Inherited pathologic mutations and family history in patients with prostate cancer.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 185-185
Author(s):  
Shuwen Lin ◽  
Elisa M. Ledet ◽  
Joshua Schiff ◽  
Emma M. Ernst ◽  
Cathryn E. Garvey ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Ovarian Cancer ◽  
Dna Repair ◽  
Genetic Testing ◽  
Family History ◽  
San Francisco ◽  
Metastatic Disease ◽  
Cancer Center ◽  
Pathogenic Variants ◽  
Significant Difference

185 Background: In prostate cancer (PCa), germline pathogenic variants have previously been underestimated. PCa patients (pts) with DNA repair defects have a higher percentage of non-PCa family history (FH) with the most common cancers being derived from the breast, GI tract, ovary, pancreas, lymphoma/leukemia. The goal of this study was to evaluate and characterize pathogenic variants detected in PCa patients undergoing both enhanced FH screening and genetic testing. Methods: In this single-institution study, 535 PCa pts from Tulane Cancer Center over the last year underwent enhanced FH screening, and FH of PCa and other cancers were collected. 124 PCa pts including those with both localized and metastatic disease were identified to have a FH that met NCCN guidelines for genetic testing. Genetic testing was done using a commercially available panel (Invitae, San Francisco, CA) of 25-79 cancer-related genes for mutations and selected exonic deletions/duplications. Results: Of the 124 tested pts, 21 pts (16.9%) had ≥ 1 germline pathogenic variant (PV) and 47 pts (37.9%) had ≥ 1 germline variant of unknown significance (VUS). PVs included: BRCA2 (n = 4), BRCA1 (n = 3), CHEK2 (n = 3), MUTYH (n = 3), ATM (n = 2), TP53 (n = 2), MITF (n = 1), NBN (n = 1), PMS2 (n = 1), and (RAD51D (n = 1). Of the 124 tested pts, 68 pts (54.8%) had PCa FH, 68 (54.8%) had breast cancer FH, 22 (17.7%) had pancreatic cancer FH, 16 (12.9%) had ovarian cancer FH, and 37 (29.8%) had both breast and PCa FH. Between the pt groups (those with PVs, VUSs and negative results), there were no differences in FH rates of PCa, breast, pancreatic, or ovarian cancer. There was no significant difference in the age at diagnosis (dx) between the groups or between pts with PCa FH and those without. The median ages at dx were 65 for PV pts, 60 for VUS pts, and 59 for negative result pts. There were no statistically significant differences in initial Gleason score or metastatic disease status in these three groups (p = 0.35 and p = 0.66). Conclusions: In this dataset, FH cannot discriminate between those with and without inherited PV using a broad panel of genes that include those that alter DNA repair. The implications of these findings are broad. [Table: see text]

Germline pathologic mutations and cancer family history in prostate cancer patients.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 378-378
Author(s):  
Marcus Marie Moses ◽  
Elisa Ledet ◽  
Emma M. Ernst ◽  
Patrick Cotogno ◽  
Joshua Schiff ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Family History ◽  
San Francisco ◽  
Treatment Options ◽  
Distant Metastases ◽  
Cancer Center ◽  
Chi Square ◽  
Variant Of Uncertain Significance ◽  
Pathogenic Variants ◽  
Uncertain Significance

378 Background: Prostate cancer (PCa) patients (pts) with metastases and/or strong family history (FH) of cancer (Ca) are at higher risk of a germline mutation. The identification of alterations in PCa pts may be important for risk stratification as well as personalizing treatment options. The goal of this study was characterization of FH and pathogenic variants (PV) detected in PCa pts, with both localized and metastatic disease. Methods: 300 PCa pts from Tulane Cancer Center underwent germline testing. 265 Caucasian (C) and 35 African-Americans (AA) were tested and met the NCCN criteria for testing and/or had distant metastases (mets). Germline genetic testing was done via commercial panels (30-80 genes) (Invitae. San Francisco, Ca). PCa pts had extensive FH screening. Clinical annotation included age at diagnosis (dx), race, and presence of mets at any time. Chi square tests were used to compare clinical correlates and PVs. Results: Of the 300 pts tested, 182 pts (60.6%) had mets and 118 (39.4%) did not. 41 pts (13.6%) had ≥ 1 germline pathogenic variant (PV) and 161 pts (53.6%) had ≥ 1 germline variant of uncertain significance (VUS). PVs were detected in BRCA2 (n = 10), MUTYH (n = 8), CHEK2 (n = 6), BRCA1 (n = 4), ATM (n = 4), TP53 (n = 3), PMS2 (n = 2), BLM (n = 2), MITF (n = 2), NBN (n = 1), and RAD51D (n = 1). MUTYH and MITF are not known to be linked to prostate cancer. There was no significant relationships in FH PCa and FH non-PCa in regard to likelihood of a PV (p = .86 and p = .18). Of the 300 pts tested, 136 pts (45.3%) had PCa FH, 131 pts (43.6%) had breast Ca FH, 61 pts (20.3%) had lung Ca FH, 61 pts (20.3%) had colon Ca FH, 37 pts (12.3%) had pancreatic Ca FH, and 32 pts (10.6%) had ovarian Ca FH. 45.6% of C men (n = 121) and 42.8% of AA men (n = 15) had PCa FH. Pts with a non-PCa FH (n = 255) were 1.37 times more likely to develop mets (p = .01168). The median age of dx were 61 for PV pts, 62 for VUS pts, and 61 for negative pts (non-significant). 21/182 pts with mets (11.5%) had a PV; 8/182 (4.4%) pts with mets had a BRCA2 PV. Conclusions: In metastatic patients, FH of prostate cancer alone cannot predict those with PV. The most common Cas observed in these pts were breast, lung, colon and pancreatic. A larger cohort is needed to fully characterize and understand the co-segregation of PCa with other Cas.

Family history and pathogenic/likely pathogenic germline variants in prostate cancer patients.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 143-143
Author(s):  
Rachel Sabol ◽  
Elisa Marie Ledet ◽  
Ellen Jaeger ◽  
Marcus W. Moses ◽  
Brian E. Lewis ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Ovarian Cancer ◽  
Genetic Testing ◽  
Family History ◽  
Personal History ◽  
Sample Collection ◽  
First Degree Relatives ◽  
Pathogenic Variants ◽  
Damage Repair ◽  
History Of

143 Background: Recent literature highlights the importance of germline genetic testing in prostate cancer (PCa) patients. Surprisingly, a literature review indicates that family history records are incomplete in published studies. Methods: Prospective and complete family history data were gathered from 496 men in a single institution with a personal history of PCa who underwent germline genetic testing using a panel of at least 79 genes (Invitae testing) from 2016-2020. Comprehensive FH were obtained in all PCa patients in this database and analysis of prevalent FH was assessed at the time of sample collection. Age, race, metastastes at any time, and Gleason score were also ascertained. MUTYH heterozygotes were not considered pathogenic. Results: Pathogenic/likely pathogenic variants (PV/LPVs) were not associated with age at diagnosis, race, or presence of metastasis. Men with Gleason scores 8-10 at time of diagnosis were more likely to have PV/LPV ( P= 0.004). One or more first degree relatives (FDR) with any cancer with was not predictive for germline PV/LPVs for men with PCa ( P= 0.96). Analysis of patients with one or more FDR with breast, prostate, ovarian, or pancreatic cancer revealed that only FDR with breast cancer ( P = 0.028) or ovarian cancer ( P = 0.015) was predictive for PV/LPVs. Though one or more FDR with prostate cancer did not predict a PV/LPV in the overall panel, further analysis indicate that a history of a FDR with PCa was predictive for PV/LPV in a DNA damage repair (DDR) gene ( P= 0.044). Conclusions: In men with a personal history of PCa, germline PV/LPVs were associated with a FDR with breast or ovarian cancer. A FDR with PCa was predictive for PV/LPV in DDR genes. These data emphasize the contribution of FH to germline genetic testing results in a cohort with complete ascertainment of cancer in first degree relatives.

Germline variants and family history in caucasian and African-American prostate cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e16548-e16548
Author(s):  
Elisa M. Ledet ◽  
Emma M. Ernst ◽  
Joshua Schiff ◽  
Shuwen Lin ◽  
Brian E. Lewis ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
African American ◽  
Genetic Testing ◽  
Family History ◽  
San Francisco ◽  
Testing Methods ◽  
Chi Square ◽  
Genetic Studies ◽  
Pathogenic Variants ◽  
Unknown Significance

e16548 Background: Family history (FH) is a well-documented risk factor for prostate cancer (PCa). Previously, germline pathogenic variants (PVs) have been identified in metastatic PCa. The goal of this study was to fully evaluate cancer FH and assess PVs detected in PCa patients undergoing both detailed FH ascertainment and germline genetic testing. Methods: FHs were collected from 535 PCa pts (Caucasian (Ca) n = 359, African American (AA) n = 85, Other n = 18) at Tulane from 2015-2016. Age at diagnosis, Gleasons, and the presence of metastases at any time were noted for these pts. Chi-square and the Mann-Whitney U tests were performed to identify relationships between clinical parameters and FH. 124 PCa pts including those with both localized and metastatic disease were identified with FHs that met guidelines for genetic testing. Genetic testing was done using a commercially available panel (Invitae, San Francisco, CA) of 25-79 cancer-related genes for mutations/selected exon deletions/duplications. Results: Of the 124 tested pts, 20 pts (16.1%) had ≥ 1 germline PV and 47 pts (37.9%) had ≥ 1 germline variant unknown significance. PVs included: BRCA2 (n = 4), BRCA1 (n = 3), CHEK2 (n = 3), MUTYH (n = 3), ATM (n = 2), TP53 (n = 1), MITF (n = 1), NBN (n = 1), PMS2 (n = 1), and RAD51D (n = 1). No PVs were detected in AA pts (n = 20). 435 of 535 PCa pts (81.3%) had a cancer FH with prostate (37.8%), breast (28.2%), lung (16.4%), colorectal (14.8%), and pancreatic (7.5%) cancer being most common. 281 pts (52.5%) had ≥ 2 relatives with cancer. Pts with PCa FH were more likely to be dx age ≤ 55 (p = 0.017). Median age was younger at dx for pts with PCa FH (p = 0.0005). PCa FH did not alter Gleason or metastatic rate. FH influenced age at dx for Ca men (p = 0.0009, 58 vs. 62.5 and Ca men with PCa FH) were 1.55x more likely to develop metastases (p = 0.035). In AA pts, there were no significant associations between FH, and metastases or age at dx. Conclusions: The most prevalent germline mutations in this cohort were in DNA repair pathway genes. Pts with PCa FH were younger at dx than those without PCa FH. Further studies are needed to understand the co-segregation of PCa with other cancers and genetic studies are needed to clarify the mechanisms of these trends which may differ between Ca and AA men.

scholarly journals The genetic analysis of a founder Northern American population of European descent identifies FANCI as a candidate familial ovarian cancer risk gene

2020 ◽  
Author(s):  
Caitlin T Fierheller ◽  
Laure Guitton-Sert ◽  
Wejdan M Alenezi ◽  
Timothée Revil ◽  
Kathleen K Oros ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Repair ◽  
Family History ◽  
Serous Carcinoma ◽  
Ovarian Cancer Risk ◽  
Repair Pathway ◽  
Degree Relative ◽  
Pathogenic Variants ◽  
Familial Ovarian Cancer ◽  
History Of

AbstractSome familial ovarian cancer (OC) could be due to rare risk alleles in genes that each account for a relatively small proportion of cases not due to BRCA1 and BRCA2, major risk genes in the homologous recombination (HR) DNA repair pathway. We report a new candidate OC risk allele, FANCI c.1813C>T in a Fanconi anemia (FA) gene that plays a role upstream of the HR DNA repair pathway. This variant was identified by whole exome sequencing of a BRCA1 and BRCA2 mutation-negative French Canadian (FC) OC family from a population exhibiting founder effects. In FCs, the c.1813C>T allele was detected in 7% (3/43) of familial and 1.6% (7/439) of sporadic OC cases; and in 3.7% (3/82) of familial breast cancer (BC) cases with a family history of OC and in 1.9% (3/158) of BC only families. This allele was significantly associated with FC BRCA1 and BRCA2 mutation-negative OC families (OR=5.6; 95%CI=1.6-19; p=0.006). Although FANCI c.1813C>T was detected in 2.5% (74/2950) of cancer-free FC females, carriers had a personal history of known OC risk reducing factors, and female/male carriers were more likely to have reported a first-degree relative with OC (ρ=0.037; p=0.011). Eight rare potentially pathogenic FANCI variants were identified in 3.3% (17/516) of Australian OC cases, including 10 carriers of FANCI c.1813C>T. Potentially pathogenic FANCI variants were significantly more common in AUS OC cases with a family history of OC than in isolated OC cases (p=0.027). The odds ratios (OR) were >3 for carriers of any of the seven rarest FANCI alleles, and 1.5 for c.1813C>T. Data from the OC Association Consortium revealed that the ORs for the c.1813C>T allele were highest for the most common OC subtypes. Localization of FANCD2, part of the FANCI-FANCD2 (ID2) binding complex in the FA pathway, to sites of induced DNA damage was severely impeded in cells expressing the p.L605F isoform. This isoform was expressed at a reduced level; unstable by formaldehyde or mitomycin C treatment; and exhibited sensitivity to cisplatin but not to olaparib (a poly [ADP-ribose] polymerase inhibitor). By tissue microarray analyses, FANCI protein was robustly expressed in fallopian tube epithelial cells but expressed at low-to-moderate levels in 88% (83/94) of high-grade serous carcinoma OC samples. This is the first study to describe potentially pathogenic variants in OC in a member of the ID2 complex of the FA DNA repair pathway. Our data suggest that potentially pathogenic FANCI variants may modify OC risk in cancer families.

Inherited germline mutations in men with prostate cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e16564-e16564
Author(s):  
Robert Reid ◽  
Marcie DiGiovanni ◽  
Ryan Bernhisel ◽  
Krystal Brown ◽  
Jennifer Saam ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Genetic Testing ◽  
Family History ◽  
Hereditary Cancer ◽  
Clinical Information ◽  
Nccn Guidelines ◽  
Commercial Laboratory ◽  
Pathogenic Variants ◽  
Age Of Diagnosis ◽  
History Of

e16564 Background: Recent studies have demonstrated a high prevalence of pathogenic variants (PVs) in genes that confer hereditary cancer risk among men with metastatic prostate cancer (PC); however, PC does not currently receive attention as an indication for genetic testing. We assessed the clinical features of men with PC who received clinical testing as well as the distribution of PVs identified. Methods: A commercial laboratory database was queried to identify men with PC who underwent testing with a multi-gene hereditary cancer panel from September 2013–September 2016. Clinical information was obtained from provider-completed test request forms. Individuals with PC only were evaluated separately from those who had ≥1 additional malignancy. Personal/family history was evaluated relative to the 2013 NCCN guidelines for hereditary breast and ovarian cancer (HBOC) testing. Results: Overall, 700 men with a personal history of PC were identified: 384 (54.9%) with only PC and 316 (45.1%) with PC and ≥1 additional malignancy. The most common additional malignancies were colorectal (115) and breast cancer (105). The median age of diagnosis in men with only PC was 57.5, which is younger than tested men who had an additional malignancy (62) and the SEER data (2009-2013) for all men with PC (66). HBOC testing criteria were met by 75.9% of men, including 44 (6.3%) who met based only on a personal/family history of PC and 202 (28.9%) who met in part due to a personal/family history of PC. PVs were identified in 14.0% of all men: 11.5% of men with PC only and 17.1% of men with PC and a second malignancy (see Table). Conclusions: PC patients selected for genetic testing here were younger than men diagnosed with PC from the general population (SEER), and almost half had a diagnosis of an additional malignancy. They also have a high positive mutation rate across a broad spectrum of genes. [Table: see text]

Inherited germline mutations in men with prostate cancer.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 357-357
Author(s):  
Robert Reid ◽  
Marcie DiGiovanni ◽  
Ryan Bernhisel ◽  
Krystal Brown ◽  
Jennifer Saam ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Genetic Testing ◽  
Family History ◽  
Hereditary Cancer ◽  
Clinical Information ◽  
Nccn Guidelines ◽  
Pathogenic Variants ◽  
Seer Data ◽  
Age Of Diagnosis ◽  
History Of

357 Background: Recent studies have demonstrated a high prevalence of pathogenic variants (PVs) in genes that confer hereditary cancer risk among men with metastatic prostate cancer (PC); however, PC does not currently receive attention as an indication for genetic testing. We assessed the clinical features of men with PC who received clinical testing as well as the distribution of PVs identified. Methods: Men with PC who underwent testing with a multi-gene hereditary cancer panel (Myriad Genetic Laboratories) from September 2013–September 2017 were included. Clinical information was obtained from provider-completed test request forms. Individuals with PC only were evaluated separately from those who had ≥1 additional malignancy. Personal/family history was evaluated relative to the 2013 NCCN guidelines for hereditary breast and ovarian cancer (HBOC) testing. Results: Overall, 1004 men with a personal history of PC were identified: 606 (60.4%) with only PC and 398 (39.6%) with PC and ≥1 additional malignancy. The most common additional malignancies were breast (136) and colorectal cancer (134). The median age of diagnosis in men with only PC was 59, which is younger than tested men who had an additional malignancy (63) and the SEER data (2009-2013) for all men with PC (66). HBOC testing criteria were met by 78.0% of men, including 68 (6.8%) who met based only on a personal/family history of PC and 330 (32.9%) who met in part due to a personal/family history of PC. PVs were identified in 12.9% of all men: 11.2% of men with PC only and 15.4% of men with PC and a second malignancy (Table). Conclusions: PC patients selected for genetic testing here were younger than men diagnosed with PC from the general population (SEER), and about a third had a diagnosis of an additional malignancy. They also have a high positive mutation rate across a broad spectrum of genes. [Table: see text]

Association of neuroendocrine phenotype with platinum chemotherapy outcomes in men with metastatic prostate cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e16532-e16532
Author(s):  
Michael Sandon Humeniuk ◽  
Rajan T Gupta ◽  
Megan Ann McNamara ◽  
Sundhar Ramalingam ◽  
Michael Roger Harrison ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Cohort Analysis ◽  
Objective Response ◽  
Cancer Center ◽  
Retrospective Cohort Analysis ◽  
Platinum Based Chemotherapy ◽  
Significant Difference ◽  
Secondary Endpoints ◽  
Platinum Chemotherapy

e16532 Background: DNA repair defects are common in men with mCRPC, and platinum chemotherapy may have a role in selected patients. We aimed to determine whether neuroendocrine variant prostate cancer (NEPC) is associated with a greater response to platinum chemotherapy, as compared to CRPC with adenocarcinoma histology (AdenoCRPC). Methods: We conducted a retrospective cohort analysis of all patients with prostate cancer treated with platinum chemotherapy at the Duke Cancer Center between 2005-15. The primary endpoint was objective response rate (RESIST v1.1; ORR); secondary endpoints were PSA decline, progression-free (PFS) and overall survival (OS). Outcomes were compared by histologic phenotype (NEPC vs. AdenoCRPC). Results: Between 2005-2015, 73 men, including 56 with AdenoCRPC and 17 with NEPC, were treated with platinum-based chemotherapy for mCRPC. Carboplatin-docetaxel and carboplatin/cisplatin etoposide were the most common regimens. Fifteen men (21%) were M1 at diagnosis. Among NEPC patients, 3 had primary NEPC/small cell carcinoma at diagnosis, while 14 had NEPC transformation after hormonal therapy. Overall, 24% of NEPC men received prior docetaxel vs. 75% of AdenoCRPC men. Partial responses were observed in 59% in men with NEPC vs. 25% for AdenoCRPC. Primary progressive disease occurred in 24% (NEPC) vs. 48% (AdenoCRPC). PSA declines with platinum chemotherapy were more common in NEPC (median 72% decline) vs. AdenoCRPC (median 24% decline). There was no significant difference in median PFS or OS between phenotypes (NEPC PFS 5.1 mo, OS 8.5 mo; AdenoCRPC PFS 4.3 mo, OS 10.0 mo; p = NS). For second platinum chemotherapy, ORR and PFS in NEPC vs AdenoCRPC were 67% and 5.2 months vs. 14% and 4.6 months. Conclusions: Our data suggest that men with NEPC histology have a greater probability of objective response and PSA decline with platinum chemotherapy vs. men with AdenoCRPC. However, PFS and OS are similar across histologic phenotypes, indicating similar times to resistance to platinum chemotherapy. Biomarkers of platinum sensitivity are needed, and evaluation of DNA repair defects in this setting may provide a greater opportunity for precision medicine approaches to DNA damaging agents.

Evaluation of a Mainstream Model of Genetic Testing for Men With Prostate Cancer

2020 ◽  
pp. OP.20.00399
Author(s):  
Tahlia Scheinberg ◽  
Annabel Goodwin ◽  
Emilia Ip ◽  
Anthony Linton ◽  
Blossom Mak ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Genetic Testing ◽  
San Francisco ◽  
Standard Of Care ◽  
Inherited Cancer ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Counseling And Testing ◽  
Timely Access ◽  
Brca1 Brca2

PURPOSE: To identify the approximately 12% with inherited cancer predisposition, all men with metastatic prostate cancer (mPC) should be offered germline genetic testing. This guides treatment choices and impacts cancer prevention in the family. Limited genetic services globally present a barrier to testing. This study tested a potential solution, “mainstreaming,” where counseling and testing are performed by the patient’s oncologist. PATIENTS AND METHODS: Men with mPC at three Australian sites were offered germline genetic testing at their medical oncology appointment. Panel testing ( ATM, BRCA1, BRCA2, BRIP1, CHEK2, EPCAM, FANCA, HOXB13, MLH1, MSH2, MSH6, NBN, PALB2, PMS2, RAD51D, and TP53) was performed on saliva/blood (Invitae, San Francisco, CA). Primary outcomes were clinician and patient satisfaction. Secondary outcomes included mutation rates and resource allocation. RESULTS: Of 66 men offered testing, 63 (95%) accepted. Four pathogenic variants were identified (two BRCA2, one NBN, and one MSH6). Fifty patients and nine clinicians completed questionnaires. Satisfaction was high. All patients were pleased to have had testing overall, 98% (46 of 47) to have had testing at their usual oncology appointment, and all to receive results from their usual specialist, rather than a separate genetics appointment. A total of 88% (7 of 8) of clinicians felt confident, and all were satisfied with mainstreaming. Mainstreaming was resource efficient, requiring 87% fewer genetic consultations than traditional genetic counseling. CONCLUSION: This study demonstrates that mainstreaming of men with mPC is feasible, resource efficient, and satisfactory for clinicians and patients. Widespread implementation as standard of care would facilitate timely access to genetic testing for men with mPC.

Germline mutations in DNA repair genes in a large series of unselected Chinese prostate cancer patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e17523-e17523
Author(s):  
Yu Wei ◽  
Yao Zhu ◽  
Junlong Wu ◽  
Dingwei Ye ◽  
Hao Zeng ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Genetic Testing ◽  
Family History ◽  
High Risk ◽  
Cancer Patients ◽  
Germline Mutations ◽  
Dna Repair Genes ◽  
History Of ◽  
Repair Genes

e17523 Background: Germline DNA repair gene (DRG) mutations has emerged as a potential determinant of cancer risk and therapeutic response in PCa. Despite substantial advances in delineating the germline mutation in DRGs among Caucasian population, the prevalence of mutations in DRGs are largely unknown among a large series of unselected prostate cancer patients in Chinese population. Methods: We enrolled 1003 prostate cancer patients from three different hospitals in China, unselected for family history of cancer or age at diagnosis. All patients received germline genetic testing using a clinician-selected multi-gene panel. The 18 DNA repair genes and HOXB13, which has established or emerging potential clinical actionability in PCa, were analyzed in our study. Results: A total of 94 (9.7%) deleterious germline mutations were identified among the 1003 unselected prostate cancer patients. Of these, 5.6% patients carried a BRCA1 or BRCA2 mutations (5.2% in BRCA2 and 0.4% in BRCA1), 3.6% patients carried other DRG mutations (including 10 genes) and 0.5% patients carried HOXB13 mutations. Besides, variants with uncertain significance (VUS) were found in approximately 45% patients. We also divided 633 metastatic PCa patients into 542 de novo metastastic PCa and 91 recurrent metastastic PCa and found mutation frequencies did not differ between these two groups (9.0% vs 11.6%, p = 0.6). Patients with younger age of onset or family history of cancers were more likely to harbour germline mutations in DRGs. However, the rate of germline mutations were still at a high level for patients more than 70 years old (6.7%) and patients without family history of cancers (7.5%). There is no statistically significant difference in the mutation frequencies between patients with metastasis and without metastasis (7.5% vs 9.2%, p = 0.4), which may be because 85% patients without metastasis in our cohort were in high to very high risk group or have lymph node metastasis. Conclusions: To our knowledge, our study reported the largested series of Chinese PCa patients who received germline genetic testing. Our study provided a rationality for germline genetic testing criteria from high risk to metastastic PCa regardless of family history considering the high proportion. In addition, we recommended a multigene panel covering 13 genes ( ATM, BRCA1, BRCA2, CHEK2, FANCA, HOXB13, MSH2, MSH6, NBN, PALB2, RAD51C, RAD51D, TP53) in China. Nevertheless, the high prevalence of VUS (45%) in Chinese PCa patients warrant further efforts.

scholarly journals The evolving role of germline genetic testing and management in prostate cancer: Report from the Princess Margaret Cancer Centre International Retreat

2021 ◽  
Vol 15 (12) ◽  
Author(s):  
Roderick Clark ◽  
Miran Kenk ◽  
Kristen McAlpine ◽  
Emily Thain ◽  
Kirsten M. Farncombe ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Genetic Testing ◽  
Genetic Risk ◽  
Genetic Disorders ◽  
Future Research ◽  
Policy Action ◽  
Cancer Centre ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
International Experts

Introduction: Prostate cancer is a significant cause of cancer mortality. It has been well-established that certain germline pathogenic variants confer both an increased risk of being diagnosed with prostate cancer and dying of prostate cancer.1 There are exciting developments in both the availability of genetic testing and opportunities for improved treatment of patients. On August 19, 2020, the Princess Margaret Cancer Centre in Toronto, Ontario, hosted a virtual retreat, bringing together international experts in urology, medical oncology, radiation oncology, medical genetics, and translational research, as well as a patient representative. We are pleased to provide this manuscript as a review of those proceedings for Canadian clinicians. Recommendations: We drafted several recommendations for future research and policy action based on this meeting: 1) Need for increased access to funding for germline testing for the common genetic disorders associated with increased risk of prostate cancer. 2) A need for increased research into identifying genetic factors influencing risk stratification, treatment response, and outcomes of prostate cancer within Canadian populations at increased genetic risk for prostate cancer. 3) Need for increased awareness about genetic risk factors among the Canadian public. 4) Need for research on patient perspectives and psychosocial outcomes in individuals identified to be at increased genetic risk of prostate cancer. 5) We support the creation of specialized multidisciplinary clinics that specialize in tailored care for patients at increased genetic risk of prostate cancer.

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