Subfertility increases risk of testicular cancer: evidence from population-based semen samples

Hanson, Heidi A.; Anderson, Ross; Aston, Kenneth I.; Carrell, Douglas T.; Smith, Ken R.; Hotaling, James

doi:10.1016/j.fertnstert.2015.10.027

Cited by 104 publications

(96 citation statements)

References 19 publications

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“…Similar to our prior work, we found this elevated cancer risk in oligozoospermic but not azoospermic men and their family members. 17 A possible explanation for this is that the aberrant stem cells found in both these groups could theoretically represent a somatic stem cell dysregulation leading to cancer. However, the genetics underlying this are so disordered in the azoospermic group that they are nonfunctional and not associated with familial cancer risk.…”

Section: Discussionmentioning

confidence: 99%

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Childhood Cancer Risk in the Siblings and Cousins of Men with Poor Semen Quality

et al. 2017

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Purpose Poor semen quality is associated with reduced somatic health and increased cancer risk. Infertility and cancer are increasingly being linked by epidemiologists and basic scientists. We sought to identify semen parameters associated with an increased childhood cancer risk in the family members of subfertile men. Materials and Methods We performed a retrospective cohort study in men from the SHARE (Subfertility Heath and Assisted Reproduction) study who underwent semen analysis between 1994 and 2011. We used fertile population controls from the Utah Population Data Base. Our primary outcome was the risk of any childhood (18 years or younger) cancer in the siblings and cousins of men who underwent semen analysis compared to fertile, age matched controls. Cox proportional hazard regression models were used to test the association between semen quality and childhood cancer incidence. Results We selected 10,511 men with complete semen analysis and an equal number of fertile controls. These men had a total of 63,891 siblings and 327,753 cousins. A total of 170 and 958 childhood cancers were identified in siblings and cousins, respectively. The 3 most common cancers diagnosed in siblings were acute lymphoblastic leukemia in 37, brain cancer in 35 and Hodgkin lymphoma in 15. Oligozoospermia was associated with a twofold increased risk of any childhood cancer and a threefold increased risk of acute lymphoblastic leukemia in the siblings of subfertile men compared to fertile controls (HR 2.09, 95% CI 1.18–3.69 vs HR 3.07, 95% CI 1.11–8.46). Conclusions Siblings of men with oligozoospermia are at increased risk for any-site cancer and acute lymphoblastic leukemia. This suggests a shared genetic/epigenetic insult or an environmental exposure that merits further investigation.

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Section: Discussionmentioning

confidence: 99%

“…Details regarding the subcategorization of semen parameters in this data set were previously published. 17 …”

Section: Methodsmentioning

confidence: 99%

Childhood Cancer Risk in the Siblings and Cousins of Men with Poor Semen Quality

et al. 2017

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“…In cases where men had more than one semen sample (17% of patients), the average concentration, count, and motility across measures was used. Figure 2 shows the definitions for each semen parameter (Hanson et al, 2016). In general, each parameter is either divided into azoospermic, oligozoospermic, normozoospermic and hyperzoospermic categories or is divided into quartiles.…”

Section: Semen Parametersmentioning

confidence: 99%

Risk of childhood mortality in family members of men with poor semen quality

et al. 2016

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STUDY QUESTION: What is the familial childhood mortality in first-degree (FDR) and second-degree relatives (SDR) of patients undergoing semen analysis (SA)?SUMMARY ANSWER: The relationship between infertility and congenital malformations (CM) in offspring is complex, with an increased risk of death due to CM in FDR, but not SDR, of men with lower semen parameters.WHAT IS KNOWN ALREADY: Semen quality is an established predictor of men's somatic health. We can gain a better understanding of possible genetic or environmental determinants of the infertility phenotype by exploring familial aggregation of childhood mortality in relatives of men with poor semen quality.STUDY DESIGN, SIZE, DURATION: Retrospective cohort study from the Subfertility, Health and Assisted Reproduction study (cohort compiled 1996-2011) linked with patient/familial information from the Utah Population Database (UPDB). Index cases included a clinicreferred sample of 12 889 men who underwent SA and had adequate familial and follow-up data in the UPDB. Parameters of semen quality included: semen concentration, sperm count, motility, total motile count, sperm head morphology, sperm tail morphology and vitality.PARTICIPANTS/MATERIALS, SETTING, METHODS: SA data were collected from two tertiary medical center andrology laboratories that have captured~90% of all SA performed in Utah since 2004. Age-and sex-matched fertile controls were selected to create the comparison group for determining risk of childhood death (to age 20 years) in family members. A total of 79 750 siblings and 160 016 aunts/ uncles were used to investigate the familial aggregation of childhood mortality. The main outcome was childhood mortality in FDR and SDR of men with SA and their matched controls. All-cause and cause-specific Cox proportional hazard models were used to test the association between semen quality and childhood mortality in family members. Cause-specific models were considered for cancer and CM. MAIN RESULTS AND THE ROLE OF CHANCE:In the cohort of men with SA, there were 406 (1.0%) deaths in FDR and 772 (1.1%) deaths in SDR due to any cause. There was no significant difference in the risk of all-cause childhood mortality between the relatives of men with SA and the fertile control group [hazard ratio (HR) Female = 1.08, 95% CI = 0.88, 1.32; HR Male = 0.88, 95% CI = 0.75, 1.04]. We found no association between semen quality and risk for childhood cancer mortality in FDR or SDR (HR FDR = 0.98, 95% CI = 0.62, 1.54; HR SDR = 1.12, 95% CI = 0.83, 1.50). The FDR of men with SA and fertile controls were followed on average for 19.71 and 19.73 years, respectively. During this period of follow-up, FDR of men with SA had an unadjusted 40% relative risk of increased CM-related death. After stratifying by semen parameters and adjusting for birth year, we found FDR of men with worse semen quality, and notably azoospermic men (HR = 2.69, 95% CI = 1.24,5.84), were at higher risk of CM-related death. LIMITATIONS REASONS FOR CAUTION:A large proportion of men with SA in the stu...

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“…Cohort studies with information on prospectively-obtained semen parameters have consistently found an association between impaired semen quality and risk of testicular cancer [14–19]. When the lag-time between semen analysis and cancer diagnosis was considered, the risk of testicular cancer seemed to be especially increased in the same year or in the year after semen analysis [5, 15], although it was also evident for longer lag times, indicating that the association was affected by reverse causation and/or detection bias to a certain extent.…”

Section: Discussionmentioning

confidence: 99%

“…sperm count and motility, serum Inhibin B, FSH, and testosterone) are less consistent and more difficult to investigate than the number of children fathered, due to problems of reverse causation, measurement errors, and recall and detection bias. Cohort studies of men evaluated for infertility [14–19] have found an increased risk of testicular cancer among those with abnormal semen analyses or male-factor infertility. These studies have the strength of prospective measurements of fertility, often using semen analysis, but they may be affected by other sources of bias, including confounding by cryptorchidism, and detection bias.…”

Section: Introductionmentioning

confidence: 99%

Subfertility and Risk of Testicular Cancer in the EPSAM Case-Control Study

et al. 2016

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Background/objectivesIt has been suggested that subfertility and testicular cancer share genetic and environmental risk factors. We studied both subfertility and the strongest known testicular cancer susceptibility gene, the c-KIT ligand (KITLG), whose pathway is involved in spermatogenesis.MethodsThe EPSAM case-control study is comprised of testicular cancer patients from the Province of Turin, Italy, diagnosed between 1997 and 2008. The present analysis included 245 cases and 436 controls from EPSAM, who were aged 20 years or older at diagnosis/recruitment. The EPSAM questionnaire collected information on factors such as number of children, age at first attempt to conceive, duration of attempt to conceive, use of assisted reproduction techniques, physician-assigned diagnosis of infertility, number of siblings, and self-reported cryptorchidism. Genotyping of the KITLG single nucleotide polymorphism (SNP) rs995030 was performed on the saliva samples of 202 cases and 329 controls.ResultsTesticular cancer was associated with the number of children fathered 5 years before diagnosis (odds ratio (OR) per additional child: 0.78, 95% confidence interval (CI): 0.58–1.04) and sibship size (OR per additional sibling: 0.76, 95% CI: 0.66–0.88). When considering the reproductive history until 1 year before diagnosis, attempting to conceive for at least 12 months or fathering a child using assisted reproduction techniques was not associated with the risk of testicular cancer, nor was age at first attempt to conceive or physician-assigned diagnosis of infertility. The SNP rs995030 was strongly associated with risk of testicular cancer (per allele OR: 1.83; 95%CI: 1.26–2.64), but it did not modify the association between number of children and the risk of testicular cancer.ConclusionThis study supports the repeatedly reported inverse association between number of children and risk of testicular cancer, but it does not find evidence of an association for other indicators of subfertility.

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Subfertility increases risk of testicular cancer: evidence from population-based semen samples

Cited by 104 publications

References 19 publications

Childhood Cancer Risk in the Siblings and Cousins of Men with Poor Semen Quality

Childhood Cancer Risk in the Siblings and Cousins of Men with Poor Semen Quality

Risk of childhood mortality in family members of men with poor semen quality

Subfertility and Risk of Testicular Cancer in the EPSAM Case-Control Study

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