortality burden through primary prevention, as it has been for other tumor entities. Credentialing any
additional modifiable risk factor is poised to have a significant impact, given the quickly rising burden of
prostate cancer with the aging of the global population.