Doctors Catalona, Theodorescu, and Svendsen are recruiting research participants for a new study: family studies of BRCA2-related prostate cancer

Categories: Winter 2022

Prostate cancer is the most common cancer in men.  Age, family history of prostate cancer, and germline variation are the most

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Research leads the way to a cure.                                     © Dan Oldfield

established risk factors, with as much as 57% of the variability in prostate cancer risk estimated to be due to genetic factors.  About 5% to 15% of cases are believed to be associated with inherited gene alterations. Hereditary prostate cancers can be caused by rare high-penetrance variants in cancer-associated genes, such as BRCA2, and common low-penetrance variants (single nucleotide polymorphisms – SNPs) that increase an individual’s lifetime risk of prostate cancer. Most high-penetrance variants associated with hereditary prostate cancer follow pattern of inheritance in which all first-degree relatives (parents, siblings, and children) have a 50% risk of inheriting the same variant.

BRCA1 and BRCA2 mutations

The BRCA1 and BRCA2 genes are responsible for helping cells repair DNA damage. If these genes are mutated in certain ways, DNA damage cannot be correctly repaired. Germline mutations of the BRCA genes are DNA alterations inherited from a parent in the sperm or egg, and the mutation is present in every cell in the body. Male carriers of pathogenic BRCA mutations occur in all races and ethnicities but are relatively more common among persons of Ashkenazi Jewish ancestry, rendering them at an increased risk for prostate cancer and the aggressive forms of the disease as well as other cancers (breast, ovarian, pancreatic, and others).

Understanding family history, genetics, and other risk factors can be helpful in navigating a prostate cancer diagnosis. Tests have been developed to help determine if an individual’s BRCA genes are mutated. For these individuals with a family history of prostate cancer, discovering the genetic etiology of hereditary prostate cancer and the clinical phenotypes associated with each variant has broad clinical utility. Identification of an inherited pathogenic BRCA variant may have implications for both male and female relatives concerning whether to implement surveillance and/or risk-reducing interventions aimed at reducing mortality. These advances are likely to reduce the burden on health systems and individuals compared with managing the disease at advanced stages. Furthermore, identifying an inherited pathogenic BRCA mutation may improve predicting therapeutic responses to treatments such as Poly-ADP-Ribose-Polymerase (PARP) inhibition, platinum-based chemotherapy, or immunotherapy.

Common low-penetrance genetic variants (modifier SNPs) for prostate cancer risk

To date, genome-wide association and fine-mapping studies of prostate cancer have discovered ~400 germline (germline means being  present in all cells in the body) risk SNPs increasing the risk for prostate cancer with some being more frequent in specific populations. Polygenic risk scores (PRS) comprised of these variants have been shown to identify men at higher risk of prostate cancer, with 50% of the aggressive cases aggregating in the top 20th percentile of the PRS.

Recent studies have shown that the PRS is associated with a wide range of absolute prostate cancer (and breast cancer) risk levels for male BRCA1 and BRCA2 mutation carriers. For example, the prostate cancer risk in BRCA2 mutation carriers varied from 34.1% to 87.6% for the 5th and 95th percentiles of the PRS distributions respectively. Thus, the prostate cancer risk conveyed by BRCA mutations varies depending on an individual’s specific profile of common risk SNPs. This implies that to comprehensively assess the genetic risk of prostate cancer, it is important to consider both the rare (e.g., BRCA mutations) and common (SNPs) variants.

It is therefore especially relevant to explore the molecular basis of the SNPs that modify the BRCA2 effects by creating a model of prostate cells containing the donor’s BRCA mutation as well as his unique profile of SNPs that may modify the BRCA2-associated risk inherited from each of his parents that can be studied with molecular genetics and molecular biology methods. Gene editing techniques can then be used to examine the interactions between the BRCA mutation and the modifier SNPs to study the target pathways implicated. This will help define more precisely the predictive roles of BRCA2 genes and other DNA repair genes on the behavior of localized and advanced prostate cancer.

The opportunity to advance the science is increased by enrolling all consenting members of families that have multiple members carrying the pathogenic BRCA mutation, as all individual family members will have different unique set of modifier SNPs.

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“He who plants a tree, plants a hope.” -Lucy Larcom                                © David Taylor

Stem Cells

Recent research efforts have focused on reprogramming mature cells to return them back into stem cells, rather than using embryonic stem cells (ESCs).  The use of ESCs involves many technical and ethical problems. Our studies will not use cells from embryos, but use “reprogramming “of mature cells.

In 2007, Japanese researchers found an amazing way to transform mature cells, like skin or blood cells, directly into stem cells without using human eggs. A Nobel Prize was awarded for this research. They found a combination of proteins that, if injected into mature cells, gradually reprogrammed the mature cells into stem cells. This procedure is much simpler than cloning, and every lab can quite easily produce stem cells from almost every type of cell.  “Reprogramming” is a process in which regular, mature cells are transformed back (are induced) into “induced pluripotent stem cells” (called iPSCs).

In collaboration with Dr. Catalona, Drs. Dan Theodorescu and Clive Svendsen and the Cedars-Sinai team will develop a model of human prostate cancer using induced pluripotent stem cells (iPSC) from men who carry BRCA2 mutations (the Cedars team has already done this for ovarian cancer in women who carry BRCA1 mutations) (See page 1 article, Quest Spring 2022, Volume 30, Number 1). They will take human white blood cells from a blood sample “back in time” to when these cells were capable of making any cell type in the body. Researchers will then differentiate them forward into prostate cells carrying the BRCA2 mutation in a petri dish. Using the BRCA2 mutated prostate cells, researchers use state-of-the-art genetic engineering and molecular biology research to study the mechanisms of transformation into aggressive cancer. This model also will be used in cell signaling studies in drug screening to design future therapies. The bank of iPSC that the core will create may be shared with academic and commercial institutions around the world.

Drs. Catalona, Theodorescu, and Svendsen are now recruiting men (and male family members) who carry a BRCA2 mutation and men with metastatic prostate cancer (more likely to have undetected DNA-repair gene deficiencies) to participate in this study. This research is being undertaken to discover the causes of prostate cancer and how it is passed along in families in using the BRCA 2 mutation as a model system. This study has been approved by the researchers’ Institutional Review Boards, whose function it is to protect the rights of research subjects and to oversee ethical issues. Participants will be asked to sign a consent and authorization for research, give a blood sample (3 tubes-less than one ounce), and fill out a questionnaire. If you wish to participate, please contact Dr. Catalona at 312-695-4471.

 

 

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