Intraductal/ductal histology and lymphovascular invasion are associated with germline DNA‐repair gene mutations in prostate cancer
Background Germline mutations in genes mediating DNA repair are common in men with recurrent and advanced prostate cancer, and their presence may alter prognosis and management. We aimed to define pathological and clinical characteristics associated with germline DNA‐repair gene mutations, to facili...
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| Vydáno v: | The Prostate Ročník 78; číslo 5; s. 401 - 407 |
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| Hlavní autoři: | , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
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United States
Wiley Subscription Services, Inc
01.04.2018
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| ISSN: | 0270-4137, 1097-0045, 1097-0045 |
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| Abstract | Background
Germline mutations in genes mediating DNA repair are common in men with recurrent and advanced prostate cancer, and their presence may alter prognosis and management. We aimed to define pathological and clinical characteristics associated with germline DNA‐repair gene mutations, to facilitate selection of patients for germline testing.
Methods
We retrospectively evaluated 150 unselected patients with recurrent or metastatic prostate cancer who were offered germline genetic testing by a single oncologist using a clinical‐grade assay (Color Genomics). This platform utilizes next‐generation sequencing from saliva to interrogate 30 cancer‐susceptibility genes. Presence or absence of a deleterious germline mutation was correlated with histological and clinical characteristics, and with family history of cancer. All patients with DNA‐sequence alterations (pathogenic or variants) were offered genetic counseling.
Results
Between July 2016 and July 2017, 150 consecutive patients underwent germline testing; pathogenic mutations were identified in 21 men (14%). Among those with germline mutations, 9 (43%) were in BRCA2, 3 (14%) were in ATM, 3 (14%) were in CHEK2, and 2 (9%) were in BRCA1. While there were no associations between germline mutations and age, tumor stage, Gleason sum or family history; mutation‐positive patients had lower median PSA levels at diagnosis (5.5 vs 8.6 ng/mL, P = 0.01) and unique pathologic features. Namely, men with germline mutations were more likely to harbor intraductal/ductal histology (48% vs 12%, P < 0.01) and lymphovascular invasion (52% vs 14%, P < 0.01). Finally, 44% of patients with a positive germline test would not have been offered genetic screening according to current National Comprehensive Cancer Network (NCCN) guidelines.
Conclusions
Presence of intraductal/ductal histology and lymphovascular invasion appear to be associated with pathogenic germline DNA‐repair gene mutations in men with prostate cancer, and identification of these features may help to select patients for germline testing. NCCN guidelines may be inadequate in predicting which prostate cancer patients should undergo genetic screening. |
|---|---|
| AbstractList | Background
Germline mutations in genes mediating DNA repair are common in men with recurrent and advanced prostate cancer, and their presence may alter prognosis and management. We aimed to define pathological and clinical characteristics associated with germline DNA‐repair gene mutations, to facilitate selection of patients for germline testing.
Methods
We retrospectively evaluated 150 unselected patients with recurrent or metastatic prostate cancer who were offered germline genetic testing by a single oncologist using a clinical‐grade assay (Color Genomics). This platform utilizes next‐generation sequencing from saliva to interrogate 30 cancer‐susceptibility genes. Presence or absence of a deleterious germline mutation was correlated with histological and clinical characteristics, and with family history of cancer. All patients with DNA‐sequence alterations (pathogenic or variants) were offered genetic counseling.
Results
Between July 2016 and July 2017, 150 consecutive patients underwent germline testing; pathogenic mutations were identified in 21 men (14%). Among those with germline mutations, 9 (43%) were in BRCA2, 3 (14%) were in ATM, 3 (14%) were in CHEK2, and 2 (9%) were in BRCA1. While there were no associations between germline mutations and age, tumor stage, Gleason sum or family history; mutation‐positive patients had lower median PSA levels at diagnosis (5.5 vs 8.6 ng/mL, P = 0.01) and unique pathologic features. Namely, men with germline mutations were more likely to harbor intraductal/ductal histology (48% vs 12%, P < 0.01) and lymphovascular invasion (52% vs 14%, P < 0.01). Finally, 44% of patients with a positive germline test would not have been offered genetic screening according to current National Comprehensive Cancer Network (NCCN) guidelines.
Conclusions
Presence of intraductal/ductal histology and lymphovascular invasion appear to be associated with pathogenic germline DNA‐repair gene mutations in men with prostate cancer, and identification of these features may help to select patients for germline testing. NCCN guidelines may be inadequate in predicting which prostate cancer patients should undergo genetic screening. Germline mutations in genes mediating DNA repair are common in men with recurrent and advanced prostate cancer, and their presence may alter prognosis and management. We aimed to define pathological and clinical characteristics associated with germline DNA-repair gene mutations, to facilitate selection of patients for germline testing.BACKGROUNDGermline mutations in genes mediating DNA repair are common in men with recurrent and advanced prostate cancer, and their presence may alter prognosis and management. We aimed to define pathological and clinical characteristics associated with germline DNA-repair gene mutations, to facilitate selection of patients for germline testing.We retrospectively evaluated 150 unselected patients with recurrent or metastatic prostate cancer who were offered germline genetic testing by a single oncologist using a clinical-grade assay (Color Genomics). This platform utilizes next-generation sequencing from saliva to interrogate 30 cancer-susceptibility genes. Presence or absence of a deleterious germline mutation was correlated with histological and clinical characteristics, and with family history of cancer. All patients with DNA-sequence alterations (pathogenic or variants) were offered genetic counseling.METHODSWe retrospectively evaluated 150 unselected patients with recurrent or metastatic prostate cancer who were offered germline genetic testing by a single oncologist using a clinical-grade assay (Color Genomics). This platform utilizes next-generation sequencing from saliva to interrogate 30 cancer-susceptibility genes. Presence or absence of a deleterious germline mutation was correlated with histological and clinical characteristics, and with family history of cancer. All patients with DNA-sequence alterations (pathogenic or variants) were offered genetic counseling.Between July 2016 and July 2017, 150 consecutive patients underwent germline testing; pathogenic mutations were identified in 21 men (14%). Among those with germline mutations, 9 (43%) were in BRCA2, 3 (14%) were in ATM, 3 (14%) were in CHEK2, and 2 (9%) were in BRCA1. While there were no associations between germline mutations and age, tumor stage, Gleason sum or family history; mutation-positive patients had lower median PSA levels at diagnosis (5.5 vs 8.6 ng/mL, P = 0.01) and unique pathologic features. Namely, men with germline mutations were more likely to harbor intraductal/ductal histology (48% vs 12%, P < 0.01) and lymphovascular invasion (52% vs 14%, P < 0.01). Finally, 44% of patients with a positive germline test would not have been offered genetic screening according to current National Comprehensive Cancer Network (NCCN) guidelines.RESULTSBetween July 2016 and July 2017, 150 consecutive patients underwent germline testing; pathogenic mutations were identified in 21 men (14%). Among those with germline mutations, 9 (43%) were in BRCA2, 3 (14%) were in ATM, 3 (14%) were in CHEK2, and 2 (9%) were in BRCA1. While there were no associations between germline mutations and age, tumor stage, Gleason sum or family history; mutation-positive patients had lower median PSA levels at diagnosis (5.5 vs 8.6 ng/mL, P = 0.01) and unique pathologic features. Namely, men with germline mutations were more likely to harbor intraductal/ductal histology (48% vs 12%, P < 0.01) and lymphovascular invasion (52% vs 14%, P < 0.01). Finally, 44% of patients with a positive germline test would not have been offered genetic screening according to current National Comprehensive Cancer Network (NCCN) guidelines.Presence of intraductal/ductal histology and lymphovascular invasion appear to be associated with pathogenic germline DNA-repair gene mutations in men with prostate cancer, and identification of these features may help to select patients for germline testing. NCCN guidelines may be inadequate in predicting which prostate cancer patients should undergo genetic screening.CONCLUSIONSPresence of intraductal/ductal histology and lymphovascular invasion appear to be associated with pathogenic germline DNA-repair gene mutations in men with prostate cancer, and identification of these features may help to select patients for germline testing. NCCN guidelines may be inadequate in predicting which prostate cancer patients should undergo genetic screening. Germline mutations in genes mediating DNA repair are common in men with recurrent and advanced prostate cancer, and their presence may alter prognosis and management. We aimed to define pathological and clinical characteristics associated with germline DNA-repair gene mutations, to facilitate selection of patients for germline testing. We retrospectively evaluated 150 unselected patients with recurrent or metastatic prostate cancer who were offered germline genetic testing by a single oncologist using a clinical-grade assay (Color Genomics). This platform utilizes next-generation sequencing from saliva to interrogate 30 cancer-susceptibility genes. Presence or absence of a deleterious germline mutation was correlated with histological and clinical characteristics, and with family history of cancer. All patients with DNA-sequence alterations (pathogenic or variants) were offered genetic counseling. Between July 2016 and July 2017, 150 consecutive patients underwent germline testing; pathogenic mutations were identified in 21 men (14%). Among those with germline mutations, 9 (43%) were in BRCA2, 3 (14%) were in ATM, 3 (14%) were in CHEK2, and 2 (9%) were in BRCA1. While there were no associations between germline mutations and age, tumor stage, Gleason sum or family history; mutation-positive patients had lower median PSA levels at diagnosis (5.5 vs 8.6 ng/mL, P = 0.01) and unique pathologic features. Namely, men with germline mutations were more likely to harbor intraductal/ductal histology (48% vs 12%, P < 0.01) and lymphovascular invasion (52% vs 14%, P < 0.01). Finally, 44% of patients with a positive germline test would not have been offered genetic screening according to current National Comprehensive Cancer Network (NCCN) guidelines. Presence of intraductal/ductal histology and lymphovascular invasion appear to be associated with pathogenic germline DNA-repair gene mutations in men with prostate cancer, and identification of these features may help to select patients for germline testing. NCCN guidelines may be inadequate in predicting which prostate cancer patients should undergo genetic screening. BackgroundGermline mutations in genes mediating DNA repair are common in men with recurrent and advanced prostate cancer, and their presence may alter prognosis and management. We aimed to define pathological and clinical characteristics associated with germline DNA‐repair gene mutations, to facilitate selection of patients for germline testing.MethodsWe retrospectively evaluated 150 unselected patients with recurrent or metastatic prostate cancer who were offered germline genetic testing by a single oncologist using a clinical‐grade assay (Color Genomics). This platform utilizes next‐generation sequencing from saliva to interrogate 30 cancer‐susceptibility genes. Presence or absence of a deleterious germline mutation was correlated with histological and clinical characteristics, and with family history of cancer. All patients with DNA‐sequence alterations (pathogenic or variants) were offered genetic counseling.ResultsBetween July 2016 and July 2017, 150 consecutive patients underwent germline testing; pathogenic mutations were identified in 21 men (14%). Among those with germline mutations, 9 (43%) were in BRCA2, 3 (14%) were in ATM, 3 (14%) were in CHEK2, and 2 (9%) were in BRCA1. While there were no associations between germline mutations and age, tumor stage, Gleason sum or family history; mutation‐positive patients had lower median PSA levels at diagnosis (5.5 vs 8.6 ng/mL, P = 0.01) and unique pathologic features. Namely, men with germline mutations were more likely to harbor intraductal/ductal histology (48% vs 12%, P < 0.01) and lymphovascular invasion (52% vs 14%, P < 0.01). Finally, 44% of patients with a positive germline test would not have been offered genetic screening according to current National Comprehensive Cancer Network (NCCN) guidelines.ConclusionsPresence of intraductal/ductal histology and lymphovascular invasion appear to be associated with pathogenic germline DNA‐repair gene mutations in men with prostate cancer, and identification of these features may help to select patients for germline testing. NCCN guidelines may be inadequate in predicting which prostate cancer patients should undergo genetic screening. |
| Author | Antonarakis, Emmanuel S. Luo, Jun Markowski, Mark C. Isaacs, William B. Isaacsson Velho, Pedro Silberstein, John L. Lotan, Tamara L. |
| AuthorAffiliation | 1 Johns Hopkins Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, Maryland 2 Brady Urological Institute, Johns Hopkins University, Baltimore, Maryland 3 Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland |
| AuthorAffiliation_xml | – name: 1 Johns Hopkins Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, Maryland – name: 3 Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland – name: 2 Brady Urological Institute, Johns Hopkins University, Baltimore, Maryland |
| Author_xml | – sequence: 1 givenname: Pedro surname: Isaacsson Velho fullname: Isaacsson Velho, Pedro organization: Johns Hopkins University – sequence: 2 givenname: John L. surname: Silberstein fullname: Silberstein, John L. organization: Johns Hopkins University – sequence: 3 givenname: Mark C. surname: Markowski fullname: Markowski, Mark C. organization: Johns Hopkins University – sequence: 4 givenname: Jun surname: Luo fullname: Luo, Jun organization: Johns Hopkins University – sequence: 5 givenname: Tamara L. surname: Lotan fullname: Lotan, Tamara L. organization: Johns Hopkins School of Medicine – sequence: 6 givenname: William B. orcidid: 0000-0001-6599-6775 surname: Isaacs fullname: Isaacs, William B. organization: Johns Hopkins University – sequence: 7 givenname: Emmanuel S. orcidid: 0000-0003-0031-9655 surname: Antonarakis fullname: Antonarakis, Emmanuel S. email: eantona1@jhmi.edu organization: Johns Hopkins University |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/29368341$$D View this record in MEDLINE/PubMed |
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Germline mutations in genes mediating DNA repair are common in men with recurrent and advanced prostate cancer, and their presence may alter... Germline mutations in genes mediating DNA repair are common in men with recurrent and advanced prostate cancer, and their presence may alter prognosis and... BackgroundGermline mutations in genes mediating DNA repair are common in men with recurrent and advanced prostate cancer, and their presence may alter... |
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| SubjectTerms | Adult Aged Aged, 80 and over BRCA1 protein BRCA2 protein cancer Deoxyribonucleic acid DNA DNA Repair Family medical history Genes Genetic counseling Genetic screening Germ-Line Mutation germline Histology Humans Lymph Nodes - pathology Lymphatic Metastasis Male Metastases Middle Aged Mutation mutations Neoplasm Metastasis Neoplasm Staging Nucleotide sequence prostate Prostate cancer Prostatic Neoplasms - genetics Prostatic Neoplasms - pathology Prostatic Neoplasms, Castration-Resistant - genetics Prostatic Neoplasms, Castration-Resistant - pathology Retrospective Studies Saliva |
| Title | Intraductal/ductal histology and lymphovascular invasion are associated with germline DNA‐repair gene mutations in prostate cancer |
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