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Introduction

Cancer biomarkers and fertility
      Infertility has been increasingly recognized as a possible biomarker for cancer risk. There is significant data linking these two seemingly disparate diseases in infertile men and burgeoning data linking them in infertile women. Here we investigate the possible mechanisms whereby one shared genetic or epigenetic insult could confer increased risk for both infertility and cancer.

      Key Words

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      Increasingly, genetic and epigenetic profiling have become critical tools in our diagnostic and treatment armamentaria. Since the human genome was sequenced, the medical landscape has been fundamentally altered by new therapies that hold the promise of personalized medicine informed by an individual's unique genetic and epigenetic profile.
      In infertility, we have been at the forefront of this with techniques such as carrier screening and preimplantation genetic screening and diagnosis. However, we have lagged behind other fields, particularly oncology, where genetic and epigenetic testing have driven a revolution in cancer diagnosis and treatment tailored to the genetic profile of an individual's tumor.
      Interestingly, our field shares much in common with oncology, at least in terms of underlying biology. Male infertility, for example, likely represents a dysregulation of the exquisite balance between spermatogonial stem cell self-renewal and differentiation. This is probably mainly driven by an as yet unknown number of genetic variants or epigenetic perturbations that alter these cells, resulting in infertility. The most extreme case of this is azoospermia, resulting in spermatogenic failure. Similarly, at its core, cancer is driven by a fundamental dysregulation of cellular renewal and differentiation.
      Although the number of oocytes ovulated during a woman's reproductive life are fixed, like sperm, oocytes must remain ready to initiate a complex series of events culminating in embryogenesis. Thus, both cell lines must tightly regulate their transcription in order to remain poised for embryogenesis but not allow unchecked differentiation. Additionally, the local micro-environment is also a key contributor to this process and helps regulate these events, much as in oncogenesis where the tumor micro-environment has become a flourishing area of research.
      Recently, a body of work has accumulated linking infertility and cancer. Multiple papers have shown that male infertility is a risk factor for cancer later in life (PMID 25463997, 26604070). Additionally, burgeoning evidence has shown that female infertility may also be associated with this risk (PMID 27817040). On the female side, there is a significant body of literature examining the impact of stimulation protocols on incident cancer risk. However, the literature is not as robust on whether female infertility, without the additional risk of stimulation protocols, is an independent risk factor for cancer.
      Understanding the mechanistic underpinnings between infertility and cancer is vitally important to advancing the field, demonstrating the relevance of infertility to public health and, potentially, enabling us to use some of the techniques from oncologic science to facilitate personalized medicine. Increasingly, many in our field have come to believe that there may be a shared genetic or epigenetic insult that predisposes men and women to infertility and cancer. Alternatively, there may be a shared environmental exposure that could underlie or exacerbate this problem. Regardless, understanding the genetic and epigenetic factors underlying this association has tremendous potential to advance our field and yield broad insight into the fundamental biology of both of these diseases.
      In this month's Views and Reviews, five articles are presented highlighting the possible drivers of this association and characterizing the epidemiologic data linking these two diseases. We hope that these reviews will stimulate others to explore the mechanistic, demographic and epidemiologic implications of these findings.
      The first article by Hanson et al. (
      • Hanson B.M.
      • Eisenberg M.I.
      • Hotaling J.M.
      Male Infertility: a biomarker of individual and familial cancer risk.
      ) examines how male infertility, as characterized by an abnormal semen analysis, is associated primarily with future risk of testis and prostate cancers as well as melanoma, bladder cancer, thyroid cancer, lymphoma and leukemia. It also explores how this risk extends beyond individuals to their family members. In other words, not only an infertile proband but his first and second degree family members are at increased risk of cancer, suggesting that there may be a shared genetic predisposition that is propagated through the germline.
      Next, Nagirnaja et al. (
      • Nagirnaja L.
      • Aston K.I.
      • Conrad D.F.
      The genetic intersection of male infertility and cancer.
      ) discuss the reported genetic associations between infertility and cancer, and use database searches from annotated known oncogenes and genes important for spermatogenesis to identify a set of candidate genes that could link these two diseases. The review also considers how shared heritable genetic factors could influence both conditions, and how complex analyses of rare variants in conjunction with omics data can be useful in studying these diseases. Finally, and perhaps most importantly, the authors conclude that large-scale genomic studies in both fields are necessary to achieve the ultimate goal of germline screening for cancer and infertility susceptibility loci in order to bring the vision of personalized medicine to the intersection of these two diseases.
      James et al. (
      • James E.
      • Jenkins T.G.
      Epigenetics, infertility, and cancer: future directions.
      ) explore how epigenetic perturbations could provide a shared foundation for both diseases. After giving a broad overview of epigenetics as it relates to male infertility, they outline potential mechanisms whereby disruptions of the epigenome could predispose men to infertility and cancer, review imprinting and describe the role of epigenetics in transgenerational inheritance. They also pose the intriguing question of whether an epigenetic disturbance(s) could underlie both of these diseases. Further, they postulate that epigenetic alterations may operate through a “two-hit” hypothesis, similar to oncogenes, whereby one epimutation predisposes to infertility and the other results in cancer.
      Daum and colleagues (
      • Daum H.
      • Peretz T.
      • Laufer N.
      BRCA mutations and reproduction.
      ) elegantly summarize current perspectives on BRCA1 and BRCA2 as independent risk factors for breast and ovarian cancers, as well as thoroughly review their impact on ovarian reserve, fertility and ovarian response to stimulation protocols. They present several approaches utilized to attenuate estradiol (E2) levels during IVF stimulation, all aimed at reducing breast exposure to high E2 levels. They ably describe the dilemmas experienced by affected couples and practitioners when considering PGD to eliminate transmission of these potentially devastating mutations. They concur that further studies are needed to elucidate the role of BRCA mutations in fertility and ovarian function.
      Finally, Kang and Rosenwaks (
      • Kang H.J.
      • Rosenwaks Z.
      P53 and reproduction.
      ) explore the role of tumor protein 53 (TP53)—a tumor suppressor gene responsible for protective mechanisms aimed at species survival—in reproduction. They poignantly point out that malfunction of the TP53 pathway is a hallmark of human tumors, e.g. inheritance of only one functional copy of TP53 results in Li-Fraumeni syndrome, characterized by early adult sarcomas, breast and brain cancers. Moreover, TP53 and its homologues TP63 and TP73 play important roles in male and female germ cell survival, spermatogenesis and implantation. Indeed, TP53 null mice produce low leukemia inhibitory factor (LIF) and exhibit reduced implantation rates. The authors also discuss the role of TP53 in human recurrent pregnancy loss (RPL), e.g. pro/pro polymorphism has been associated with RPL. The authors readily admit that elucidating the impact of PT53 in reproduction is difficult and verifying its biological impact continues to represent a challenge.
      Our hope is that the five contributions in this Views and Reviews will serve as a springboard for other investigators to examine the fascinating intersection of cancer and infertility. While we now have significant insight into fertility after cancer treatment, or oncofertility, we would submit to the Fertility and Sterility readership that understanding how the genome and epigenome confer shared risk of infertility and cancer is equally important and may generate new targets for the treatment of infertility. It is important to note that the study of the epidemiologic and mechanistic associations between infertility and cancer are distinct from oncofertility, which examines fertility after cancer treatment. We hope that this review will showcase the great work being done in this area, the importance of clinicians collaborating with basic and translational researchers and the need for large-scale databases to study the intersection of these two disease processes.

      References

        • Hanson B.M.
        • Eisenberg M.I.
        • Hotaling J.M.
        Male Infertility: a biomarker of individual and familial cancer risk.
        Fertil Steril. 2017; 109: 6-19
        • Nagirnaja L.
        • Aston K.I.
        • Conrad D.F.
        The genetic intersection of male infertility and cancer.
        Fertil Steril. 2017; 109: 20-26
        • James E.
        • Jenkins T.G.
        Epigenetics, infertility, and cancer: future directions.
        Fertil Steril. 2017; 109: 27-32
        • Daum H.
        • Peretz T.
        • Laufer N.
        BRCA mutations and reproduction.
        Fertil Steril. 2017; 109: 33-38
        • Kang H.J.
        • Rosenwaks Z.
        P53 and reproduction.
        Fertil Steril. 2017; 109: 39-43