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A stratified genetic risk assessment for testicular cancer.

ABSTRACT: Three genome-wide association studies of testicular cancer have uncovered predisposition alleles in or near KITLG, BAK1, SPRY4, TERT, ATF7IP and DMRT1. We investigated whether testicular cancer-risk alleles can be utilized in the clinical setting. We employed the receiver operating characteristic curves for genetic risk models to measure the discriminatory power of a risk variant-based risk model, and found that the newly discovered variants provided a discriminatory power of 69.2%. This suggested that about 69.2% of the time, a randomly selected patient with testicular cancer had a higher estimated risk than the risk for a randomly selected control subject. Using a multiplicative model, we estimated that white men in the top 1% of genetic risk as defined by eight risk variants had a relative risk that was 10.5-fold greater than that for the general white male population. This risk differential does not appear to be clinically useful, given the relative rarity and highly curable nature of testicular germ cell tumour (TGCT). In the authors' view, a stratified genetic risk assessment strategy might be useful, theoretically, for men who also have independent clinical risk factors for testicular cancer. Several established TGCT risk factors, such as cryptorchidism (RR=4.8) and male infertility (SIR=2.8) might prove useful in that context, but we currently do not know whether these testicular cancer-risk loci are associated with, or independent of, such clinical risk factors. More research is required before we can utilize testicular cancer-risk loci for clinically meaningful risk prediction.

SUBMITTER: Kratz CP

PROVIDER: S-EPMC3145032 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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A stratified genetic risk assessment for testicular cancer.

Kratz C P CP Greene M H MH Bratslavsky G G Shi J J

International journal of andrology 20110512 4 Pt 2

Three genome-wide association studies of testicular cancer have uncovered predisposition alleles in or near KITLG, BAK1, SPRY4, TERT, ATF7IP and DMRT1. We investigated whether testicular cancer-risk alleles can be utilized in the clinical setting. We employed the receiver operating characteristic curves for genetic risk models to measure the discriminatory power of a risk variant-based risk model, and found that the newly discovered variants provided a discriminatory power of 69.2%. This suggest ...[more]

PMID: 21564132

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Project description:Background: Testicular cancer survivors (TCS) are at significantly increased risk for cardiovascular disease (CVD), with metabolic syndrome (MetS) an established risk factor. No study has addressed clinical and genetic MetS risk factors in North American TCS. Patients and Methods: TCS were aged <55 years at diagnosis and received first-line chemotherapy. Patients underwent physical examination, and had lipid panels, testosterone, and soluble cell adhesion molecule-1 (sICAM-1) evaluated. A single nucleotide polymorphism in rs523349 (5-?-reductase gene, SRD5A2), recently implicated in MetS risk, was genotyped. Using standard criteria, MetS was defined as ?3 of the following: hypertension, abdominal obesity, hypertriglyceridemia, decreased high-density lipoprotein (HDL) cholesterol level, and diabetes. Matched controls were derived from the National Health and Nutrition Examination Survey. Results: We evaluated 486 TCS (median age, 38.1 years). TCS had a higher prevalence of hypertension versus controls (43.2% vs 30.7%; P<.001) but were less likely to have decreased HDL levels (23.7% vs 34.8%; P<.001) or abdominal obesity (28.2% vs 40.1%; P<.001). Overall MetS frequency was similar in TCS and controls (21.0% vs 22.4%; P=.59), did not differ by treatment (P=.20), and was not related to rs523349 (P=.61). For other CVD risk factors, TCS were significantly more likely to have elevated low-density lipoprotein (LDL) cholesterol levels (17.7% vs 9.3%; P<.001), total cholesterol levels (26.3% vs 11.1%; P<.001), and body mass index ?25 kg/m2 (75.1% vs 69.1%; P=.04). On multivariate analysis, age at evaluation (P<.001), testosterone level ?3.0 ng/mL (odds ratio [OR], 2.06; P=.005), and elevated sICAM-1 level (ORhighest vs lowest quartile, 3.58; P=.001) were significantly associated with MetS. Conclusions and Recommendations: Metabolic abnormalities in TCS are characterized by hypertension and increased LDL and total cholesterol levels but lower rates of decreased HDL levels and abdominal obesity, signifying possible shifts in fat distribution and fat metabolism. These changes are accompanied by hypogonadism and inflammation. TCS have a high prevalence of CVD risk factors that may not be entirely captured by standard MetS criteria. Cancer treatment-associated MetS requires further characterization.

Project description:Background: Cervical screening programs target entire populations, although it is well established that cervical cancer risks can vary >100-fold based, in particular, on the woman's screening history. Since cervical screening switched to Human Papillomavirus (HPV) testing as the primary screening method, the risk differences are even larger as different HPV types may vary in associated cancer risk by 100 times. Furthermore, HPV infections with the most oncogenic types are declining dramatically because of HPV vaccination programs. Tailoring screening intensity based on the known cancer risk of the individual (risk-stratified screening) therefore has great potential to increase both the sensitivity and specificity. Within Horizon 2020 a major project for Risk-stratified Screening for Cervical Cancer (RISCC) has therefore been launched. We performed a pilot study of risk-stratified screening to evaluate feasibility and acceptability of offering vaginal HPV self-sampling tests to women with a higher risk of cervical cancer. Methods: We identified resident women who had had either i) atypical glandular cells in screening tests during the past six years (risk >150/100,000 woman-years) or ii) abnormal screening findings above the age of 50, but without sufficient follow-up (risk >65/100,000). The women were invited, either by short message service (SMS) or physical letters, to order an HPV self-sampling kit via the study web-platform. The returned self-collected samples were tested for HPV. If positive, women were invited for clinical follow-up. Results: Among 920 targeted women, 191 (21%) placed an order and 163 (18%) returned a self-collected sample. Among all tested samples, 19 (12%) were positive for hrHPV and 18 of these women attended clinical follow-up. Conclusions: SMS invitations to high-risk women complemented with physical letters are feasible and result in substantial requests for kits and submission of samples. Future work will focus on improving the efficiency of the procedure and further increasing attendance.

Project description:BackgroundThe functional acute kidney injury (AKI) diagnostic tests serum creatinine (SCr) and urine output are imprecise and make management challenging. Combining tubular injury biomarkers with functional markers reveal AKI phenotypes that may facilitate personalized care. However, when and in whom to obtain injury biomarkers remains unclear.MethodsThis was a prospective, observational study of patients admitted to a pediatric intensive care unit (PICU). Using the Renal Angina Index (RAI), subjects were screened for the presence (RAI+) or absence (RAI-) of renal angina 12 h post-admission and assigned an AKI phenotype using urinary NGAL (NGAL+: ≥150 ng/ml) and SCr (SCr+: ≥KDIGO Stage 1). Outcomes for each AKI phenotype were assessed and compared by RAI status.ResultsIn all, 200/247 (81%) subjects were RAI+. RAI+ subjects who were NGAL+ had higher risk of Day 3 AKI, renal replacement therapy use, and mortality and fewer ventilator- and PICU-free days, compared to NGAL-, irrespective of Day 0 SCr. Similar findings were not demonstrated in RAI- subjects, though NGAL+/SCr+ was associated with fewer ventilator- and PICU-free days compared to NGAL-/SCr+.ConclusionsNGAL- and SCr-based AKI phenotypes provide improved prognostic information in children with renal angina (RAI+) and/or with SCr elevation. These populations may be appropriate for targeted biomarker testing.ImpactNew consensus recommendations encourage the integration of kidney tubular injury biomarkers such as urinary NGAL with serum creatinine for diagnosis and staging of acute kidney injury; however, no structured testing framework exists guiding when to test and in whom. Urinary NGAL- and serum creatinine-based acute kidney injury phenotypes increase diagnostic precision in critically ill children experiencing renal angina (RAI+) or serum creatinine-defined acute kidney injury. These data provide preliminary evidence for a proposed framework for directed urinary NGAL assessment in the pediatric intensive care unit.

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A stratified genetic risk assessment for testicular cancer.

Publications

A stratified genetic risk assessment for testicular cancer.

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