Cancer risk and male Infertility: Unravelling predictive biomarkers and prognostic indicators

In recent years, there has been a global increase in cases of male infertility. There are about 30 million cases of male infertility worldwide and male reproductive health is showing rapid decline in last few decades. It is now recognized as a potential risk factor for developing certain types of cancer, particularly genitourinary malignancies like testicular and prostate cancer. Male infertility is considered a potential indicator of overall health and an early biomarker for cancer. Cases of unexplained male factor infertility have high levels of oxidative stress and oxidative DNA damage and this induces both denovo germ line mutations and epimutations due to build up of 8-hydroxy 2 deoxygunaosine abase which is highly mutagenic and also induces hypomethylation and genomic instability. Consequently, there is growing evidence to explore the various factors contributing to an increased cancer risk. Currently, the available prognostic and predictive biomarkers associated with semen characteristics and cancer risk are limited but gaining significant attention in clinical research for the diagnosis and treatment of elevated cancer risk in the individual and in offspring. The male germ cell being transcriptionally and translationally inert has a highly truncated repair mechanism and has minimal antioxidants and thus most vulnerable to oxidative injury due to environmental factors and unhealthy lifestyle and social habits. Therefore, advancing our understanding requires a thorough evaluation of the pathophysiologic mechanisms at the DNA, RNA, protein, and metabolite levels to identify key biomarkers that may underlie the pathogenesis of male infertility and associated cancer. Advanced methodologies such as genomics, epigenetics, proteomics, transcriptomics, and metabolomics stand at the forefront of cutting-edge approaches for discovering novel biomarkers, spanning from infertility to associated cancer types. Henceforth, in this review, we aim to assess the role and potential of recently identified predictive and prognostic biomarkers, offering insights into the success of assisted reproductive technologies, causes of azoospermia and idiopathic infertility, the impact of integrated holistic approach and lifestyle modifications, and the monitoring of cancer susceptibility, initiation and progression. Comprehending these biomarkers is crucial for providing comprehensive counselling to infertile men and cancer patients, along with their families.