The Y chromosome has recognized functions in promoting male sex determination and regulating aspects of fertility. However, recent work has demonstrated important roles for the Y chromosome and Y-encoded genes in multiple domains of male health, including cancer. It is well established that males experience shorter lifespans than females, and this sex bias on overall mortality is accentuated in populations with longer life expectancy, in part related to elevated rates of cancer. The majority of human malignancies exhibit a sex bias with elevated frequencies in males. For many of these cancer types, the disparity has not been explained by environmental risk factors such as tobacco use. Notably, loss of the Y chromosome (LOY) detected in blood cells, termed mosaic LOY, is a common event that is related to advancing age and is associated with a shortened lifespan. Mosaic LOY is linked to increased incidence and mortality across a range of malignancies. Furthermore, tumors arising in different anatomic sites exhibit different frequencies of partial or complete Y chromosome loss. Causal oncogenic or tumor-suppressive roles have been documented for several Y-encoded genes, such as lysine-specific demethylase 5 D, that exert pleiotropic effects on cellular functions by virtue of genome-wide regulation of gene activity. In this review, we discuss aspects of the Y chromosome relevant to oncology. The recent completion of the entire human Y-chromosome sequence provides a reference map of Y-encoded genes and regulatory elements to enable causal molecular studies that may explain and exploit the marked disparity in male cancer risk and mortality.

The human Y chromosome is a male-specific chromosome responsible for sex determination (1). Although genes encoded on the Y chromosome regulate important aspects of fertility, recent studies have linked the Y chromosome to a variety of diseases that demonstrate sex disparities with elevated frequencies in males, including cardiovascular pathology, neurodegenerative diseases, and cancer (2). Notably, loss of the Y chromosome (LOY) detected in blood cells, termed mosaic LOY (mLOY), is the most common postzygotic mosaic mutation in aging males and is associated with a shortened lifespan (2, 3). mLOY is linked to increased incidence and mortality across a range of malignancies that include lung, bladder, and prostate cancers. In addition, tumors arising in different anatomic sites exhibit a wide range of somatic LOY frequencies within cancer cells, which are associated with genomically unstable tumors and poor prognosis. Recent studies also demonstrate the contributions of genes encoded on the Y chromosome for differential outcomes to cancer therapeutics.

This review provides an overview of the human Y chromosome and LOY mosaicism in male health and diseases in the context of oncology. The associations between mLOY observed in peripheral blood and incidence rates of human malignancies are highlighted, with a focus on the risks that contribute to LOY and the molecular mechanisms resulting from LOY that influence cancer sex disparities and adverse outcomes. The recent completion of the full human Y-chromosome reference genome sequence by the Telomere-to-Telomere consortium provides a key foundation for future work (4).

The human Y chromosome is one of the shortest nuclear chromosomes with the least number of coding genes and is notable for an unusual evolutionary history (4). The X and Y sex chromosomes evolved from homologous autosomes over a period of 300 million years (5, 6). Although 98% of ancestral genes survive on the contemporary X chromosome, the gradual loss of recombination potential led to sequence degradation and the accumulation of repetitive elements, leaving only 3% of the 1,500 genes estimated to have existed on the ancestral autosome remaining on the contemporary Y chromosome. These include a preferential retention of X–Y gene pairs that regulate transcription, translation, and protein stability and the acquisition of new genes specialized in male reproduction (7).

The Y chromosome is structurally comprised of three regions: (i) the male-specific region of the Y chromosome (MSY), (ii) two pseudoautosomal regions—PAR1 and PAR2; and (iii) a heterochromatin region on the q-arm (Fig. 1). Due to uniparental inheritance, the MSY portion does not undergo recombination during meiosis (8), resulting in the Y chromosome being passed directly from father to son with very little alteration. This feature is useful in the context of genealogy for ascertaining the direct lineage of male ancestry. Due to challenges in genome assemblies resulting from extensive regions of tandem repeats, segmental duplications, and long palindromes, the complete Y-chromosome sequence was only recently reported in detail by the Telomere-to-Telomere consortium in 2023 (4). This work determined a Y-chromosome size of 62.4 million base pairs encoding 693 genes and 883 transcripts, of which 106 genes (488 transcripts) have protein-coding potential. The genes within the MSY region are organized into three major classes based on their evolutionary relationships and sequence conservation: (i) X-degenerate region (XDR), (ii) X-transposed region, and (iii) ampliconic region. A large fraction of the genes with protein-coding potential are contained within nine MSY-specific gene families with high sequence identity within families. The remaining protein-coding genes are generally single copies. There are also families of non-coding genes.

Figure 1.

Structure of the human Y chromosome. The Y chromosome consists of three regions: MSY, two pseudoautosomal regions (PAR1 and PAR2), and a heterochromatin region on the q-arm. The MSY portion is unique to the Y chromosome. This region does not undergo recombination during meiosis and includes genes notable for regulating fundamental cellular processes, which are highlighted in red.

Figure 1.

Structure of the human Y chromosome. The Y chromosome consists of three regions: MSY, two pseudoautosomal regions (PAR1 and PAR2), and a heterochromatin region on the q-arm. The MSY portion is unique to the Y chromosome. This region does not undergo recombination during meiosis and includes genes notable for regulating fundamental cellular processes, which are highlighted in red.

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The X-transposed region class genes exhibit up to 99% homology with DNA sequences on the q21 region of the X chromosome resulting from X–Y transposition. The XDR class genes comprise pseudogenes or single-copy homologs (60%–96% identity) of X-linked genes, of which a subset encodes highly similar but nonidentical proteins. Many XDR class genes are ubiquitously expressed. Genes within the ampliconic region exist as 9 families of multiple near-identical copies termed amplicons, ranging from 2 copies for VCY to 45 copies for TSPY. Notably, the expression of most ampliconic genes is highly restricted to the testis.

Due to massive gene decay, the Y chromosome was long considered a “genetic wasteland,” and its importance was thought to be mainly limited to testis determination and spermatogenesis. Of the surviving ancestral genes, four genes, sex-determining region Y (SRY), RBMY, TSPY, and HSFY, are normally expressed exclusively in the testis and have diverged substantially from X chromosome homologs (SOX3, RBMX, TSPX, and HSFX). The SRY gene is a member of the SOX gene family of transcription factors that initiates a gene expression program in the undifferentiated gonad, resulting in the formation of seminiferous tubules and the subsequent differentiation of Leydig cells and testosterone production. De novo mutations in the SRY high-mobility group region are associated with lack of testicular differentiation and XY female sex reversal.

Discussion surrounding the impact of the Y chromosome on health and disease gained significant attention when it was determined that more than 50% of active Y-encoded genes, including distinct MSY proteins, are expressed in nongonadal tissue (9). These include genes with homologs on the X chromosome, designated X–Y pairs that are notable for regulating fundamental cellular processes, including chromatin organization, UTY/UTX (KDM6C/KDM6A) and SMCY/SMCX [lysine-specific demethylase 5 D (KDM5D)/KDM5C]; gene transcription/regulation, ZFY/ZFX and TBL1Y/TBL1X; RNA splicing, RBMY/RBMX; protein translation, RPS4Y1/RPS4X, EIFAY/EIFAX, and DDX3Y/DDX3X; and protein degradation, USP9Y/USP9X (7). By virtue of the role these factors exert in regulating genomic output, they have the potential to produce broad effects with respect to cell, organ, and human physiology. In keeping with their high level of sequence identity, these homologs were largely considered to have redundant or overlapping functions that maintain gene dosage. However, recent work has demonstrated distinctive functions for the Y-encoded versus X-encoded genes, supporting biological differences that could underlie sex-associated disease disparities. Following this finding, multiple relationships have been established between the Y chromosome and disease, including cardiovascular (10), neurodegenerative (11), and oncologic conditions (12, 13).

It is well established that males experience shorter lifespans than females, and this sex bias on overall mortality is accentuated in populations with longer life expectancy. This suggests that the underlying factors driving male versus female mortality influence age-associated diseases. One male-specific feature observed with advanced age—and recently linked to age-associated pathologies—involves mLOY ascertained in blood cells (2).

Somatic mosaicism indicates the presence of two (or more) genetically distinct populations of cells within an individual (14). The differences in genomes of these cells may range from single nucleotides to entire chromosomes. The most common type of postzygotic somatic genomic variation observed in human cells is sex chromosome mosaicism—more specifically, LOY (refs. 15, 16). mLOY was first reported more than 60 years ago (17) and is most commonly noted as Y aneuploidy in a fraction of circulating white blood cells. The cause of cellular LOY is explained by chromosome missegregation events during mitosis. The expansion of aberrant hematopoietic clones with LOY allows for the detection of leukocyte subpopulations comprising ∼10% of the nucleated blood cells using modern genomics tools such as SNP arrays and high-throughput DNA sequencing methods.

Studies have demonstrated that age is the most substantial risk factor for mLOY: in a large population cohort, the frequency of mLOY was found to be negligible in males before age 50 years, ∼1% in males <60 years old, and then increasing exponentially with advancing age to reach a prevalence of 18% in males more than 80 years old (18, 19), whereas other studies report higher frequencies (15, 16). However, mLOY is not universal: longitudinal studies analyzing mLOY in serially collected blood samples in aging males showed that in about one third of the individuals, it increased with age, whereas other subjects did not show a substantial change over a period spanning more than 20 years. This indicates that other factors play a role in mLOY in which cumulative effects of risk factors contribute to variations between individuals (Fig. 2).

Figure 2.

Risk factors for mLOY. Studies have demonstrated that age is the most substantial risk factor for mLOY and that the risk increases with age (18). Cigarette smoking is the most substantial risk factor after advanced age. Other environmental risk factors that may contribute to mLOY are outdoor air pollution, obesity, and heavy alcohol consumption. In addition to age and environmental risk factors, there are genetic and biological mechanisms that can lead to mLOY. Individuals with African ancestry have lower frequencies of autosomal and LOY mosaicism compared with individuals with European ancestry, whereas no statistically significant difference was reported between European and Asian ancestries. Obesity is associated with lower rates of mLOY. To date, GWAS have identified more than 150 loci that are associated with mLOY.

Figure 2.

Risk factors for mLOY. Studies have demonstrated that age is the most substantial risk factor for mLOY and that the risk increases with age (18). Cigarette smoking is the most substantial risk factor after advanced age. Other environmental risk factors that may contribute to mLOY are outdoor air pollution, obesity, and heavy alcohol consumption. In addition to age and environmental risk factors, there are genetic and biological mechanisms that can lead to mLOY. Individuals with African ancestry have lower frequencies of autosomal and LOY mosaicism compared with individuals with European ancestry, whereas no statistically significant difference was reported between European and Asian ancestries. Obesity is associated with lower rates of mLOY. To date, GWAS have identified more than 150 loci that are associated with mLOY.

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Environmental stressors are reported to be associated with acquiring mLOY. Several independent cohort studies suggest that cigarette smoking is the most substantial risk factor after advanced age, with a prevalence exceeding 40% in smokers of age 70 years (19, 20). The risk of mLOY progressively declines over time in former smokers, but it remains elevated up to 20 years after quitting (19). Outdoor air pollution is another factor that may contribute to leukocyte mLOY, as is heavy alcohol consumption (18, 21). For reasons that remain to be established, a lower percentage of mLOY has been reported in males classified as obese relative to men with a normal body mass index (Fig. 2; ref. 18).

Besides age and environmental risk factors, genetic and biological mechanisms have been identified that associate with mLOY and have plausible causal effects that promote mLOY. The first genomic locus associated with mLOY susceptibility is near the T-cell leukemia/lymphoma A1 gene, a coactivator of the oncogenic AKT kinase which is involved in T- and B-cell malignancies (19). Subsequent genome-wide association studies (GWAS) identified >150 loci that associate with mLOY, including a spectrum of genes involved in cell-cycle regulation, genomic instability, and cancer susceptibility (15). Ancestry is also a contributing factor to mLOY. Although a substantial overlap of susceptibility loci between Asian and European populations was reported (22), individuals with African ancestry had lower frequencies of autosomal and LOY mosaicism (18, 23), and several susceptibility loci for mLOY have higher frequencies in European populations than in African populations (24).

A growing body of research within the past decade has shown a correlation between LOY mosaicism and various age-related diseases. The risk for Alzheimer disease is 6.8-fold greater in males with mLOY (25), and mLOY is associated with higher levels of Alzheimer disease–related biomarkers and more rapid cognitive decline (26). mLOY in the blood is independently associated with major cardiovascular events in severely atherosclerotic individuals (27) and heart attack or stroke in the general population (18). mLOY is also linked to increased rates of diabetes (18), macular degeneration (28), and rare autoimmune diseases such as autoimmune thyroiditis (29) and primary biliary cirrhosis (30). Associations between mLOY and cancer are detailed below.

Overall, the impact of mLOY on all-cause mortality risk in males has been demonstrated in multiple studies. In a population-based analysis, the median survival among males with mLOY was 5.5 years shorter than that among controls, representing a 50% decrease in survival time (31). An increased proportion of cells affected by mLOY are associated with a higher risk of all-cause mortality (18).

Males have a significantly higher incidence rate for 32 of 35 (91%) distinct cancer types arising in different tissues and organs (32). For five cancer types, the disparity exceeds fourfold. For 13 cancer types, known risk factors do not explain this discrepancy, suggesting that genetic and epigenetic effects yet to be discovered may play a role. In this context, the Y chromosome may contribute to sex-associated disparities in cancer incidence rates and outcomes. Because LOY is most readily measured in peripheral blood, its association with cancer was first investigated in hematologic malignancies, in which mLOY was reported in myeloproliferative diseases and leukemia (3335). However, the biological significance of this association was not originally clear as both mLOY and these neoplastic disorders are age-related. To address the functional consequence of Y loss, mouse models were generated with mLOY in hematopoietic stem and progenitor cells using CRISPR/Cas9 gene editing (36). LOY was shown to increase measures of DNA damage, clonal hematopoiesis, and leukemogenesis, providing strong evidence that mLOY has a direct effect on these processes. As discussed in more detail later, further experimentation determined that alterations in the Y-encoded gene KDM5D recapitulated key pathogenic features of complete LOY.

Numerous studies have investigated the potential correlation between LOY mosaicism in peripheral blood cells and higher incidence and mortality rates of nonhematologic malignancies (Table 1). Males with mLOY measured in peripheral blood were determined to have a higher risk of developing several types of solid malignancies and suffered increased cancer-related deaths (31). Other studies have found weak or no association between mLOY and overall cancer risk or survival but reported associations between mLOY and specific cancer types such as prostate, colon, and bladder carcinomas (19, 33, 34). A study of 207,603 males in the UK Biobank cohort reported a modestly increased overall risk of developing a solid tumor in individuals with mLOY in a dose–response trend, whereby a greater proportion of blood leukocytes with LOY were associated with higher cancer risk (35).

Table 1.

Studies investigating the relationships between LOY and cancer.

Cancer typeMain findingReference
Pan-cancer and population studies 
 Population study A UK Biobank analysis of mCAs in 500,000 individuals determined that mLOY and mLOX mCAs occur at rates >1,000-fold compared with autosomal mCAs (37
 Population study A study of 1,153 males determined that mLOY increases the risk of nonhematologic cancer, all-cause mortality, and cancer-related mortality (31
 Population study A study of 85,542 individuals identified genomic loci associated with mLOY, genomic instability, and cancer susceptibility (33
 Population study A UK Biobank study of 207,603 males determined a modest association between mLOY and risk of developing a solid tumor with a specific focus on lung cancer (35
 Population study A UK Biobank study of 205,011 individuals identified germline variants associated with mLOY, an elevated risk of several types of cancer, and genomic instability (15
 Analyses of GTEx and TCGA A metric of EDY strongly associated with LOY and cancer risk and a high rate of amplification in the EGFR pathway (38
 Analyses of TCGA tumors A study of genomic alterations across a spectrum of 5,000 tumors identified frequent somatic LOY as a passenger or driver event: LOY associated with survival in uveal melanoma (39
 Analyses of TCGA tumors A study of 13 cancer types involving 2,375 patients identified a wide range of LOY in tumors and associations with specific oncogenes including TP53, MET, KRAS, and EGFR (40
GI cancers 
 Esophageal cancer A study of 30 esophageal squamous carcinomas identified LOY in all tumors, ranging from 1% to 80% of malignant cells with no association with cancer behavior (41
 Esophageal cancer Loss of a Y-encoded lncRNA, LINC00278, associated with smoking exposure and the development of esophageal squamous cell carcinoma (42
 Esophageal cancer A study of 29 esophageal cancers and 53 other aerodigestive tract cancers identified a high rate of tumor LOY in esophageal cancer (93%) but low rates in other GI tumors (43
 Esophageal cancer A study of 890 esophageal carcinomas demonstrated that tumor LOY and lack of T cell infiltration associated with worse overall survival (44
 Colorectal and pancreatic cancer mLOY in peripheral blood associated with the presence of colorectal cancers and pancreatic cancers, and the cancer association was independent of age (45
 Colon cancer The Y-encoded gene KDM5D promoted colon cancer progression and immune evasion in preclinical models and associated with mutations in the KRAS oncogene (46
 Colon cancer A study of 101 male patients with colorectal cancer identified significantly higher rates of mLOY in peripheral blood compared with controls (34
Genitourinary cancers 
 Bladder cancer This study determined that LOY is an early event in urothelial cancer development. No correlation was seen between LOY and clinical outcome (47
 Bladder cancer LOY in bladder cancers correlated with adverse outcomes with studies in model systems and patients demonstrating an association between tumor LOY and response to immune therapy (48
 Prostate cancer Y chromosome loss was determined to be a rare event in prostate cancer, but its presence was associated with a high Gleason grade (49
 Prostate cancer The Y-encoded gene KDM5D was shown to suppress the invasive ability of prostate cancer cells and repressed metastatic gene programs (50
 Prostate cancer KDM5D was determined to interact with and modify the transcriptional activity of the androgen receptor and also altered tumor sensitivity to docetaxel chemotherapy (51
 Prostate cancer Loss of KDM5D was determined to accelerate prostate cancer cell proliferation, leading to DNA replication stress, and served as a biomarker to predict the efficacy of ATR inhibition (52
 Prostate cancer A higher genetically predicted increase in mLOY was associated with an increase in the risk of prostate cancer in a European population cohort but not in an East Asian population cohort (53
 Testicular cancer A study of individuals with testicular germ cell tumors found an association between mLOY and familial germ cell tumors but not with the incidence of nonfamilial germ cell tumors (54
 Gonadoblastoma A review of the genomics and molecular biology of gonadoblastoma involving undifferentiated gonadal tissues with the retention of the Y-chromosome gene TSPY1 (55
Hematologic malignancies 
 AML LOY was determined to be a distinct, although uncommon, clonal cytogenetic marker for acute leukemia. LOY associated with an aggressive course in patients with AML and MDS (56
 MDS A high percentage of bone marrow cells with LOY were reported to associate with the development of MDS (57
 MDS Analyses of LOY in CD34+ peripheral blood cells determined that a threshold of 21% cells with LOY distinguished between age-related mLOY and MDS (58
 MDS and AML LOY clones comprising more than 75% of bone marrow cells were determined to indicate a possible hematologic disease–associated clonal population (59
 MDS and AML A study of bone marrow LOY identified a statistically significant increase in AML/MDS in individuals with complete LOY (60
 AML and clonal hematopoiesis A preclinical study engineering mLOY in hematopoietic stem and progenitor cells increased DNA damage and the development of AML, partially through the loss of KDM5D (36
Hepatocellular cancer 
 An analysis of genomic alterations in male hepatocellular carcinoma cell lines determined that 18 of 21 cell lines demonstrated cLOY (61
Lung cancer 
 A study of lung carcinoma identified a higher risk of death among male patients who have a tumor with deficiency in the Y-encoded gene KDM5D (62
 mLOY was associated with lower rates of lung cancer and better outcomes in nonsmokers but not in smokers (63
Male breast cancer 
 The frequency of mLOY strongly correlated with age but was less prevalent in males diagnosed with breast cancer compared with the controls (64
 cLOY was identified in 12.7% of male breast cancer cases and was associated with ER- and PR-negative tumors. cLOY did not associate with outcomes (65
Kidney cancer 
 cLOY was identified in 77% of papillary RCC with lower rates in other histologies. cLOY in RCC associated with favorable disease outcomes (66
 Patients with metastatic RCC with cLOY showed improved progression-free survival (67
Head and neck cancer 
 Head and neck squamous carcinomas with cLOY exhibited worse overall survival and overexpressed genes involved in resistance to radiotherapy and chemotherapy (68
 A cytogenetic analysis of 64 head and neck cancers identified 26 cases (40%) with cLOY associated with poor clinical outcomes (69
Cancer typeMain findingReference
Pan-cancer and population studies 
 Population study A UK Biobank analysis of mCAs in 500,000 individuals determined that mLOY and mLOX mCAs occur at rates >1,000-fold compared with autosomal mCAs (37
 Population study A study of 1,153 males determined that mLOY increases the risk of nonhematologic cancer, all-cause mortality, and cancer-related mortality (31
 Population study A study of 85,542 individuals identified genomic loci associated with mLOY, genomic instability, and cancer susceptibility (33
 Population study A UK Biobank study of 207,603 males determined a modest association between mLOY and risk of developing a solid tumor with a specific focus on lung cancer (35
 Population study A UK Biobank study of 205,011 individuals identified germline variants associated with mLOY, an elevated risk of several types of cancer, and genomic instability (15
 Analyses of GTEx and TCGA A metric of EDY strongly associated with LOY and cancer risk and a high rate of amplification in the EGFR pathway (38
 Analyses of TCGA tumors A study of genomic alterations across a spectrum of 5,000 tumors identified frequent somatic LOY as a passenger or driver event: LOY associated with survival in uveal melanoma (39
 Analyses of TCGA tumors A study of 13 cancer types involving 2,375 patients identified a wide range of LOY in tumors and associations with specific oncogenes including TP53, MET, KRAS, and EGFR (40
GI cancers 
 Esophageal cancer A study of 30 esophageal squamous carcinomas identified LOY in all tumors, ranging from 1% to 80% of malignant cells with no association with cancer behavior (41
 Esophageal cancer Loss of a Y-encoded lncRNA, LINC00278, associated with smoking exposure and the development of esophageal squamous cell carcinoma (42
 Esophageal cancer A study of 29 esophageal cancers and 53 other aerodigestive tract cancers identified a high rate of tumor LOY in esophageal cancer (93%) but low rates in other GI tumors (43
 Esophageal cancer A study of 890 esophageal carcinomas demonstrated that tumor LOY and lack of T cell infiltration associated with worse overall survival (44
 Colorectal and pancreatic cancer mLOY in peripheral blood associated with the presence of colorectal cancers and pancreatic cancers, and the cancer association was independent of age (45
 Colon cancer The Y-encoded gene KDM5D promoted colon cancer progression and immune evasion in preclinical models and associated with mutations in the KRAS oncogene (46
 Colon cancer A study of 101 male patients with colorectal cancer identified significantly higher rates of mLOY in peripheral blood compared with controls (34
Genitourinary cancers 
 Bladder cancer This study determined that LOY is an early event in urothelial cancer development. No correlation was seen between LOY and clinical outcome (47
 Bladder cancer LOY in bladder cancers correlated with adverse outcomes with studies in model systems and patients demonstrating an association between tumor LOY and response to immune therapy (48
 Prostate cancer Y chromosome loss was determined to be a rare event in prostate cancer, but its presence was associated with a high Gleason grade (49
 Prostate cancer The Y-encoded gene KDM5D was shown to suppress the invasive ability of prostate cancer cells and repressed metastatic gene programs (50
 Prostate cancer KDM5D was determined to interact with and modify the transcriptional activity of the androgen receptor and also altered tumor sensitivity to docetaxel chemotherapy (51
 Prostate cancer Loss of KDM5D was determined to accelerate prostate cancer cell proliferation, leading to DNA replication stress, and served as a biomarker to predict the efficacy of ATR inhibition (52
 Prostate cancer A higher genetically predicted increase in mLOY was associated with an increase in the risk of prostate cancer in a European population cohort but not in an East Asian population cohort (53
 Testicular cancer A study of individuals with testicular germ cell tumors found an association between mLOY and familial germ cell tumors but not with the incidence of nonfamilial germ cell tumors (54
 Gonadoblastoma A review of the genomics and molecular biology of gonadoblastoma involving undifferentiated gonadal tissues with the retention of the Y-chromosome gene TSPY1 (55
Hematologic malignancies 
 AML LOY was determined to be a distinct, although uncommon, clonal cytogenetic marker for acute leukemia. LOY associated with an aggressive course in patients with AML and MDS (56
 MDS A high percentage of bone marrow cells with LOY were reported to associate with the development of MDS (57
 MDS Analyses of LOY in CD34+ peripheral blood cells determined that a threshold of 21% cells with LOY distinguished between age-related mLOY and MDS (58
 MDS and AML LOY clones comprising more than 75% of bone marrow cells were determined to indicate a possible hematologic disease–associated clonal population (59
 MDS and AML A study of bone marrow LOY identified a statistically significant increase in AML/MDS in individuals with complete LOY (60
 AML and clonal hematopoiesis A preclinical study engineering mLOY in hematopoietic stem and progenitor cells increased DNA damage and the development of AML, partially through the loss of KDM5D (36
Hepatocellular cancer 
 An analysis of genomic alterations in male hepatocellular carcinoma cell lines determined that 18 of 21 cell lines demonstrated cLOY (61
Lung cancer 
 A study of lung carcinoma identified a higher risk of death among male patients who have a tumor with deficiency in the Y-encoded gene KDM5D (62
 mLOY was associated with lower rates of lung cancer and better outcomes in nonsmokers but not in smokers (63
Male breast cancer 
 The frequency of mLOY strongly correlated with age but was less prevalent in males diagnosed with breast cancer compared with the controls (64
 cLOY was identified in 12.7% of male breast cancer cases and was associated with ER- and PR-negative tumors. cLOY did not associate with outcomes (65
Kidney cancer 
 cLOY was identified in 77% of papillary RCC with lower rates in other histologies. cLOY in RCC associated with favorable disease outcomes (66
 Patients with metastatic RCC with cLOY showed improved progression-free survival (67
Head and neck cancer 
 Head and neck squamous carcinomas with cLOY exhibited worse overall survival and overexpressed genes involved in resistance to radiotherapy and chemotherapy (68
 A cytogenetic analysis of 64 head and neck cancers identified 26 cases (40%) with cLOY associated with poor clinical outcomes (69

Abbreviations: AML, acute myelogenous leukemia; ER, estrogen receptor; GI, gastrointestinal; mCA, mosaic chromosome alteration; MDS, myelodysplasia; mLOX, mosaic loss of the X chromosome; PR, progesterone receptor; cLOY, cancer cell loss of the Y chromosome; EDY, extreme downregulation of Y-chromosome gene expression.

The mechanisms by which leukocyte mLOY influences the development and/or outcomes of nonhematologic malignancies remain to be definitively established. Hypotheses include defects in immune cell functions that are regulated via Y-chromosome genes resulting in compromised immune surveillance mechanisms. Studies of gene expression comparing leukocytes with versus without LOY identified hundreds of alterations in autosomal genes, including a subset specifically involved in immune functions and others regulating general cell processes such as proliferation (15, 70).

LOY may also serve as a biomarker that reflects more general underlying host genomic or biochemical instability. In this context, GWAS-identified variants associating with mLOY preferentially localize near genes involved in cancer susceptibility, drivers of tumor growth, and targets of cancer therapies (15). Notably, mLOY-related variants also correlated with known susceptibility variants for several solid tumors, including checkpoint kinase 2 and telomerase reverse transcriptase. In this context, an mLOY genetic risk score comprising 156 variants is also associated with an increased risk of developing testicular germ cell tumor, prostate cancer, glioma, renal cell carcinoma (RCC), and lung cancer (15). Collectively, these results support a shared mechanism that underlies cancer susceptibility (and other pathologies) across multiple cell/tissue types that are reflected by the proxy trait of mLOY measured in blood cells (33).

Aneuploidy with partial or complete loss of specific chromosomes is commonly observed in tumor cell genomes across a range of human cancer types (71). This reflects both underlying deficits in genome maintenance mechanisms and the preferential selection for the loss of chromosomal regions harboring genes that confer tumor suppressor functions. Several pan-cancer genome analyses have been performed to ascertain the frequency, associated genomic features, and consequences of LOY in cancer cells (cLOY). These large-scale sequencing studies of cancer genomes and transcriptomes have enabled accurate assessments of cLOY in malignancies that span a wide range of organs and tissues and provided insights with respect to the role of cLOY as a driver versus passenger event.

The prevalence of cLOY was evaluated in a study of 13 cancer types using data derived from The Cancer Genome Atlas (TCGA) project involving tumors from 2,375 patients (40). Marked differences in the frequency of cancers with cLOY were observed depending on the tissue of origin, with several malignancies, notably glioblastoma and thyroid carcinoma, with almost no tumors exhibiting cLOY and others, such as kidney papillary carcinomas, with rates exceeding 70%. cLOY tumors exhibited other metrics of genome instability, including TP53 mutations, aneuploidy, and elevated mutation levels. A mutation signature associated with smoking was observed in lung and head and neck carcinomas with cLOY. Several cancer types demonstrated a sex bias incidence that correlated with cLOY frequencies. Squamous carcinoma of the head and neck was the only cancer type in which shorter survival was associated with cLOY (40).

A deep analysis of cLOY in ∼5,000 primary tumors from male patients in TCGA cohort also reported a wide range of cLOY frequencies based on organ and tissue types (39). Overall, ∼30% of all tumors analyzed demonstrated either complete or relative LOY, and cLOY was associated with loss or reduction in the expression of genes encoded on the Y chromosome. Survival analyses identified overall pan-cancer associations between cLOY and poor outcomes. However, wide ranges in cLOY were observed, with 80% of renal papillary cancers and 57% of esophageal cancers demonstrating cLOY, whereas less than 2% of thymomas and pheochromocytomas exhibited Y loss.

Consistent with prior studies, the pan-cancer assessments determined that cLOY occurred more frequently in tumors with genome doubling, aneuploidy, and TP53 inactivation. Consequently, the associations between cLOY and general measures of genome instability challenge conclusions with respect to whether cLOY is a passenger or a driver of malignant progression. In support of causal roles, a focus on uveal melanoma, a rare malignancy with male sex bias, found that cLOY did not associate with TP53 alterations or genome instability, yet uveal melanomas with cLOY exhibited significantly higher rates of metastatic spread and worse survival (39). It was also noted that mutations in Y-chromosome homologs KDM5C and KDM6A on the X chromosome were associated with cLOY in bladder cancer, clear-cell kidney cancer, and lung squamous carcinoma, supporting a two-hit inactivation mechanism for these genes with documented tumor suppressor functions (39).

It is possible to phenocopy LOY effects through epigenetic mechanisms that silence or downregulate genes on the Y chromosome. A composite measure reflecting either genomic or epigenomic functional Y loss involves quantitating the expression of genes located on the Y chromosome. A readout of this metric has been termed extreme downregulation of Y-chromosome gene expression (EDY; ref. 38). EDY was evaluated using data derived from 47 nondiseased tissues from the GTEx project and 12 cancer types from TCGA. Overall, EDY was observed in at least one benign tissue from 37% of the individuals sampled. Across the 12 cancer types analyzed, EDY and cLOY were highly correlated. Transcript levels of the Y-encoded genes, DDX3Y, EIF1AY, KDM5D, RPS4Y1, UTY, and ZFY, were significantly downregulated in tumors and are notable for having homologs on the X chromosome, with four genes exhibiting male-biased somatic loss of function mutations that co-occur with LOY and EDY (72). Methylation patterns on the Y chromosome are also associated with EDY, explaining a component of the discordance between cLOY and EDY and supporting a role for epigenetic mechanisms contributing to oncogenic processes influenced by Y-chromosome genes.

In addition to pan-cancer analyses, deep assessments of cLOY in specific tumor types have been reported. A study of 516 urothelial bladder cancers identified cLOY as an early and frequent event, but cLOY was not associated with recurrence, progression, or survival (47). An analysis of a small number of pancreatic cancer cell lines and primary carcinomas reported that the majority of tumors exhibited cLOY, whereas the Y chromosome was intact in benign cells and pancreatitis samples (73). A study of esophageal carcinoma, a cancer with strong male disparity, determined that the Y chromosome was absent in 93% of adenocarcinomas and 63% of squamous carcinomas (43). Rates of cLOY exceeding 40% have been reported in studies of other tumor types, including head and neck cancers (69) and RCC (67). Partial cLOY was observed in 27% of primary lung carcinomas, which strongly associated with a threefold increased risk of death (62). cLOY is associated with adverse outcomes in several other malignancies, including prostate cancer (39, 74), uveal melanoma (39), and colorectal cancer (75).

The observation that the Y chromosome is lost in a substantial fraction of malignancies has prompted efforts to identify mechanisms that support causal effects. Although the majority of studies have focused on individual Y-encoded genes, several reports evaluated oncogenic processes resulting from manipulating the entire Y chromosome. To directly assess tumor-suppressive effects, a Y chromosome was introduced into the Y-null PC3 prostate cancer cell line using microcell-mediated chromosome transfer. Although in vitro effects on cell growth or invasion were not observed, the introduction of a Y chromosome markedly inhibited tumor formation in vivo; however, no specific gene or mechanism was implicated (76). To evaluate causal effects of Y loss in the context of hematologic malignancies, which are associated with mLOY, mice were genetically engineered to harbor Y deletions in hematopoietic progenitor cells by CRISPR/Cas9 editing (36). These mice demonstrated clonal hematopoiesis as well as enhanced rates of leukemia. Further analyses implicated KDM5D as a key Y-encoded mediator of DNA damage and leukemogenesis.

Several studies have now demonstrated associations and causal roles for KDM5D in oncogenesis and male cancer disparities (Fig. 3). KDM5D is a member of a family of enzymes that demethylate histone H3 lysine 4 residues to regulate gene expression via chromatin reorganization (77). A study of lung carcinomas found strong associations between cLOY and extensive autosomal hypomethylation, pointing to alterations in an epigenetic modifier encoded on the Y chromosome. Further studies implicated KDM5D deficiency as a key candidate, with KDM5D loss associated with adverse clinical outcomes (62). Downregulation of KDM5D in gastric cancer cells upregulated markers of epithelial-to-mesenchymal transition, including ZEB1, and increased cellular migration and invasion (78).

Figure 3.

Y-chromosome alterations contribute to cancer development and treatment outcomes. A, A study of lung carcinomas found associations between cLOY and extensive autosomal hypomethylation. KDM5D deficiency is associated with high mortality and poor prognosis (62). B, In colorectal cancer, mutant KRAS was shown to upregulate KDM5D expression in colorectal cancer cells, which in turn repressed cell tight junctions, increased cell invasion, and downregulated MHC class 1 components and antigen presentation (46). C, In vitro and in vivo models of bladder cancer demonstrated a role for Y chromosome–encoded genes UTY and KDM5D in regulating antitumor immune responses. Y tumors in mice had higher infiltration of dysfunctional CD8+ T cells and immunosuppressive macrophages and showed increased response to anti-PD1 treatment compared with Y+ tumors. Mice engrafted with Y bladder cancer cells and patients with evidence of LOY or loss of UTY or KDM5D exhibited enhanced survival with anti-PDL1 therapy compared with tumors and patients with an intact Y chromosome (48). D, KDM5D loss increased the expression of key invasion–associated genes in prostate cancer. KDM5D loss was shown to promote resistance to taxane chemotherapy and accelerate mitotic entry with concomitant DNA replication stress, which enhanced tumor sensitivity to inhibitors of the ATR kinase (52).

Figure 3.

Y-chromosome alterations contribute to cancer development and treatment outcomes. A, A study of lung carcinomas found associations between cLOY and extensive autosomal hypomethylation. KDM5D deficiency is associated with high mortality and poor prognosis (62). B, In colorectal cancer, mutant KRAS was shown to upregulate KDM5D expression in colorectal cancer cells, which in turn repressed cell tight junctions, increased cell invasion, and downregulated MHC class 1 components and antigen presentation (46). C, In vitro and in vivo models of bladder cancer demonstrated a role for Y chromosome–encoded genes UTY and KDM5D in regulating antitumor immune responses. Y tumors in mice had higher infiltration of dysfunctional CD8+ T cells and immunosuppressive macrophages and showed increased response to anti-PD1 treatment compared with Y+ tumors. Mice engrafted with Y bladder cancer cells and patients with evidence of LOY or loss of UTY or KDM5D exhibited enhanced survival with anti-PDL1 therapy compared with tumors and patients with an intact Y chromosome (48). D, KDM5D loss increased the expression of key invasion–associated genes in prostate cancer. KDM5D loss was shown to promote resistance to taxane chemotherapy and accelerate mitotic entry with concomitant DNA replication stress, which enhanced tumor sensitivity to inhibitors of the ATR kinase (52).

Close modal

Several studies have evaluated KDM5D in prostate cancers, with up to 40% of tumors demonstrating loss or downregulated expression, which is associated with metastases and poor outcomes (50, 79). KDM5D loss increased the expression of key invasion–associated genes, including matrix metalloproteinases and the epithelial-to-mesenchymal transition driver Slug (50). KDM5D loss was also shown to promote resistance to taxane chemotherapy and accelerate mitotic entry with concomitant DNA replication stress, which enhanced tumor sensitivity to inhibitors of the ATR kinase (51, 52).

cLOY occurs in 10% to 40% of bladder cancers, in which cLOY and low expression of Y-encoded genes KDM5D, UTY/KDM6C, TBL1Y and ZFY associate with poor outcomes (48, 80, 81). To evaluate the functional contribution of cLOY to tumor progression, an analysis of Y+ and Y mouse bladder cancer models demonstrated no differences in cell proliferation in vitro under either 2D or 3D culture conditions, but Y tumor cells exhibited significantly greater growth rates compared with Y+ tumor cells when injected into immune-competent mouse hosts (48). However, this growth disparity was eliminated when Y and Y+ tumor cells were introduced into immunocompromised mice. These phenotypes were recapitulated when the Y chromosome was deleted from Y+ cells using CRISPR/Cas9 gene editing technology. Furthermore, specific deletion of the Y-encoded gene UTY or KDM5D in Y+ cells or re-expression of UTY or KDM5D in Y cells reproduced the differential growth effects of Y versus Y+ tumors on intact or immunocompromised hosts, demonstrating a role for Y chromosome–encoded genes in regulating antitumor immune responses. Y tumors in mice had higher infiltration of dysfunctional CD8+ T cells and immunosuppressive macrophages and showed an increased response to anti-PD1 treatment compared with Y+ tumors. Consistent with these findings, male patients with bladder cancer with cLOY demonstrated higher proportions of exhausted CD8+ T cells and T regulatory cells and higher levels of PDL1 expression. Notably, mice engrafted with Y bladder cancer cells and patients with evidence of LOY or loss of UTY or KDM5D exhibited enhanced survival with anti-PDL1 therapy compared with tumors and patients with an intact Y chromosome. Consistent with the results in prostate cancer and hematologic malignancies, cLOY was associated with evidence of elevated DNA damage responses (48).

Although the majority of studies demonstrate tumor-suppressive roles for the Y chromosome and Y-encoded genes, context may be relevant. In colorectal cancer, males with oncogenic KRAS mutations were shown to have substantially worse outcomes relative to females, whereas sex-biased outcomes were not evident in patients with colorectal cancer without KRAS alterations (46). Genetically engineered mouse models recapitulated these findings, and cross-species analyses identified KDM5D as a potential driver of these sex-based differential outcomes. Mutant KRAS was shown to upregulate KDM5D expression in colorectal cancer cells via the STAT4 transcriptional activator, which in turn repressed cell tight junctions, increased cell invasion, and downregulated MHC class 1 components and antigen presentation. In analyses of both colorectal cancer mouse model systems and patient datasets, Kdm5d/KDM5D-low tumors were enriched for signatures of CD8+ T cells. Collectively, these studies indicate that intact KDM5D functions to repress immune responses and promote tumor metastases in males in the context of KRAS-driven colorectal cancer.

Genetic alterations involving the Y chromosome are strongly associated with sex disparities in the incidence and outcomes of numerous malignancies. Evidence supports mLOY measured in peripheral blood as a general marker of shared mechanisms that contribute to genomic instability. Consequently, studies of the intrinsic host and extrinsic environmental contributors to mLOY may provide insights into processes influencing neoplasia that are preventable or reversible. However, because mLOY is a high-frequency event, particularly in genomically unstable tumors, carefully designed studies that confirm causal mechanisms versus correlation should be a priority. The associations between mLOY and other health conditions, such as cardiovascular pathology, may also be relevant for assessing the risk, prevention, and treatment of side effects resulting from cancer therapeutics such as hormone suppression, chemotherapy, and immune-based therapeutics. Studies evaluating the functional relationships between mLOY and genes commonly altered in the context of clonal hematopoiesis such as DNMT3A and TET2 may also provide insights into early oncogenic processes. The recent completion of the full DNA sequence of the human Y chromosome now provides a complete inventory of genes and regulatory elements that can be used to examine the causal influence of specific Y-encoded genes on cancer biology such as those demonstrating a role for KDM5D in mediating response to chemotherapy and immune-based treatments. Notably, genes with X-chromosome paralogs such as DDX3Y/DDX3X and EIF1AY/EIF1AX exhibit context-dependent vulnerabilities and may represent viable targets in the setting of Y loss. Further research on understanding and exploiting Y chromosome–regulated effects in oncology may provide knowledge to influence cancer risk and screening strategies and individualize promising therapeutics in the context of precision oncology.

P.S. Nelson reports grants from Janssen and personal fees from Janssen, Merck, Bristol Myers Squibb, and Pfizer outside the submitted work. No disclosures were reported by the other author.

We thank the members of the Nelson Labs and the Fred Hutchinson Cancer Center/University of Washington Prostate Cancer Program for helpful discussions. This work was supported by NIH awards CA097186 (C.D. Dirican and P.S. Nelson) and CA277368 (P.S. Nelson) and DOD award PC200262 (P.S. Nelson).

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