Germline Mutations in HOXB13 and Prostate-Cancer Risk
Prostate cancer runs in families. However, the genes that affect the incidence remain largely undefined. The authors have identified a rare germline variant of a homeobox gene, HOXB13, in four families with a history of prostate cancer. Prostate cancer is the most common noncutaneous cancer diagnose...
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| Published in | The New England journal of medicine Vol. 366; no. 2; pp. 141 - 149 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Waltham, MA
Massachusetts Medical Society
12.01.2012
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| Subjects | |
| Online Access | Get full text |
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| Abstract | Prostate cancer runs in families. However, the genes that affect the incidence remain largely undefined. The authors have identified a rare germline variant of a homeobox gene,
HOXB13,
in four families with a history of prostate cancer.
Prostate cancer is the most common noncutaneous cancer diagnosed in men in the United States, with more than 240,000 new cases expected in 2011.
1
Despite the demonstration of a strong familial component, identification of the genetic basis for hereditary prostate cancer has been challenging. Linkage studies of families with hereditary prostate cancer have provided inconsistent results.
2
In contrast, genomewide association studies have led to the identification of more than 30 single-nucleotide polymorphisms (SNPs) that are consistently associated with prostate cancer.
3
However, the magnitude of risk elevation attributed to each individual SNP is low, with an increased elevation in risk by . . . |
|---|---|
| AbstractList | Prostate cancer runs in families. However, the genes that affect the incidence remain largely undefined. The authors have identified a rare germline variant of a homeobox gene,
HOXB13,
in four families with a history of prostate cancer.
Prostate cancer is the most common noncutaneous cancer diagnosed in men in the United States, with more than 240,000 new cases expected in 2011.
1
Despite the demonstration of a strong familial component, identification of the genetic basis for hereditary prostate cancer has been challenging. Linkage studies of families with hereditary prostate cancer have provided inconsistent results.
2
In contrast, genomewide association studies have led to the identification of more than 30 single-nucleotide polymorphisms (SNPs) that are consistently associated with prostate cancer.
3
However, the magnitude of risk elevation attributed to each individual SNP is low, with an increased elevation in risk by . . . Family history is a significant risk factor for prostate cancer, although the molecular basis for this association is poorly understood. Linkage studies have implicated chromosome 17q21-22 as a possible location of a prostate-cancer susceptibility gene. We screened more than 200 genes in the 17q21-22 region by sequencing germline DNA from 94 unrelated patients with prostate cancer from families selected for linkage to the candidate region. We tested family members, additional case subjects, and control subjects to characterize the frequency of the identified mutations. Probands from four families were discovered to have a rare but recurrent mutation (G84E) in HOXB13 (rs138213197), a homeobox transcription factor gene that is important in prostate development. All 18 men with prostate cancer and available DNA in these four families carried the mutation. The carrier rate of the G84E mutation was increased by a factor of approximately 20 in 5083 unrelated subjects of European descent who had prostate cancer, with the mutation found in 72 subjects (1.4%), as compared with 1 in 1401 control subjects (0.1%) (P=8.5x10(-7)). The mutation was significantly more common in men with early-onset, familial prostate cancer (3.1%) than in those with late-onset, nonfamilial prostate cancer (0.6%) (P=2.0x10(-6)). The novel HOXB13 G84E variant is associated with a significantly increased risk of hereditary prostate cancer. Although the variant accounts for a small fraction of all prostate cancers, this finding has implications for prostate-cancer risk assessment and may provide new mechanistic insights into this common cancer. (Funded by the National Institutes of Health and others.). Family history is a significant risk factor for prostate cancer, although the molecular basis for this association is poorly understood. Linkage studies have implicated chromosome 17q21-22 as a possible location of a prostate-cancer susceptibility gene.BACKGROUNDFamily history is a significant risk factor for prostate cancer, although the molecular basis for this association is poorly understood. Linkage studies have implicated chromosome 17q21-22 as a possible location of a prostate-cancer susceptibility gene.We screened more than 200 genes in the 17q21-22 region by sequencing germline DNA from 94 unrelated patients with prostate cancer from families selected for linkage to the candidate region. We tested family members, additional case subjects, and control subjects to characterize the frequency of the identified mutations.METHODSWe screened more than 200 genes in the 17q21-22 region by sequencing germline DNA from 94 unrelated patients with prostate cancer from families selected for linkage to the candidate region. We tested family members, additional case subjects, and control subjects to characterize the frequency of the identified mutations.Probands from four families were discovered to have a rare but recurrent mutation (G84E) in HOXB13 (rs138213197), a homeobox transcription factor gene that is important in prostate development. All 18 men with prostate cancer and available DNA in these four families carried the mutation. The carrier rate of the G84E mutation was increased by a factor of approximately 20 in 5083 unrelated subjects of European descent who had prostate cancer, with the mutation found in 72 subjects (1.4%), as compared with 1 in 1401 control subjects (0.1%) (P=8.5x10(-7)). The mutation was significantly more common in men with early-onset, familial prostate cancer (3.1%) than in those with late-onset, nonfamilial prostate cancer (0.6%) (P=2.0x10(-6)).RESULTSProbands from four families were discovered to have a rare but recurrent mutation (G84E) in HOXB13 (rs138213197), a homeobox transcription factor gene that is important in prostate development. All 18 men with prostate cancer and available DNA in these four families carried the mutation. The carrier rate of the G84E mutation was increased by a factor of approximately 20 in 5083 unrelated subjects of European descent who had prostate cancer, with the mutation found in 72 subjects (1.4%), as compared with 1 in 1401 control subjects (0.1%) (P=8.5x10(-7)). The mutation was significantly more common in men with early-onset, familial prostate cancer (3.1%) than in those with late-onset, nonfamilial prostate cancer (0.6%) (P=2.0x10(-6)).The novel HOXB13 G84E variant is associated with a significantly increased risk of hereditary prostate cancer. Although the variant accounts for a small fraction of all prostate cancers, this finding has implications for prostate-cancer risk assessment and may provide new mechanistic insights into this common cancer. (Funded by the National Institutes of Health and others.).CONCLUSIONSThe novel HOXB13 G84E variant is associated with a significantly increased risk of hereditary prostate cancer. Although the variant accounts for a small fraction of all prostate cancers, this finding has implications for prostate-cancer risk assessment and may provide new mechanistic insights into this common cancer. (Funded by the National Institutes of Health and others.). BackgroundFamily history is a significant risk factor for prostate cancer, although the molecular basis for this association is poorly understood. Linkage studies have implicated chromosome 17q21-22 as a possible location of a prostate-cancer susceptibility gene.MethodsWe screened more than 200 genes in the 17q21-22 region by sequencing germline DNA from 94 unrelated patients with prostate cancer from families selected for linkage to the candidate region. We tested family members, additional case subjects, and control subjects to characterize the frequency of the identified mutations.ResultsProbands from four families were discovered to have a rare but recurrent mutation (G84E) in HOXB13 (rs138213197), a homeobox transcription factor gene that is important in prostate development. All 18 men with prostate cancer and available DNA in these four families carried the mutation. The carrier rate of the G84E mutation was increased by a factor of approximately 20 in 5083 unrelated subjects of European descent who had prostate cancer, with the mutation found in 72 subjects (1.4%), as compared with 1 in 1401 control subjects (0.1%) (P=8.5×10−7). The mutation was significantly more common in men with early-onset, familial prostate cancer (3.1%) than in those with late-onset, nonfamilial prostate cancer (0.6%) (P=2.0×10−6).ConclusionsThe novel HOXB13 G84E variant is associated with a significantly increased risk of hereditary prostate cancer. Although the variant accounts for a small fraction of all prostate cancers, this finding has implications for prostate-cancer risk assessment and may provide new mechanistic insights into this common cancer. (Funded by the National Institutes of Health and others.) |
| Author | Lange, Ethan M Gielzak, Marta Walsh, Patrick C Zheng, S. Lilly Yan, Guifang Craig, David W Montie, James E Xu, Jianfeng Johng, Dorhyun Ewing, Charles M Isaacs, Sarah D Bizon, Chris Partin, Alan W Shanmugam, Vijayalakshmi Wiley, Kathleen E Isaacs, William B Wang, Yunfei Zuhlke, Kimberly A Cooney, Kathleen A Tembe, Waibhav D Izatt, Tyler Robbins, Christiane M Carpten, John D Ray, Anna M Sinari, Shripad |
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| BackLink | http://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=25482813$$DView record in Pascal Francis https://www.ncbi.nlm.nih.gov/pubmed/22236224$$D View this record in MEDLINE/PubMed |
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| CODEN | NEJMAG |
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| Snippet | Prostate cancer runs in families. However, the genes that affect the incidence remain largely undefined. The authors have identified a rare germline variant of... Family history is a significant risk factor for prostate cancer, although the molecular basis for this association is poorly understood. Linkage studies have... BackgroundFamily history is a significant risk factor for prostate cancer, although the molecular basis for this association is poorly understood. Linkage... |
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| SubjectTerms | Age Biological and medical sciences Chromosome 17 Chromosomes, Human, Pair 17 Deoxyribonucleic acid DNA DNA sequencing Genealogy General aspects Genetic Linkage Genetics Germ-Line Mutation Gynecology. Andrology. Obstetrics High-Throughput Nucleotide Sequencing Homeobox Homeodomain Proteins - genetics Humans Male Male genital diseases Medical research Medical sciences Men Middle Aged Mutation Nephrology. Urinary tract diseases Pedigree Prostate - pathology Prostate cancer Prostatic Neoplasms - genetics Prostatic Neoplasms - pathology Review boards Risk assessment Sequence Analysis, DNA Tumors Tumors of the urinary system Urinary tract. Prostate gland |
| Title | Germline Mutations in HOXB13 and Prostate-Cancer Risk |
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