Prevalence and Spectrum of Pathogenic Germline Variants in Japanese Patients With Early-Onset Colorectal, Breast, and Prostate Cancer

2020 ◽  
pp. 183-191 ◽  
Author(s):  
Xiaoxi Liu ◽  
Sadaaki Takata ◽  
Kyota Ashikawa ◽  
Tomomi Aoi ◽  
Shunichi Kosugi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Early Onset ◽  
Japanese Population ◽  
Japanese Patients ◽  
Cancer Type ◽  
Cancer Gene ◽  
Germline Variants ◽  
Pathogenic Variants ◽  
Second Tier

PUPOSE We investigated the prevalence and spectrum of pathogenic germline variants in patients with early-onset colorectal cancer (CRC), breast cancer (BC), and prostate cancer (PCA) in the Japanese population. We also identified pathogenic variants in other cancer risk genes, giving consideration to future multigene testing panels for this population. METHODS We performed whole-genome sequencing for 1,037 Japanese individuals, including patients with early-onset CRC (n = 196), BC (n = 237), and PCA (n = 215) and controls (n = 389). We screened for pathogenic variants, including single nucleotide variants and copy number variants, among well-established first-tier cancer genes for each cancer type and examined an expended second-tier panel including cancer-predisposing genes from the Cancer Gene Census. RESULTS Proportions of patients with germline pathogenic variants differed by cancer subgroup, with the highest in BC (14.8%), followed by CRC (9.2%), and PCA (3.7%). In contrast, 2 of 389 control subjects (0.5%) carried a germline pathogenic variant. In comparison with controls, the proportion of patients with pathogenic variants in the second-tier panel was increased significantly for PCA (3.7% to 11.6%, P = 2.96 × 10−4), but not for CRC or BC, after multitesting adjustment. In patients with PCA, DNA repair pathway genes in the extended panel often contained pathogenic variants ( P = .011). CONCLUSION Our analyses support the clinical usefulness of established cancer gene panels in the Japanese population for 3 major cancer types. Additional genes, especially those involved in DNA repair, might be considered for developing multipanel testing in Japanese patients with early-onset PCA.

scholarly journals Germline Pathogenic Variants in 7636 Japanese Patients With Prostate Cancer and 12 366 Controls

2019 ◽  
Vol 112 (4) ◽  
pp. 369-376 ◽  
Author(s):  
Yukihide Momozawa ◽  
Yusuke Iwasaki ◽  
Makoto Hirata ◽  
Xiaoxi Liu ◽  
Yoichiro Kamatani ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Genetic Testing ◽  
Clinical Characteristics ◽  
Statistical Tests ◽  
Japanese Patients ◽  
Pathogenic Variants ◽  
Liver Cancers ◽  
Genetics And Genomics ◽  
Genetic Testing Guidelines ◽  
And Control

AbstractBackgroundGenetic testing has been conducted in patients with prostate cancer (PCa) using multigene panels, but no centralized guidelines for genetic testing exist. To overcome this limitation, we investigated the demographic and clinical characteristics of patients with pathogenic variants.MethodsWe sequenced eight genes associated with hereditary PCa in 7636 unselected Japanese patients with PCa and 12 366 male, cancer-free control individuals. We assigned clinical significance for all 1456 variants using the American College of Medical Genetics and Genomics guidelines and ClinVar. We compared the frequency of carriers bearing pathogenic variants between cases and control participants with calculated PCa risk in each gene and documented the demographic and clinical characteristics of patients bearing pathogenic variants. All statistical tests were two-sided.ResultsWe identified 136 pathogenic variants, and 2.9% of patients and 0.8% of control individuals had a pathogenic variant. Association with PCa risk was statistically significant for variants in BRCA2 (P < .001, odds ratio [OR] = 5.65, 95% confidence interval [CI] = 3.55 to 9.32), HOXB13 (P < .001, OR = 4.73, 95% CI = 2.84 to 8.19), and ATM (P < .001, OR = 2.86, 95% CI = 1.63 to 5.15). We detected recurrent new pathogenic variants such as p.Gly132Glu of HOXB13. Patients with pathogenic variants were 2.0 years younger at diagnosis and more often had smoking and alcohol drinking histories as well as family histories of breast, pancreatic, lung, and liver cancers.ConclusionsThis largest sequencing study of PCa heredity provides additional evidence supporting the latest consensus among clinicians for developing genetic testing guidelines for PCa.

scholarly journals PARP Inhibitors in Prostate Cancer—The Preclinical Rationale and Current Clinical Development

Genes ◽  
2019 ◽  
Vol 10 (8) ◽  
pp. 565 ◽  
Author(s):  
Virtanen ◽  
Paunu ◽  
Ahlskog ◽  
Varnai ◽  
Sipeky ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trials ◽  
Dna Repair ◽  
Therapeutic Potential ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Treatment Modalities ◽  
Cancer Type ◽  
Castration Resistance ◽  
Single Strand Break

Prostate cancer is globally the second most commonly diagnosed cancer type in men.Recent studies suggest that mutations in DNA repair genes are associated with aggressive forms ofprostate cancer and castration resistance. Prostate cancer with DNA repair defects may bevulnerable to therapeutic targeting by Poly(ADP‐ribose) polymerase (PARP) inhibitors. PARPenzymes modify target proteins with ADP‐ribose in a process called PARylation and are inparticular involved in single strand break repair. The rationale behind the clinical trials that led tothe current use of PARP inhibitors to treat cancer was to target the dependence of BRCA‐mutantcancer cells on the PARP‐associated repair pathway due to deficiency in homologousrecombination. However, recent studies have proposed therapeutic potential for PARP inhibitorsin tumors with a variety of vulnerabilities generating dependence on PARP beyond the syntheticlethal targeting of BRCA1/BRCA2 mutated tumors, suggesting a wider potential than initiallythought. Importantly, PARP‐associated DNA repair pathways are also closely connected toandrogen receptor (AR) signaling, which is a key regulator of tumor growth and a centraltherapeutic target in prostate cancer. In this review, we provide an extensive overview of publishedand ongoing trials exploring PARP inhibitors in treatment of prostate cancer and discuss theunderlying biology. Several clinical trials are currently studying PARP inhibitor mono‐andcombination therapies in the treatment of prostate cancer. Integration of drugs targeting DNArepair pathways in prostate cancer treatment modalities allows developing of more personalizedcare taking also into account the genetic makeup of individual tumors.

scholarly journals Genetic characteristics of retinitis pigmentosa in 1204 Japanese patients

2019 ◽  
Vol 56 (10) ◽  
pp. 662-670 ◽  
Author(s):  
Yoshito Koyanagi ◽  
Masato Akiyama ◽  
Koji M Nishiguchi ◽  
Yukihide Momozawa ◽  
Yoichiro Kamatani ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Japanese Population ◽  
East Asian ◽  
Japanese Patients ◽  
Population Based ◽  
Genetic Profile ◽  
Genetic Characteristics ◽  
Pathogenic Variants ◽  
Recessive Genes ◽  
Dominant Genes

BackgroundThe genetic profile of retinitis pigmentosa (RP) in East Asian populations has not been well characterised. Therefore, we conducted a large-scale sequencing study to investigate the genes and variants causing RP in a Japanese population.MethodsA total of 1209 Japanese patients diagnosed with typical RP were enrolled. We performed deep resequencing of 83 known causative genes of RP using next-generation sequencing. We defined pathogenic variants as those that were putatively deleterious or registered as pathogenic in the Human Gene Mutation Database or ClinVar database and had a minor allele frequency in any ethnic population of ≤0.5% for recessive genes or ≤0.01% for dominant genes as determined using population-based databases.ResultsWe successfully sequenced 1204 patients with RP and determined 200 pathogenic variants in 38 genes as the cause of RP in 356 patients (29.6%). Variants in six genes (EYS, USH2A, RP1L1, RHO, RP1 and RPGR) caused RP in 65.4% (233/356) of those patients. Among autosomal recessive genes, two known founder variants in EYS [p.(Ser1653fs) and p.(Tyr2935*)] and four East Asian-specific variants [p.(Gly2752Arg) in USH2A, p.(Arg658*) in RP1L1, p.(Gly2186Glu) in EYS and p.(Ile535Asn) in PDE6B] and p.(Cys934Trp) in USH2A were found in ≥10 patients. Among autosomal dominant genes, four pathogenic variants [p.(Pro347Leu) in RHO, p.(Arg872fs) in RP1, p.(Arg41Trp) in CRX and p.(Gly381fs) in PRPF31] were found in ≥4 patients, while these variants were unreported or extremely rare in both East Asian and non-East Asian population-based databases.ConclusionsEast Asian-specific variants in causative genes were the major causes of RP in the Japanese population.

Need for re-evaluation of current guidelines based on results from germline genetic testing in prostate cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5009-5009 ◽  
Author(s):  
Piper L.W. Nicolosi ◽  
Scott T. Michalski ◽  
Brandy Freschi ◽  
Erin O'Leary ◽  
Rita Quintana ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Genetic Testing ◽  
Genetic Screening ◽  
Screening Methods ◽  
Germline Variants ◽  
Nccn Guidelines ◽  
Dna Repair Gene ◽  
Current Guidelines ◽  
Positive Results

5009 Background: Inherited risk for prostate cancer (PCa) is potentially associated with more aggressive disease. Recent data indicate that DNA repair gene abnormalities may be much more common than previously appreciated, especially BRCA2, ATM, CHEK2, BRCA1, RAD51D, and PALB2. Herein, we investigate the efficacy of a targeted gene panel in men with PCa and evaluate clinical factors in relationship to current guidelines for genetic screening. Methods: DNA sequencing and exon-level copy number analysis were performed in 1158 PCa patients (pts) between 2013 and 2016 at a commercial diagnostic laboratory. The genes requisitioned varied but consistently included 14 genes on a hereditary PCa panel, most of which were DNA repair genes. Evaluation included Gleason scores and eligibility for genetic screening based on any NCCN testing criteria in pts with positive findings (pathogenic, likely pathogenic, and risk allele). Results: Pathogenic findings were identified in 199 of 1158 (17.2%) pts, 13 pts (1.0%) had two variants. Roughly 75% of detected variants were in genes on the hereditary PCa panel, of which 34.4% were BRCA1/2. Positive variants in HOXB13, a gene associated only with PCa risk, were identified in eight (3.8%) pts. DNA mismatch repair variants, alterations with substantial known therapeutic implications, were detected in 1.7% of samples. A total of 12.4% of pts with Gleason scores of ≤6, compared with 15.4% of those with scores of ≥7 had a pathogenic variant. Within this cohort, 126 (63%) patients with positive results were eligible for genetic testing based on currently available NCCN guidelines, whereas 73 (37%) would not have qualified. Conclusions: Current NCCN guidelines and Gleason scores cannot be used to reliably stratify PCa pts for the presence/absence of pathogenic germline variants. Most positive results identified in this study have important management implications for pts and their families. The percentage of pts with germline variants who did not meet current genetic screening criteria underscores the need for revisiting current guidelines which cannot, at this time, reliably be used to predict pathologic findings on genetic testing.

DNA repair germline pathogenic mutation associations with treatment duration and family history in prostate cancer.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 245-245
Author(s):  
James Vu ◽  
Marcus Marie Moses ◽  
Lahiru Ranasinghe ◽  
Patrick Cotogno ◽  
Charlotte Manogue ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prostate Cancer ◽  
Dna Repair ◽  
Family History ◽  
Treatment Outcomes ◽  
Treatment Duration ◽  
Pathogenic Mutation ◽  
Germline Mutations ◽  
Cancer Type ◽  
History Of

245 Background: Germline mutation testing for metastatic prostate cancer patients creates a potential opportunity to personalize targeted therapies to improve treatment outcomes. The goal of this study was to characterize cancer family history, and evaluate treatment outcomes, in mCRPC patients with DNA repair pathogenic germline alterations. Methods: A retrospective study of metastatic PCa patients at Tulane Cancer Center identified 246 patients undergoing germline testing using panels (30-80 genes) (Color.com or Inviate.com). Clinical annotations included family history, life-extending treatments, and treatment duration. Statistical analyses including chi-square and Wilcoxon Rank Sum. Results: In the 246 patients tested for germline mutations, 27 patients (11.0%) had ≥1 DNA repair germline pathogenic mutation (BRCA2 = 11, BRCA1 = 3, CHEK2 = 5, ATM = 3, NBN = 1, PMS2 = 2, MSH2 = 1, PALB2 = 1) while 219 patients (89.0%) possessed no pathogenic mutation in these genes. Patients with a DNA repair pathogenic mutation were more likely to have > 2 family members affected by cancer, regardless of cancer type or degree of relationship (p = 0.04). In the DNA repair population, 5 pathogenic patients had no family history of cancer (18.5%, n = 5). Patients were more likely to have a germline alteration if they had 1 or more first degree relatives affected with breast cancer (p = 0.00001). Median lines of life-extending treatments to date between the pathogenic and non-pathogenic population were equal at 2. There were no significant differences in treatment duration for abiraterone (p = 0.49), enzalutamide (p = 0.99), docetaxel (p = 0.28), cabazitaxel (p = 0.53), carboplatin+docetaxel (p = 0.41), or radium-223 (p = 0.59) between the two groups. Conclusions: In this study, DNA repair pathogenic germline mutations did not affect treatment durations or lines of therapy but these studies are underpowered. The relationship between a family history of breast cancer and a DNA repair pathogenic mutation has not previously been reported.

Germline DNA repair mutations in men with prostate cancer are less frequent in African Americans as compared with Caucasians.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 258-258
Author(s):  
Piper L.W. Nicolosi ◽  
Elisa Ledet ◽  
Shan Yang ◽  
Scott T. Michalski ◽  
James Vu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Dna Repair Genes ◽  
Chi Square ◽  
Pathogenic Variants ◽  
Gene Panels ◽  
Sparse Methods ◽  
Repair Genes ◽  
Germline Testing ◽  
Identical Gene

258 Background: Pathogenic DNA repair defects are well described in Caucasian (C) men with prostate cancer (PCa) but comparative data on African-American (AA) men are sparse. Methods: Germline testing for DNA repair defects were assayed by Invitae (Invitae.com). Pathogenic variants in 14 genes were compared between AA and C men with PCa; these particular genes were also assessed by Pritchard et al NEJM 375:443, 2016. Identical gene panels were not used in all men, thus variations in assay numbers from gene to gene are noted. Chi square was used to compare proportions. Results: In the 14 genes, there were 16/214 (7.5%) AA men and 347/2488 (13.9%) C men with pathogenic findings (p=0.008). As shown in the Table, the most common pathogenic variants in AA men were BRCA2 (6/214, 2.8%), BRCA1 (3/213, 1.4%), PALB2 (2/182, 1.1%), ATM (2/206, 1.0%), RAD51C (1/148, 0.68%), CHEK2 (1/207, 0.48%), and PMS2 (1/212, 0.47%). In contrast to C men in this series, no AA men had pathogenic mutations in BARD1, BRIP1, MLH1, MSH2, MSH6, NBN, or RAD51D. Pathogenic CHEK2 was less commonly detected in AA as compared to C (p=0.03) in this dataset. Comparing our C men revealed no differences in the proportion of men with pathogenic findings compared to Pritchard et al (13.9% here vs 11.8%, P=0.15). Conclusions: AA men with PCa are less likely to have pathogenic DNA repair mutations among these 14 assayed DNA repair genes compared to C men. Limitations regarding lack of stage, Gleason scores, and FH are notable. Details on gene assays and comparison to Pritchard et al NEJM 375:443, 2016 [Table: see text]

scholarly journals Prevalence of Germline Variants in a Large Cohort of Japanese Patients with Pheochromocytoma and/or Paraganglioma

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4014
Author(s):  
Masato Yonamine ◽  
Koichiro Wasano ◽  
Yuichi Aita ◽  
Takehito Sugasawa ◽  
Katsutoshi Takahashi ◽  
...  
Keyword(s):  
Ethnic Differences ◽  
Sanger Sequencing ◽  
Clinical Decision Making ◽  
Japanese Patients ◽  
Clinical Decision ◽  
Phenotype Correlation ◽  
Germline Variants ◽  
Pathogenic Variants ◽  
Japanese Cohort ◽  
High Incidence

The high incidence of germline variants in pheochromocytoma and paraganglioma (PPGL) has been reported mainly in Europe, but not among Japanese populations in Asia. We aimed to study the prevalence of germline variants in Japanese PPGL patients and the genotype–phenotype correlation. We examined 370 PPGL probands, including 43 patients with family history and/or syndromic presentation and 327 patients with apparently sporadic (AS) presentation. Clinical data and blood samples were collected, and the seven major susceptibility genes (MAX, SDHB, SDHC, SDHD, TMEM127, VHL, and RET) were tested using Sanger sequencing. Overall, 120/370 (32.4%) patients had pathogenic or likely pathogenic variants, with 81/327 (24.8%) in AS presentation. SDHB was the most frequently mutated gene (57, 15.4%), followed by SDHD (27, 7.3%), and VHL (18, 4.9%). The incidence of metastatic PPGL was high in SDHB carriers (21/57, 36.8%). A few unique recurrent variants (SDHB c.137G>A and SDHB c.470delT) were detected in this Japanese cohort, highlighting ethnic differences. In summary, almost a quarter of patients with apparently sporadic PPGL in Japan harboured germline variants of the targeted genes. This study reinforces the recommendation in Western guidelines to perform genetic testing for PPGL and genotype-based clinical decision-making in the Japanese population.

scholarly journals Correction: Rare germline variants in DNA repair genes and the angiogenesis pathway predispose prostate cancer patients to develop metastatic disease

2019 ◽  
Vol 120 (8) ◽  
pp. 867-867
Author(s):  
Martina Mijuskovic ◽  
Edward J. Saunders ◽  
Daniel A. Leongamornlert ◽  
Sarah Wakerell ◽  
Ian Whitmore ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Cancer Patients ◽  
Metastatic Disease ◽  
Dna Repair Genes ◽  
Germline Variants ◽  
Repair Genes ◽  
Angiogenesis Pathway

scholarly journals Inherited DNA Repair Gene Mutations in Men with Lethal Prostate Cancer

Genes ◽  
2020 ◽  
Vol 11 (3) ◽  
pp. 314 ◽  
Author(s):  
Tommi Rantapero ◽  
Tiina Wahlfors ◽  
Anna Kähler ◽  
Christina Hultman ◽  
Johan Lindberg ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Dna Repair Genes ◽  
Carrier Rate ◽  
Single Nucleotide Variants ◽  
Repair Gene ◽  
Germline Variants ◽  
Dna Repair Gene ◽  
Significant Difference ◽  
Repair Genes

Germline variants in DNA repair genes are associated with aggressive prostate cancer (PrCa). The aim of this study was to characterize germline variants in DNA repair genes associated with lethal PrCa in Finnish and Swedish populations. Whole-exome sequencing was performed for 122 lethal and 60 unselected PrCa cases. Among the lethal cases, a total of 16 potentially damaging protein-truncating variants in DNA repair genes were identified in 15 men (12.3%). Mutations were found in six genes with CHEK2 (4.1%) and ATM (3.3%) being most frequently mutated. Overall, the carrier rate of truncating variants in DNA repair genes among men with lethal PrCa significantly exceeded the carrier rate of 0% in 60 unselected PrCa cases (p = 0.030), and the prevalence of 1.6% (p < 0.001) and 5.4% (p = 0.040) in Swedish and Finnish population controls from the Exome Aggregation Consortium. No significant difference in carrier rate of potentially damaging nonsynonymous single nucleotide variants between lethal and unselected PrCa cases was observed (p = 0.123). We confirm that DNA repair genes are strongly associated with lethal PrCa in Sweden and Finland and highlight the importance of population-specific assessment of variants contributing to PrCa aggressiveness.

scholarly journals Pathogenic Variants in Cancer Predisposition Genes and Prostate Cancer Risk in Men of African Ancestry

2020 ◽  
pp. 32-43 ◽  
Author(s):  
Marco Matejcic ◽  
Yesha Patel ◽  
Jenna Lilyquist ◽  
Chunling Hu ◽  
Kun Y. Lee ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
African American ◽  
Cancer Risk ◽  
African Ancestry ◽  
Prostate Cancer Risk ◽  
Aggressive Prostate Cancer ◽  
Aggressive Disease ◽  
Pathogenic Variants ◽  
Predisposition Genes

PURPOSE In studies of men of European ancestry, rare pathogenic variants in DNA repair pathway genes have been shown to be associated with risk of aggressive prostate cancer. The contribution of rare coding variation to prostate cancer risk in men of African ancestry has not been established. METHODS We sequenced a panel of 19 DNA repair and cancer predisposition genes in 2,453 African American and 1,151 Ugandan cases and controls with prostate cancer. Rare variants were classified as pathogenic or putatively functionally disruptive and examined in association with prostate cancer risk and disease aggressiveness in gene and pathway-level association analyses. RESULTS Pathogenic variants were found in 75 of 2,098 cases (3.6%) and 31 of 1,481 controls (2.1%; odds ratio [OR], 1.82; 95% CI, 1.19 to 2.79; P = .0044), with the association being stronger for more aggressive disease phenotypes (OR, 3.10; 95% CI, 1.54 to 6.23; P = .0022). The highest risks for aggressive disease were observed with pathogenic variants in the ATM, BRCA2, PALB2, and NBN genes, with ORs ranging from approximately 4 to 15 in the combined study sample of African American and Ugandan men. Rare, nonpathogenic, nonsynonymous variants did not have a major impact on risk of overall prostate cancer or disease aggressiveness. CONCLUSION Rare pathogenic variants in DNA repair genes have appreciable effects on risk of aggressive prostate cancer in men of African ancestry. These findings have potential implications for panel testing and risk stratification in this high-risk population.

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