Targeted prostate cancer screening in men with mutations in <i>BRCA1</i> and <i>BRCA2</i> detects aggressive prostate cancer: preliminary analysis of the results of the IMPACT study

Mitra, Anita; Bancroft, Elizabeth; Barbáchano, Yolanda; Page, Elizabeth; Foster, Christopher S.; Jameson, Charles; Mitchell, Gillian; Lindeman, Geoffrey J.; Stapleton, Andrew J.; Suthers, Graeme; Evans, D. Gareth; Crüger, Dorthe Gylling; Blanco, Ignacio; Mercer, Catherine; Kirk, Judy; Mæhle, Lovise; Hodgson, Shirley; Walker, Lisa; Izatt, Louise; Douglas, Gillian; Tucker, Kathy; Dorkins, Huw; Clowes, Virginia; Male, Alison; Donaldson, Alan; Brewer, Carole; Doherty, Rebecca; Bulman, Barbara; Osther, Palle Jørn Sloth; Salinas, Mónica; Eccles, Diana; Axcrona, Karol; Jobson, Irene; Newcombe, Barbara; Cybulski, Cezary; Rubinstein, Wendy S.; Buys, Saundra S.; Townshend, Sharron; Friedman, Eitan; Domchek, Susan M.; Cajal, Teresa Ramón y; Spigelman, Allan D.; Teo, Soo Hwang; Nicolai, Nicola; Aaronson, Neil K.; Ardern‐Jones, Audrey; Bangma, Chris H.; Dearnaley, David P.; Eyfjörd, Jórunn E.; Falconer, Alison; Grönberg, Henrik; Hamdy, Freddie C.; Jóhannsson, Óskar Þór; Khoo, Vincent; Kóte-Jarai, Zsofia; Lilja, Hans; Lubiński, Jan; Melia, Jane; Moynihan, Clare; Peock, Susan; Rennert, Gad; Schröder, Fritz H.; Sibley, Paul; Suri, Mohnish; Wilson, Penny; Bignon, Y. J.; Strom, Sara S.; Tischkowitz, Marc; Liljegren, Annelie; Ilenčíková, Denisa; Abele, A.; Kyriacou, Kyriacos; Asperen, Christi J. van; Kiemeney, Lambertus A.; Easton, Douglas F.; Eeles, Rosalind

doi:10.1111/j.1464-410x.2010.09648.x

Cited by 89 publications

(68 citation statements)

References 53 publications

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“…Early diagnosis in these patients may be crucial, and currently, the IMPACT study is evaluating the utility of PSA-based PCa screening in asymptomatic BRCA1 and BRCA2 mutation carriers. 95 At this time, there is no evidence as to which is the most appropriate radical treatment for BRCA mutation carriers with local PCa. Although clinical trials to assess the most adequate management of these cases are still needed, radical treatment with either surgery or radiotherapy seems to be preferable to active surveillance, even for low-risk cases.…”

Section: Discussionmentioning

confidence: 99%

The role of BRCA1 and BRCA2 in prostate cancer

Castro¹,

Eeles²

2012

Asian J Androl

135

105

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One of the strongest risk factors for prostate cancer is a family history of the disease. Germline mutations in the breast cancer predisposition gene 2 (BRCA2) are the genetic events known to date that confer the highest risk of prostate cancer (8.6-fold in men f65 years). Although the role of BRCA2 and BRCA1 in prostate tumorigenesis remains unrevealed, deleterious mutations in both genes have been associated with more aggressive disease and poor clinical outcomes. The increasing incidence of prostate cancer worldwide supports the need for new methods to predict outcome and identify patients with potentially lethal forms of the disease. As we present here, BRCA germline mutations, mainly in the BRCA2 gene, are one of those predictive factors. We will also discuss the implications of these mutations in the management of prostate cancer and hypothesize on the potential for the development of strategies for sporadic cases with similar characteristics.

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Section: Discussionmentioning

confidence: 99%

The role of BRCA1 and BRCA2 in prostate cancer

Castro¹,

Eeles²

2012

Asian J Androl

135

105

View full text Add to dashboard Cite

show abstract

“…Although routine PSA screening is not currently recommended in Australia (27), the results presented here suggest that in this group of men, PSA-based case selection may have clinical utility. The current IMPACT study is examining the utility of PSA-based case selection in BRCA mutation carriers to identify prostate cancer in presymptomatic patients (28). In year 1, 3.3% prostate cancers were detected by PSA screening (28).…”

Section: Discussionmentioning

confidence: 99%

“…The current IMPACT study is examining the utility of PSA-based case selection in BRCA mutation carriers to identify prostate cancer in presymptomatic patients (28). In year 1, 3.3% prostate cancers were detected by PSA screening (28). As The IMPACT study also offers a prostate biopsy to all men at study exit, it may be able to provide important insights into the prevalence of prostate cancer in this cohort as well as an indication of an appropriate PSA threshold for biopsy.…”

Section: Discussionmentioning

confidence: 99%

Decreased Prostate Cancer-Specific Survival of Men with BRCA2 Mutations from Multiple Breast Cancer Families

Thorne

Willems

Niedermayr

et al. 2011

Cancer Prevention Research

105

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The role of a germ-line BRCA2 mutation in the development of prostate cancer is established, but the clinical presentation linked to outcome for this group of men has not been well described.A total of 148 men from 1,423 families were ascertained from the kConFab consortium. Each participant met the following criteria: (i) a verified case of prostate cancer; (ii) confirmed as either a carrier or noncarrier of a family-specific BRCA pathogenic mutation; (iii) comprehensive clinical and treatment data were available. Clinical data were linked to treatment received and overall survival was analyzed by Kaplan-Meier.Prostate cancer in men from breast cancer-prone families has a high risk of disease progression, irrespective of mutation status. BRCA2 mutation carriers have an increased risk of death and prostate cancer-related death [HR (95% CI) 4.5 (2.12-9.52), P ¼ 8.9 Â 10 À5 ] by comparison with noncarriers. Serum PSA readings taken prior to diagnosis in 90% of all men, age adjusted, were above clinical significance. Following D'Amico risk stratification, 77.5% of BRCA2 mutation carriers and 58.7% of noncarriers had high-risk disease. BRCA2 mutation status was also an independent prognostic indicator of overall survival. Furthermore, there was a poor overall survival outcome for both the BRCA2 mutation carriers and noncarriers given curative-intent treatment.All men in breast cancer-prone families are at risk of developing aggressive prostate cancer. This information is significant and should be included in discussions with genetic counselors and medical professionals when discussing prostate cancer treatment options for men in these families, irrespective of mutation status.

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“…The potential clinical relevance of phase for prediction and prevention can be illustrated in MP1 by the cancer-related gene BRCA1. Male carriers of mutations are at increased risk of developing prostate cancer (Mitra et al 2011). However, MP1 has all BRCA1 mutations in cis leaving one of the two gene forms intact, which could potentially attenuate or eliminate harmful effects.…”

Section: à6mentioning

confidence: 99%

A comprehensively molecular haplotype-resolved genome of a European individual

Suk

McEwen

Duitama³

et al. 2011

Genome Res.

111

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Independent determination of both haplotype sequences of an individual genome is essential to relate genetic variation to genome function, phenotype, and disease. To address the importance of phase, we have generated the most complete haplotype-resolved genome to date, “Max Planck One” (MP1), by fosmid pool-based next generation sequencing. Virtually all SNPs (>99%) and 80,000 indels were phased into haploid sequences of up to 6.3 Mb (N50 ∼1 Mb). The completeness of phasing allowed determination of the concrete molecular haplotype pairs for the vast majority of genes (81%) including potential regulatory sequences, of which >90% were found to be constituted by two different molecular forms. A subset of 159 genes with potentially severe mutations in either cis or trans configurations exemplified in particular the role of phase for gene function, disease, and clinical interpretation of personal genomes (e.g., BRCA1). Extended genomic regions harboring manifold combinations of physically and/or functionally related genes and regulatory elements were resolved into their underlying “haploid landscapes,” which may define the functional genome. Moreover, the majority of genes and functional sequences were found to contain individual or rare SNPs, which cannot be phased from population data alone, emphasizing the importance of molecular phasing for characterizing a genome in its molecular individuality. Our work provides the foundation to understand that the distinction of molecular haplotypes is essential to resolve the (inherently individual) biology of genes, genomes, and disease, establishing a reference point for “phase-sensitive” personal genomics. MP1's annotated haploid genomes are available as a public resource.

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Targeted prostate cancer screening in men with mutations in BRCA1 and BRCA2 detects aggressive prostate cancer: preliminary analysis of the results of the IMPACT study

Cited by 89 publications

References 53 publications

The role of BRCA1 and BRCA2 in prostate cancer

The role of BRCA1 and BRCA2 in prostate cancer

Decreased Prostate Cancer-Specific Survival of Men with BRCA2 Mutations from Multiple Breast Cancer Families

A comprehensively molecular haplotype-resolved genome of a European individual

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