Identification of a prostate cancer susceptibility locus on chromosome 7q11–21 in Jewish families

Friedrichsen, Danielle M.; Stanford, Janet L.; Isaacs, Sarah D.; Janer, Marta; Chang, Bao Li; Deutsch, Kerry; Gillanders, Elizabeth M.; Kolb, Suzanne; Wiley, Katherine E.; Badzioch, Michael D.; Zheng, S. Lilly; Walsh, Patrick C.; Jarvik, Gail P.; Hood, Leroy; Trent, Jeffrey M.; Isaacs, William B.; Ostrander, Elaine A.; Xu, Jianfeng

doi:10.1073/pnas.0308336100

Cited by 23 publications

(11 citation statements)

References 65 publications

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“…CNVs in the region have previously been reported in control populations [57]. Chromosome 7q11-21 has previously been associated with cancer [58,59] and interestingly, both regions identified in the current study (7q11.21 and 16p11.2) have been found as CN gains in small bowel adenocarcinomas [60], which raises questions whether this is evidence in favour of the findings of the current study, or calls into question the stringency of the analysis which reported it.…”

Section: Discussionmentioning

confidence: 99%

Continuing difficulties in interpreting CNV data: lessons from a genome-wide CNV association study of Australian HNPCC/lynch syndrome patients

et al. 2013

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BackgroundHereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome (LS) is a cancer syndrome characterised by early-onset epithelial cancers, especially colorectal cancer (CRC) and endometrial cancer. The aim of the current study was to use SNP-array technology to identify genomic aberrations which could contribute to the increased risk of cancer in HNPCC/LS patients.MethodsIndividuals diagnosed with HNPCC/LS (100) and healthy controls (384) were genotyped using the Illumina Human610-Quad SNP-arrays. Copy number variation (CNV) calling and association analyses were performed using Nexus software, with significant results validated using QuantiSNP. TaqMan Copy-Number assays were used for verification of CNVs showing significant association with HNPCC/LS identified by both software programs.ResultsWe detected copy number (CN) gains associated with HNPCC/LS status on chromosome 7q11.21 (28% cases and 0% controls, Nexus; p = 3.60E-20 and QuantiSNP; p < 1.00E-16) and 16p11.2 (46% in cases, while a CN loss was observed in 23% of controls, Nexus; p = 4.93E-21 and QuantiSNP; p = 5.00E-06) via in silico analyses. TaqMan Copy-Number assay was used for validation of CNVs showing significant association with HNPCC/LS. In addition, CNV burden (total CNV length, average CNV length and number of observed CNV events) was significantly greater in cases compared to controls.ConclusionA greater CNV burden was identified in HNPCC/LS cases compared to controls supporting the notion of higher genomic instability in these patients. One intergenic locus on chromosome 7q11.21 is possibly associated with HNPCC/LS and deserves further investigation. The results from this study highlight the complexities of fluorescent based CNV analyses. The inefficiency of both CNV detection methods to reproducibly detect observed CNVs demonstrates the need for sequence data to be considered alongside intensity data to avoid false positive results.

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Section: Discussionmentioning

confidence: 99%

Continuing difficulties in interpreting CNV data: lessons from a genome-wide CNV association study of Australian HNPCC/lynch syndrome patients

et al. 2013

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“…[43][44][45] Since the post hoc analysis indicated a strong linkage signal with homogeneity among the Hasidic Jewish families, association mapping may be especially suitable in this population because of its limited number of founders. 38,39,46,47 Furthermore, one would expect enrichment for homozygous segments surrounding susceptibility genes among pVUR cases from this population. We did not detect regions of homozygosity within the chromosome 12 locus in the Hasidic Jewish patients, but this may be due to the lack of close consanguinity among families studied.…”

Section: Discussionmentioning

confidence: 99%

A Recessive Gene for Primary Vesicoureteral Reflux Maps to Chromosome 12p11-q13

Weng

Sanna‐Cherchi

Hensle

et al. 2009

Journal of the American Society of Nephrology

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Primary vesicoureteral reflux (pVUR) is one of the most common causes of pediatric kidney failure. Linkage scans suggest that pVUR is genetically heterogeneous with two loci on chromosomes 1p13 and 2q37 under autosomal dominant inheritance. Absence of pVUR in parents of affected individuals raises the possibility of a recessive contribution to pVUR. We performed a genome-wide linkage scan in 12 large families segregating pVUR, comprising 72 affected individuals. To avoid potential misspecification of the trait locus, we performed a parametric linkage analysis using both dominant and recessive models. Analysis under the dominant model yielded no signals across the entire genome. In contrast, we identified a unique linkage peak under the recessive model on chromosome 12p11-q13 (D12S1048), which we confirmed by fine mapping. This interval achieved a peak heterogeneity LOD score of 3.6 with 60% of families linked. This heterogeneity LOD score improved to 4.5 with exclusion of two high-density pedigrees that failed to link across the entire genome. The linkage signal on chromosome 12p11-q13 originated from pedigrees of varying ethnicity, suggesting that recessive inheritance of a high frequency risk allele occurs in pVUR kindreds from many different populations. In conclusion, this study identifies a major new locus for pVUR and suggests that in addition to genetic heterogeneity, recessive contributions should be considered in all pVUR genome scans.

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“…In addition to these three linkage regions, multiple chromosomal regions have been suggested to harbor PCa susceptibility genes from multiple genome-wide linkage analyses in PCa families ascertained in North America, Europe and Australia. [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44] Notably, the International Consortium for Prostate Cancer Genetics (ICPCG) was formed in 1996 to coordinate efforts among investigators across the world for identifying PCa susceptibility genes. To date, more than 2000 families with at least two men affected with PCa have been recruited by members of ICPCG.…”

Section: Rare and High-penetrance Pca Susceptibility Genesmentioning

confidence: 99%

Prostate cancer risk-associated genetic markers and their potential clinical utility

Xu¹,

Sun²,

Zheng³

2013

Asian J Androl

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Prostate cancer (PCa) is one of the most common cancers among men in Western developed countries and its incidence has increased considerably in many other parts of the world, including China. The etiology of PCa is largely unknown but is thought to be multifactorial, where inherited genetics plays an important role. In this article, we first briefly review results from studies of familial aggregation and genetic susceptibility to PCa. We then recap key findings of rare and high-penetrance PCa susceptibility genes from linkage studies in PCa families. We devote a significant portion of this article to summarizing discoveries of common and low-penetrance PCa risk-associated single-nucleotide polymorphisms (SNPs) from genetic association studies in PCa cases and controls, especially those from genome-wide association studies (GWASs). A strong focus of this article is to review the literature on the potential clinical utility of these implicated genetic markers. Most of these published studies described PCa risk estimation using a genetic score derived from multiple risk-associated SNPs and its utility in determining the need for prostate biopsy. Finally, we comment on the newly proposed concept of genetic score; the notion is to treat it as a marker for genetic predisposition, similar to family history, rather than a diagnostic marker to discriminate PCa patients from non-cancer patients. Available evidence to date suggests that genetic score is an objective and better measurement of inherited risk of PCa than family history. Another unique feature of this article is the inclusion of genetic association studies of PCa in Chinese and Japanese populations.

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Identification of a prostate cancer susceptibility locus on chromosome 7q11–21 in Jewish families

Cited by 23 publications

References 65 publications

Continuing difficulties in interpreting CNV data: lessons from a genome-wide CNV association study of Australian HNPCC/lynch syndrome patients

Continuing difficulties in interpreting CNV data: lessons from a genome-wide CNV association study of Australian HNPCC/lynch syndrome patients

A Recessive Gene for Primary Vesicoureteral Reflux Maps to Chromosome 12p11-q13

Prostate cancer risk-associated genetic markers and their potential clinical utility

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