Family History of Breast or Prostate Cancer and Prostate Cancer Risk

Barber, Lauren E.; Gerke, Travis; Markt, Sarah C.; Peisch, Samuel; Wilson, Kathryn M.; Ahearn, Thomas U.; Giovannucci, Edward; Parmigiani, Giovanni; Mucci, Lorelei A.

doi:10.1158/1078-0432.ccr-18-0370

Cited by 73 publications

(67 citation statements)

References 27 publications

(56 reference statements)

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“…PCa is one of the heritable malignancies and 10–20% of PCa patients have a family history of cancer that is associated with an elevated risk of lethal disease . Prostate remains the most frequently reported site for cancer development in males with breast cancer 1/2 ( BRCA1/2 ) genetic aberrations, and germline mutations in BRCA1 and BRCA2 genes increase risk of PCa development up to 4.5‐fold and 8.3‐fold, correspondingly .…”

Section: Introductionmentioning

confidence: 99%

BRCA1 and EZH2 cooperate in regulation of prostate cancer stem cell phenotype

Gorodetska

Lukiyanchuk

Peitzsch

et al. 2019

Intl Journal of Cancer

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Prostate cancer (PCa) is the second most common malignancy and the sixth leading cause of cancer-related death among men worldwide. Prostate carcinogenesis is driven by the accumulation of genetic and epigenetic aberrations, which regulate cancer cell transition between a stem-and nonstem-cell state and accelerate tumor evolution. Elevated expression of enhancer of zeste homolog 2 (EZH2) histone methyltransferase, a core member of the polycomb repressive complex 2 (PRC2), results in cancer progression through histone methylation-driven tumor cells dedifferentiation. Previous studies demonstrated that tumor suppressor breast cancer 1 (BRCA1) is a negative regulator of PRC2-dependent H3K27 methylation. Our recent studies revealed that inhibition of EZH2-mediated histone methylation radiosensitizes prostate cancer stem cells (CSCs) population. However, the link between BRCA1 and EZH2 in regulation of prostate CSCs remains elusive. Present study demonstrated that BRCA1 and EZH2 are coregulated in patients' tumors and PCa cell lines, and cooperate in regulation of CSC phenotype and properties. Knockdown of BRCA1 expression significantly increases the number and the size of tumor spheres. Inhibition of BRCA1 and EZH2 expression leads to an increase of aldehyde dehydrogenase (ALDH)-positive cell population that is, at least partially, attributed to the upregulation of ALDH1A3 protein. Treatment with a global histone methylation inhibitor 3-Deazaneplanocin A abrogates this regulation, downregulates BRCA1 and EZH2 expression and has an inhibitory effect on the tumorigenic properties of radioresistant PCa cells in vivo. We found that EZH2/BRCA1 signaling mechanisms play an important role in the maintenance of prostate CSC properties and may be a promising target for tumor treatment.

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Section: Introductionmentioning

confidence: 99%

BRCA1 and EZH2 cooperate in regulation of prostate cancer stem cell phenotype

Gorodetska

Lukiyanchuk

Peitzsch

et al. 2019

Intl Journal of Cancer

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“…A possible explanation stems from the association between a family history of PCa and increased PSA screening. [32][33][34] Although PSA screening does not seem to wholly account for the association between a family history of PCa and PCa risk, 1,34,35 its increased adoption among men with a family history of PCa means that such men are more likely to be diagnosed with lower stage disease. [36][37][38] Given that the TMPRSS2: ERG gene fusion is associated with higher stage PCa, 7 it is perhaps unsurprising that we found a family history of PCa to be more strongly associated with ERG-negative disease.…”

Section: Discussionmentioning

confidence: 99%

“…Family history of prostate cancer (PCa) is a well‐established risk factor for PCa incidence . Men with an affected father have a more than two‐fold greater risk of PCa and those with an affected brother have a more than three‐fold greater risk .…”

Section: Introductionmentioning

confidence: 99%

“…Family history of prostate cancer (PCa) is a well-established risk factor for PCa incidence. 1 Men with an affected father have a more than two-fold greater risk of PCa and those with an affected brother have a more than three-fold greater risk. 2 Furthermore, twin studies indicate that nearly 60% of the variability in PCa liability can be attributed to genetic factors, 3,4 making PCa one of the most heritable malignancies.…”

Section: Introductionmentioning

confidence: 99%

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Family history of prostate cancer and the incidence of ERG‐ and phosphatase and tensin homolog‐defined prostate cancer

Hashim

Gonzalez‐Feliciano

Ahearn

et al. 2019

Intl Journal of Cancer

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Family history is among the strongest known risk factors for prostate cancer (PCa). Emerging data suggest molecular subtypes of PCa, including two somatic genetic aberrations: fusions of androgen‐regulated promoters with ERG and, separately, phosphatase and tensin homolog (PTEN) loss. We examined associations between family history and incidence of these subtypes in 44,126 men from the prospective Health Professionals Follow‐up Study. ERG and PTEN status were assessed by immunohistochemistry. Multivariable competing risks models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations between self‐reported family history of PCa and molecular subtypes of disease. Thirteen percent of men had a positive family history of PCa at baseline. During a median follow‐up of 18.5 years, 5,511 PCa cases were diagnosed. Among them, 888 were assayed for ERG status (47% ERG‐positive) and 715 were assayed for PTEN loss (14% PTEN null). Family history was more strongly associated with risk of ERG‐negative (HR: 2.15; 95% CI: 1.71–2.70) than ERG‐positive (HR: 1.49; 95% CI: 1.13–1.95) disease (pheterogeneity: 0.04). The strongest difference was among men with an affected father (HRERG‐negative: 2.09; 95% CI: 1.64–2.66; HRERG‐positive: 1.30; 95% CI: 0.96–1.76; pheterogeneity: 0.01). Family history of PCa was positively associated with both PTEN null (HR: 2.10; 95% CI: 1.26–3.49) and PTEN intact (HR: 1.72; 95% CI: 1.39–2.13) PCa (pheterogeneity: 0.47). Our results indicate that PCa family history may be positively associated with PCa in all ERG and PTEN subtypes, suggesting a role of genetic susceptibility in their development. It is possible that ERG‐negative disease could be especially associated with positive family history.

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“…Furthermore, these currently available models are useful only for the minority of individuals who have a positive FH; as most individuals who develop cancer, especially at a young age, do not have a known FH of the disease. [9][10][11] Through the present clinical trial, GRSs were used clinically as part of a multivariate model that included FH of disease as well as other clinical risk factors, to stratify patients based on their individual genetic risk of developing a disease. Investigators, in consultation with surgical oncology specialists, developed unique genetic tests to identify SNPs as well as implementation models (Appendix A) to guide more personalized risk strati cation and screening for colorectal, breast, and prostate cancer in a primary care setting.…”

Section: Introductionmentioning

confidence: 99%

Assessing the Clinical Utility of Genetic Risk Scores for Targeted Cancer Screening

Conran

Shi

Resurreccion

et al. 2020

Preprint

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Background: Genome-wide association studies have identified thousands of disease-associated single nucleotide polymorphisms (SNPs). A subset of these SNPs may be additively combined to generate genetic risk scores (GRSs) that confer risk for a specific disease. Although the clinical validity of GRSs to predict risk of specific diseases has been well established, there is still a great need to determine their clinical utility by applying GRSs in primary care for cancer risk assessment and targeted intervention.Methods: This clinical study involved 281 primary care patients without a personal history of breast, prostate or colorectal cancer who were 40-70 years old. DNA was obtained from a pre-existing biobank at NorthShore University HealthSystem. GRSs for colorectal cancer and breast or prostate cancer were calculated and shared with participants through their primary care provider. Additional data was gathered using questionnaires as well as electronic medical record information. A t-test or Chi-square test was applied for comparison of demographic and key clinical variables among different groups.Results: The median age of the 281 participants was 58 years and the majority were female (66.6%). One hundred one (36.9%) participants received 2 low risk scores, 99 (35.2%) received 1 low risk and 1 average risk score, 37 (13.2%) received 1 low risk and 1 high risk score, 23 (8.2%) received 2 average risk scores, 21 (7.5%) received 1 average risk and 1 high risk score, and no one received 2 high risk scores. Before receiving GRSs, younger patients and women reported significantly more worry about risk of developing cancer. After receiving GRSs, those who received at least one high GRS reported significantly more worry about developing cancer. There were no significant differences found between gender, age, or GRS with regards to participants’ reported optimism about their future health neither before nor after receiving GRS results.Conclusions: Genetic risk scores that quantify an individual’s risk of developing breast, prostate and colorectal cancers as compared with a race-defined population average risk have potential clinical utility as a tool for risk stratification and to guide cancer screening in a primary care setting.

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Family History of Breast or Prostate Cancer and Prostate Cancer Risk

Abstract: Our study found that men with a family history of breast or prostate cancer had elevated prostate cancer risks, including risk of lethal disease. These findings have translational relevance for cancer risk prediction in men.

Cited by 73 publications

References 27 publications

BRCA1 and EZH2 cooperate in regulation of prostate cancer stem cell phenotype

BRCA1 and EZH2 cooperate in regulation of prostate cancer stem cell phenotype

Family history of prostate cancer and the incidence of ERG‐ and phosphatase and tensin homolog‐defined prostate cancer

Assessing the Clinical Utility of Genetic Risk Scores for Targeted Cancer Screening

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