Publications by authors named "John G Anema"

8 Publications

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Sex specific associations in genome wide association analysis of renal cell carcinoma.

Eur J Hum Genet 2019 10 23;27(10):1589-1598. Epub 2019 Jun 23.

Russian N.N. Blokhin Cancer Research Centre, Moscow, Russian Federation.

Renal cell carcinoma (RCC) has an undisputed genetic component and a stable 2:1 male to female sex ratio in its incidence across populations, suggesting possible sexual dimorphism in its genetic susceptibility. We conducted the first sex-specific genome-wide association analysis of RCC for men (3227 cases, 4916 controls) and women (1992 cases, 3095 controls) of European ancestry from two RCC genome-wide scans and replicated the top findings using an additional series of men (2261 cases, 5852 controls) and women (1399 cases, 1575 controls) from two independent cohorts of European origin. Our study confirmed sex-specific associations for two known RCC risk loci at 14q24.2 (DPF3) and 2p21(EPAS1). We also identified two additional suggestive male-specific loci at 6q24.3 (SAMD5, male odds ratio (OR) = 0.83 [95% CI = 0.78-0.89], P = 1.71 × 10 compared with female odds ratio (OR) = 0.98 [95% CI = 0.90-1.07], P = 0.68) and 12q23.3 (intergenic, OR = 0.75 [95% CI = 0.68-0.83], P = 1.59 × 10 compared with OR = 0.93 [95% CI = 0.82-1.06], P = 0.21) that attained genome-wide significance in the joint meta-analysis. Herein, we provide evidence of sex-specific associations in RCC genetic susceptibility and advocate the necessity of larger genetic and genomic studies to unravel the endogenous causes of sex bias in sexually dimorphic traits and diseases like RCC.
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http://dx.doi.org/10.1038/s41431-019-0455-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777615PMC
October 2019

Comparison of RENAL, PADUA, CSA, and PAVP Nephrometry Scores in Predicting Functional Outcomes After Partial Nephrectomy.

Urology 2019 02 11;124:160-167. Epub 2018 Aug 11.

Spectrum Health, Grand Rapids, MI; Michigan State University College of Human Medicine, Grand Rapids, MI. Electronic address:

Objective: To evaluate the accuracy of radius, exophytic/endophytic, nearness to collecting system/sinus, anterior/posterior, and location relative to polar lines (RENAL), preoperative aspects and dimensions used for anatomical classification (PADUA), contact surface area (CSA), and preoperative assessment of volume preservation (PAVP) nephrometry scores in predicting postoperative renal functional outcomes after partial nephrectomy (PN). Few studies have compared the accuracy of tumor complexity systems directly in the same set of PN patients.

Materials And Methods: Patients treated with robotic, laparoscopic, or open PN having available imaging (n = 344) were examined. The ability of 4 systems to predict nadir estimated glomerular filtration rate (eGFR [median postoperative day 1]) and new baseline eGFR (median: 0.95 year) was analyzed using univariable and multivariable models.

Results: Median preoperative, nadir, and new baseline eGFR were 79 (interquartile range [IQR]: 63-97), 65 (IQR: 47-85), and 80 (IQR: 63-99) mL/min/1.73 m. Multivariable models incorporating RENAL, PADUA, CSA, or PAVP were similarly predictive of postoperative renal function (nadir eGFR: R = 0.683-0.688, new baseline eGFR: R = 0.775). In univariable analysis, all 4 complexity systems were predictors of nadir GFR (each P < .05), with RENAL (P = .045), CSA (P = .027), and PAVP (P = .012) also significantly predicting nadir eGFR in multivariable models. No complexity system was significantly associated with new baseline eGFR in multivariable analysis, with only RENAL (P = .023) and PAVP (P = .049) having a statistically significant association in univariable analysis.

Conclusion: RENAL, PADUA, CSA, and PAVP are all predictors of early postoperative renal function. RENAL and PAVP provided the greatest predictive ability for later renal functional outcomes.
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http://dx.doi.org/10.1016/j.urology.2018.03.055DOI Listing
February 2019

Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma.

Eur Urol 2017 11 7;72(5):747-754. Epub 2017 Aug 7.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department Health and Human Services, Bethesda, MS, USA.

Background: Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings.

Objective: We performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations.

Design, Setting, And Participants: Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length.

Outcome Measurements And Statistical Analysis: Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis.

Results And Limitations: Longer genetically inferred telomere length was associated with an increased risk of RCC (OR=2.07 per predicted kilobase increase, 95% confidence interval [CI]:=1.70-2.53, p<0.0001). As a sensitivity analysis, we excluded two telomere length variants in linkage disequilibrium (R>0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR=1.73, 95% CI=1.36-2.21, p<0.0001). Exploratory analyses for individual histologic subtypes suggested comparable associations with the telomere length GRS for clear cell (N=5573, OR=1.93, 95% CI=1.50-2.49, p<0.0001), papillary (N=573, OR=1.96, 95% CI=1.01-3.81, p=0.046), and chromophobe RCC (N=203, OR=2.37, 95% CI=0.78-7.17, p=0.13).

Conclusions: Our investigation adds to the growing body of evidence indicating some aspect of longer telomere length is important for RCC risk.

Patient Summary: Telomeres are segments of DNA at chromosome ends that maintain chromosomal stability. Our study investigated the relationship between genetic variants associated with telomere length and renal cell carcinoma risk. We found evidence suggesting individuals with inherited predisposition to longer telomere length are at increased risk of developing renal cell carcinoma.
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http://dx.doi.org/10.1016/j.eururo.2017.07.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5641242PMC
November 2017

Genome-wide association study identifies multiple risk loci for renal cell carcinoma.

Nat Commun 2017 06 9;8:15724. Epub 2017 Jun 9.

Clinical Center of Serbia (KCS), Clinic of Urology, University of Belgrade-Faculty of Medicine, 11000 Belgrade, Serbia.

Previous genome-wide association studies (GWAS) have identified six risk loci for renal cell carcinoma (RCC). We conducted a meta-analysis of two new scans of 5,198 cases and 7,331 controls together with four existing scans, totalling 10,784 cases and 20,406 controls of European ancestry. Twenty-four loci were tested in an additional 3,182 cases and 6,301 controls. We confirm the six known RCC risk loci and identify seven new loci at 1p32.3 (rs4381241, P=3.1 × 10), 3p22.1 (rs67311347, P=2.5 × 10), 3q26.2 (rs10936602, P=8.8 × 10), 8p21.3 (rs2241261, P=5.8 × 10), 10q24.33-q25.1 (rs11813268, P=3.9 × 10), 11q22.3 (rs74911261, P=2.1 × 10) and 14q24.2 (rs4903064, P=2.2 × 10). Expression quantitative trait analyses suggest plausible candidate genes at these regions that may contribute to RCC susceptibility.
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http://dx.doi.org/10.1038/ncomms15724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5472706PMC
June 2017

Exome-wide Sequencing Shows Low Mutation Rates and Identifies Novel Mutated Genes in Seminomas.

Eur Urol 2015 Jul 14;68(1):77-83. Epub 2015 Jan 14.

Centre for Computational Biology, Duke-NUS Graduate Medical School, Singapore; Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore. Electronic address:

Background: Testicular germ cell tumors are the most common cancer diagnosed in young men, and seminomas are the most common type of these cancers. There have been no exome-wide examinations of genes mutated in seminomas or of overall rates of nonsilent somatic mutations in these tumors.

Objective: The objective was to analyze somatic mutations in seminomas to determine which genes are affected and to determine rates of nonsilent mutations.

Design, Setting, And Participants: Eight seminomas and matched normal samples were surgically obtained from eight patients.

Intervention: DNA was extracted from tissue samples and exome sequenced on massively parallel Illumina DNA sequencers. Single-nucleotide polymorphism chip-based copy number analysis was also performed to assess copy number alterations.

Outcome Measurements And Statistical Analysis: The DNA sequencing read data were analyzed to detect somatic mutations including single-nucleotide substitutions and short insertions and deletions. The detected mutations were validated by independent sequencing and further checked for subclonality.

Results And Limitations: The rate of nonsynonymous somatic mutations averaged 0.31 mutations/Mb. We detected nonsilent somatic mutations in 96 genes that were not previously known to be mutated in seminomas, of which some may be driver mutations. Many of the mutations appear to have been present in subclonal populations. In addition, two genes, KIT and KRAS, were affected in two tumors each with mutations that were previously observed in other cancers and are presumably oncogenic.

Conclusions: Our study, the first report on exome sequencing of seminomas, detected somatic mutations in 96 new genes, several of which may be targetable drivers. Furthermore, our results show that seminoma mutation rates are five times higher than previously thought, but are nevertheless low compared to other common cancers. Similar low rates are seen in other cancers that also have excellent rates of remission achieved with chemotherapy.

Patient Summary: We examined the DNA sequences of seminomas, the most common type of testicular germ cell cancer. Our study identified 96 new genes in which mutations occurred during seminoma development, some of which might contribute to cancer development or progression. The study also showed that the rates of DNA mutations during seminoma development are higher than previously thought, but still lower than for other common solid-organ cancers. Such low rates are also observed among other cancers that, like seminomas, show excellent rates of disease remission after chemotherapy.
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http://dx.doi.org/10.1016/j.eururo.2014.12.040DOI Listing
July 2015

RENAL nephrometry score predicts surgery type independent of individual surgeon's use of nephron-sparing surgery.

Urology 2012 Jul 23;80(1):157-61. Epub 2012 May 23.

Urology Division, Spectrum Health, Medical Group, 4069 Lake Drive, Grand Rapids, MI 49546, USA.

Objective: To evaluate whether surgeon factors, such as training and experience, have a strong impact on selection of surgical approach for treating renal cancers. Nephron-sparing surgery (NSS) has become the reference standard for tumors that are amenable to such an approach. Tumor size and configuration are important predictors of usage of NSS. The RENAL nephrometry score (RNS) has been developed to standardize reporting of tumor complexity, but the performance of this method within individual surgeons' practices, particularly in the community-based setting, has not been evaluated previously.

Methods: Clinical data and RNS were collected retrospectively for 300 cases performed by 5 different surgeons with varying NSS usage rates (31-74%).

Results: Mean RNS for patients undergoing NSS (6.0) and radical nephrectomy (RN) (9.3) differed significantly (P <.0001), as did tumor size (2.8 vs 6.3 cm, P <.0001). RNS was a better predictor of surgery type (R(2) = .55) than was tumor size (R(2) = .43) for all 5 surgeons. In univariable analysis, individual surgeon, surgery year, glomerular filtration rate, tumor size, RNS, and each RNS component predicted NSS vs RN (each P <.05). In multivariable analysis, surgeon, tumor size, exophytic amount, and nearness to collecting system were independent predictors of NSS usage (P <.001).

Conclusion: Despite significant variation in NSS usage by individual surgeons at a community-based health system, RNS appears to be valid for both low and high usage. With increasing usage of NSS worldwide, RNS appears to reflect current patterns and may inform future practice for surgeons of all backgrounds.
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http://dx.doi.org/10.1016/j.urology.2012.03.025DOI Listing
July 2012

Increasing use of kidney sparing approaches for localized renal tumors in a community based health system: impact on renal functional outcomes.

J Urol 2011 Oct 17;186(4):1229-35. Epub 2011 Aug 17.

Spectrum Health Hospital System and Michigan State University College of Human Medicine, Grand Rapids, Michigan 49546, USA.

Purpose: The use of partial nephrectomy and other kidney sparing approaches in national databases lags far behind practice patterns at major academic centers. The reasons and impact of this disparity are largely unknown. We examined the trend in kidney sparing approaches in a community based health care system to examine associated factors and impact on renal function.

Materials And Methods: We evaluated the records of all patients who underwent intervention for suspicious renal lesions at a single health care system between 1998 and 2010. Demographic, pathological and functional data were collected in an institutional review board approved database.

Results: During the 12 study years a kidney sparing approach was used in 35% of patients with localized renal tumors. A clear increase in the proportion of patients undergoing a kidney sparing approach was observed, including 11%, 23% and 49% during successive 4-year periods. A kidney sparing approach was used in 81% of patients with tumors 4 cm or less during 2009 to 2010. Although high volume (greater than 20 cases annually), more recently graduating (2001 or later) and fellowship trained surgeons had higher kidney sparing approach use overall (each p <0.03), the proportion of patients who underwent a kidney sparing approach increased with time in all study groups (p <0.0001). The renal functional loss in patients who underwent a kidney sparing approach and radical nephrectomy was 2% and 30%, respectively (p <0.001).

Conclusions: The kidney sparing approach rate in a community based health care system can approach rates at major academic centers. This practice pattern appears related to the addition of recent graduates and urological oncologists but also to a change in long-standing practice patterns of other community urologists. These data suggest that the use of kidney sparing approaches nationwide and the associated renal functional benefits may continue to increase.
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http://dx.doi.org/10.1016/j.juro.2011.05.081DOI Listing
October 2011