Why Y matters? The implication of loss of Y chromosome in blood and cancer

Abstract

Hematopoietic mosaic loss of Y chromosome (mLOY) has emerged as a potential male‐specific accelerator of biological aging, increasing the risk of various age‐related diseases, including cancer. Importantly, mLOY is not confined to hematopoietic cells; its presence has also been observed in nonhematological cancer cells, with the impact of this presence previously unknown. Recent studies have revealed that, whether occurring in leukocytes or cancer cells, mLOY plays a role in promoting the development of an immunosuppressive tumor microenvironment. This occurs through the modulation of tumor‐infiltrating immune cells, ultimately enabling cancer cells to evade the vigilant immune system. In this review, we illuminate recent progress concerning the effects of hematopoietic mLOY and cancer mLOY on cancer progression. Examining cancer progression from the perspective of LOY adds a new layer to our understanding of cancer immunity, promising insights that hold the potential to identify innovative and potent immunotherapy targets for cancer.

Hematopoietic mosaic loss of Y chromosome (mLOY) acts as a male‐specific accelerator of biological aging and increases susceptibility to age‐related diseases, including cancer. Recent findings indicate that hematopoietic mLOY, and its cancer cell counterpart, cancer LOY, promote an immunosuppressive tumor environment, helping cancer cells escape immune detection.

Abbreviations

AML

acute myeloid leukemia

CRC

colorectal cancer

ddPCR

droplet digital polymerase chain reaction

GWAS

genome‐wide association studies

HSPCs

hematopoietic stem and progenitor cells

ICB

immune checkpoint blockade

mLOY

mosaic loss of Y chromosome

NK

natural killer

PAR1

pseudo‐autosomal region 1

TCGA

The Cancer Genome Atlas

Tregs

regulatory T cells

WGS

whole‐genome sequencing

1. VANISHING Y CHROMOSOME: WHY Y MATTERS?

The Y chromosome embarked on a unique evolutionary journey in ancient Africa, where human civilization first arose. The ancient Y chromosome, like every other chromosome, contained thousands of genes and exchanged genetic material with its counterpart, the X chromosome, in a process known as genetic recombination. However, approximately 180 million years ago, the Y chromosome underwent a transformation that separated it from the rest of the chromosomes. As a result, it ceased genetic recombination with the X chromosome in the majority of its regions, thereby effectively isolating itself. ¹ , ² This marked the birth of sex chromosomes as we know them today, and it provided the Y chromosome with its important role in determining male sex and spermatogenesis. ³

This solicitation, however, came at a price. The Y chromosome found itself on the path of degeneration, where, in the absence of recombination with the X chromosome, ⁴ , ⁵ it became a genetic wasteland, plagued by harmful mutations. ⁶ , ⁷ It began to shrink over time, losing many of its genes in this process. ⁸ The once‐vast Y chromosome currently carries fewer than 50 coding genes. A mere shadow of its former self, it has become the smallest chromosome in the human genome. After this tumultuous period, the Y chromosome seems to have reached a stable state. However, the story of the Y chromosome is far from over. Scientists have discovered a novel phenomenon: the Y chromosome could disappear from certain cells in the body, a process known as mosaic loss of Y chromosome (mLOY). ⁹

mLOY was first discovered in circulating leukocytes, and its frequency was found to exponentially increase with age. ¹⁰ , ¹¹ , ¹² Initially considered a physiological aspect of aging, hematopoietic mLOY was later linked to an elevated risk of hematological disorders. ¹³ Furthermore, recent research has revealed an association between hematopoietic mLOY and an increased risk of various age‐related diseases. These include Alzheimer's disease, ¹⁴ , ¹⁵ , ¹⁶ diabetes mellitus, ¹⁷ macular degeneration, ¹⁸ , ¹⁹ , ²⁰ cardiovascular diseases, ¹⁷ , ²¹ , ²² , ²³ and nonhematological cancers. ²⁴ , ²⁵ More recently, it has been suggested that hematopoietic mLOY may causally contribute to the progression of heart failure by altering immune cell function, ²³ indicating mLOY as a “causal” risk factor for age‐related diseases. Importantly, mLOY is not confined to hematopoietic cells, but its presence has also been observed in nonhematological cancer cells, with the impact of this presence previously unknown. ²⁶ , ²⁷ , ²⁸ Recent studies suggest that cancer mLOY may play a role in the progression of cancers. ²⁹ , ³⁰

In this review, we present a comprehensive overview of the current research progress on the influence of mLOY on both hematopoietic and cancer cells, with a specific emphasis on its role in driving cancer progression. Although this emerging field of research demands further investigation, it provides an intriguing new perspective on the intricate interplay between the immune system and cancer.

Note: The term “mLOY” is sometimes imprecisely used only to refer to mLOY in the hematopoietic system. However, in the present manuscript, we have clearly distinguished between mLOY in hematopoietic cells and mLOY in cancer cells.

2. MOSAIC LOSS OF Y CHROMOSOME IN HEMATOPOIETIC CELLS

Men lose Y chromosomes from their leukocytes as they age. ¹⁰ , ¹¹ Aging is the most potent risk factor for mLOY in the hematopoietic cells, with over 40% of men manifesting detectable mLOY in their blood at the age of 70, in sharp contrast to the significantly lower prevalence of mLOY in younger individuals. ³¹ The fraction of leukocytes displaying mLOY (%mLOY, denoting the percentage of nucleated blood cells lacking the Y chromosome) varies among individuals and can theoretically reach as high as 100%. ¹² The lower detection limit for %mLOY can vary depending on the methodology used for the measurement. ¹² , ³¹ Large‐population studies basically employed detection techniques based on whole‐genome sequencing and/or microarray analysis, repurposing the data stored in biobank cohorts. ⁹ , ³¹ , ³² , ³³ , ³⁴ , ³⁵ However, there's still an urgent need to develop highly sensitive detection methods suitable for individual patients. In addition to age, smoking has also been highlighted as a significant risk factor that influences the proportion of mLOY in hematopoietic cells. A dose–response correlation is observed between pack years and %mLOY in current smokers. However, this effect appears to be temporary, with the intensity of association diminishing after smoking cessation, suggesting that lifestyle modifications could decrease the %mLOY in leukocytes. ²⁵ , ³²

Hematopoietic mLOY is the most prevalent somatic mutation in men, ⁹ and this phenomenon has been known for over half a century. However, due to the Y chromosome's small number of genes, which are predominantly expressed in reproductive tissues, the consequence of its absence in hematopoietic cells has been largely overlooked. However, research in the past decade has shed light on the significance of Y chromosome loss for men's health, challenging the earlier belief. Since 2014, studies have reported that hematopoietic mLOY leukocytes are associated with an increased risk of all‐cause mortality, particularly cancer‐related mortality. ⁹ , ¹³ , ³⁶ Furthermore, investigations in large cohorts have revealed associations between hematopoietic mLOY and a broad spectrum of nonmalignant conditions, including Alzheimer's disease, diabetes mellitus, macular degeneration, and cardiovascular disease. ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² , ²³ Consequently, there has been a research interest in hematopoietic mLOY and its association with age‐related diseases.

3. CAUSALITY BETWEEN HEMATOPOIETIC MLOY AND NONHEMATOLOGICAL DISEASES

An increasing body of evidence suggests that hematopoietic mLOY may be “causally” linked to diseases. ²³ , ³⁷ Single‐cell transcriptome analysis of peripheral blood has enabled the investigation of differentially expressed genes between cells lacking the expression of Y chromosome genes, such as KDM5D and UTY (presumed to be LOY), and those expressing these genes within a diverse range of immune cells. For instance, the expression of CD99, encoded on the Y chromosome in pseudo‐autosomal region 1 (PAR1), was reduced significantly at both the transcript and protein levels in many immune cells. ³⁸ Given that CD99 is crucial for the transendothelial migration of immune cells, its reduction in LOY may hinder normal immune cell migration. ³⁸ Furthermore, several immunological genes encoding cytokine receptors are also located in PAR1, including CSF2RA and IL3RA. ³⁹ In addition, LOY results in the upregulation of as many as 500 autosomal genes in leukocytes, ⁴⁰ supporting the hypothesis that mLOY in the blood may contribute to disease progression by altering the function of mutant immune cells.

Recently, our group reported a causal relationship between hematopoietic LOY and the inferior prognosis of heart failure through animal experiments. ²³ , ⁴¹ We developed a mouse model of hematopoietic mLOY (hematopoietic mLOY mice) by reconstituting the bone marrow and transplanting lineage‐negative bone marrow cells. Donor HSPCs were obtained from Cas9‐knockin mice constitutively expressing Cas9 endonuclease. Y‐depleted HSPCs were produced by transducing them with a lentivirally encoded gRNA against repetitive sequences in the Y chromosome centromere, leading to the depletion of the Y chromosome (Figure 1A). ²³ , ⁴¹ This robust methodology for Y chromosome removal has recently been adopted in mLOY cancer cell research (Figure 1B). ²⁸ Of note, mice with hematopoietic mLOY have shorter lives than those transplanted Y chromosome‐maintained HSPCs. Although the principal cause of mortality in aged hematopoietic mLOY mice remains unknown, these mice show signs of biological aging in various organs, including the lungs, kidneys, and heart, which are marked by widespread fibrosis. Moreover, these mice experienced a significant decline in cardiac function under pressure overload compared with control mice. Mechanistically, cardiac monocytes/macrophages lacking the Y chromosome, which are recruited to the heart in response to pressure overload, are more likely to exhibit profibrotic characteristics. These mLOY monocytes/macrophages stimulate the proliferation and activation of cardiac fibroblasts, leading to cardiac fibrosis (Figure 2). ²³

FIGURE 1.

Generation of Y chromosome “knockout.” (A) Generation of hematopoietic cell‐specific Y chromosome‐deficient mice. In this panel, we outline the experimental conditions used to create hematopoietic cell‐specific Y chromosome‐deficient mice, as described in the study by Sano et al. ²³ Linage‐negative cells isolated from ROSA26‐Cas9 knock‐in mice were transduced with a lentivirus vector encoding guide RNA (gRNA) targeting the centromere of the Y chromosome (LOY‐gRNA) and a fluorescent marker (tRFP). Lethally irradiated male mice aged 8–12 weeks received Y chromosome‐deficient lineage‐negative cells through retro‐orbital injection. Successful transduction of the LOY‐gRNAs and engraftment were evaluated by flow cytometry analysis of blood cells at 4–6 weeks post bone marrow transplantation. The impact of hematopoietic mLOY was assessed under the conditions of natural aging and TAC‐induced heart failure. (B) Generation of LOY in cancer cells. This panel illustrates the experimental conditions used to model LOY in cancer cells, as described in the study of Abdel‐Hafiz et al. ²⁸ Y chromosome‐deficient (Y⁻) cancer cells were generated using two methods: Method‐1: The MB49 mouse bladder cancer cell line, known to naturally lose the Y chromosome, was used. Single Y⁻ cells were selected from the heterogeneous MB49 parental population and expanded. Sixteen clones that did not exhibit Y chromosome gene expression compared with positive controls were pooled to create a polyclonal Y⁻ cell line. Method‐2: To distinguish Y chromosome loss from other potential genetic background differences between the Y⁺ and Y⁻ lines, CRISPR/Cas9‐mediated Y chromosome depletion was used to deplete the Y chromosome from Y⁺ cells, following the approach established by Sano et al. ²³ Y⁺ MB49 cells were transduced with a lentivirus containing Cas9 plasmid and selected with geneticin. Cas9‐stable Y⁺ MB49 cells were further transduced with a lentivirus vector encoding LOY‐gRNA, and tRFP⁺ cells were sorted into 96‐well plates for further culturing. Single‐cell‐derived clones were expanded and screened for Y chromosome deletion. Y⁻ cancer cells were injected subcutaneously into immune‐competent wild‐type male C57BL/6 mice to investigate the effect of LOY on tumor growth in vivo. LOY, loss of the Y chromosome; TAC, transverse aortic constriction.

FIGURE 2.

XO macrophages promote heart failure in mice. As men age, their HSPCs lose the Y chromosome. LOY monocytes originating from the bone marrow infiltrate the heart in response to cardiac injury. These cells then differentiate into LOY macrophages, replacing the existing macrophages within the heart. Intriguingly, the LOY state seems to skew these macrophages toward a Lyve1⁺Mrc1⁺ profibrotic phenotype. These LOY macrophages hyperactivate the profibrotic signaling pathways, which in turn stimulate fibroblast activation, proliferation, and excessive matrix production, leading to myocardial fibrosis and heart failure. ²³ HSPCs, hematopoietic stem and progenitor cells; LOY, loss of the Y chromosome.

4. MLOY IN TREGS AND ITS IMPLICATIONS IN CANCER PROGRESSION

The presence of LOY in regulatory T cells (Tregs) holds particular importance in the context of cancer immunology. As of July 2023, two studies on this subject are available on medRxiv, a preprint service. ²⁹ , ³⁰ While monocytes and natural killer (NK) cells exhibit a high proportion of LOY cells, it was initially believed that CD4⁺ T cells had a relatively low percentage of LOY cells. ³¹ , ³⁸ , ⁴⁰ However, recent studies have revealed that LOY is prevalent in CD4⁺ Treg cells found in both circulating blood and tumor tissues. ²⁹ , ³⁰ Tregs play an important role in immune responses, particularly in maintaining homeostasis by restricting excessive immune responses. ⁴² In the context of cancer, their role becomes particularly relevant as they can hinder antitumor immune responses, thereby facilitating cancer progression. Tregs achieve this immunosuppressing effect by suppressing cytotoxic T cells, NK cells, and other immune cells responsible for eliminating cancer cells. Consequently, increased levels of tumor‐infiltrating Tregs are often associated with a poorer prognosis in various cancer types. ²⁴ LOY Tregs in tumor environment, like other LOY immune cells, exhibit aberrant autosomal gene expression and demonstrate increased expression of immune checkpoint molecules, including PDCD1 (which encodes PD‐1) and TIGIT, when compared to Tregs without LOY. PD‐1 and TIGIT function as brakes on the immune system, and their overexpression contributes to the suppression of the antitumor immune response (Figure 3). ²⁹ , ³⁰ These findings regarding the impact of LOY on Tregs are intriguing and warrant further investigation.

FIGURE 3.

Hematopoietic and cancer mLOY negatively impact antitumor immunity. mLOY in cancer contributes to the aggressive and metastatic nature of the cancer. This can be attributed to effective evasion of T cell immunity, primarily driven by an increased expression of PD‐L1‐expressing immunosuppressive macrophages and the induction of CD8⁺ T cell exhaustion. ²⁸ In addition, LOY may alter the function of tumor‐infiltrating Tregs, steering them toward an immunosuppressive phenotype. This transformation involves the upregulation of genes encoding immune checkpoint receptors such as CTLA‐4, PD‐1, and TIGIT, leading to tumor progression. ²⁹ , ³⁰ mLOY, mosaic loss of the Y chromosome; Tregs, regulatory T lymphocytes.

Another mechanism, which may complement rather than be exclusive, linking hematopoietic mLOY to cancer is revealed through genome‐wide association studies (GWAS), a research method aimed at identifying genetic variants associated with mLOY. These studies have uncovered more than 100 genetic variants, with the majority of them enriched in pathways related to cell cycle regulation and DNA damage responses, both of which play significant roles in the initiation and progression of cancer. ⁴³ Consequently, owing to shared genetic predispositions, men who are more likely to exhibit hematopoietic mLOY may also have an increased susceptibility to cancer. ³³ This hypothesis, often referred to as the “common soil theory,” is supported by the observation that women can be at risk for cancer if they carry these genetic variants of mLOY. ³¹

5. Y CHROMOSOME LOSS IN CANCER CELLS

The loss of Y chromosome has been observed in various cancer types. ⁴⁴ , ⁴⁵ , ⁴⁶ , ⁴⁷ , ⁴⁸ , ⁴⁹ Recent advancements in the field have been greatly facilitated by the availability of extensive datasets, including those from large databases like The Cancer Genome Atlas (TCGA), which have comprehensively mapped genetic mutations. ²⁷ , ⁵⁰ The presence of mLOY in caner tissues is determined by assessing the reduced expression of Y chromosome genes. If the expression level of Y falls below that observed in females, it is designated as mLOY. Alternatively, mLOY can be identified through whole‐genome sequencing (WGS), which reveals a reduction in Y chromosome sequence reads below those of normalized autosomes. Cancer tissues exhibit a diverse landscape with varying proportions of cells that display mLOY. These proportions can vary depending on factors such as the type of cancer, disease stage, whether the cancer is primary or metastasis, and, of course, the individual patient. For instance, mLOY has been detected in 80% of renal papillary cancers, 60% of esophageal cancers, and up to 40% of bladder cancers. ⁴⁴ , ⁴⁷ , ⁴⁸ , ⁴⁹ Similarly, a high proportion of lung squamous cancers and skin melanomas exhibit mLOY. ²⁵ , ²⁷ On the other hand, certain types of cancer exhibit a considerably lower prevalence of LOY, with rates as low as 2%. ²⁷ Confounding factors, including the potential influence of hematopoietic mLOY, may skew the results. Since cancer tissues often contain infiltrating immune cells, the frequency of mLOY in these tissues may reflect the prevalence of mLOY in these immune cells and the contamination of peripheral blood cells. Unlike mLOY in blood, which is significantly associated with individuals' age, mLOY in cancer does not appear to be associated with patient age. ²⁷

Importantly, the presence of mLOY in tumors has been associated with a poorer prognosis in several types of cancer. ²⁸ Evidence suggests that mLOY in cancer is associated with an increased risk of mortality, particularly in cancers such as uveal melanoma, prostate adenocarcinoma, and mesothelioma. ²⁷ This correlation persisted after the adjustment of patients' ages. An intriguing theory proposes that cancer cells with greater aggressiveness may lose the Y chromosome. This hypothesis is based on the idea that LOY might originate in cells with genomic instability, which are already predisposed to becoming malignant. GWAS supports this idea, demonstrating that men with mLOY in their blood have more germline variants related to cell cycle regulation and DNA damage response, as discussed in the previous section. ³¹ , ³³ Furthermore, there exists a speculative idea, though yet to be proven, that cells with genomic instability might be more tolerant to LOY. ²⁸ , ³³ Indeed, a significant proportion of mLOY has been observed in cancer cells with TP53 mutations and highly aneuploid tumors, which are indicative of genomic instability. ²⁷

However, some cancers exhibit high %mLOY even in the absence of TP53 mutations or substantial aneuploidy. ²⁷ This suggests that LOY may not always result from genomic instability. On the contrary, it is plausible that LOY could contribute to the induction of instability, as evidenced by bladder cancer cell lines: When engineered to lose the Y chromosome, these cells display characteristics that are typically associated with genomic instability. ²⁸ This highlights the complex role of mLOY in cancer progression.

6. CANCER MLOY AND TUMOR IMMUNITY: PROS AND CONS

Recent research has highlighted the role of LOY in bladder cancer cells, revealing its ability to promote immune evasion. ²⁸ Bladder cancers exhibiting LOY have been shown to disrupt T cell function by upregulating the expression of immune checkpoint molecules, such as CD274, LAG3, and HAVCR2, resulting in T cell exhaustion and increased susceptibility to PD‐1‐targeted immunotherapy. ²⁸ Furthermore, cancer‐related mLOY can induce an immunosuppressive phenotype in tumor‐associated macrophages (Figure 3). These laboratory findings could have clinical relevance. For instance, male patients with bladder cancer cells expressing a low level of Y‐chromosome genes, indicative of mLOY, tend to exhibit more aggressive tumor growth. However, these aggressive tumors seem to respond better to immunotherapies, including immune checkpoint blockade (ICB) and PD‐1/PD‐L1 inhibitors, which are essential treatments for bladder cancer. ⁵¹ , ⁵² , ⁵³ These findings suggest that mLOY might represent a strategic adaptation by tumor cells to evade immune detection, with significant biological implications and potential implications for future therapeutic approaches.

It is important to note that the Y chromosome contains a limited number of genes primarily expressed in reproductive tissues; however, some of these genes are also expressed in nonreproductive tissues, including cancer cells. ⁵⁴ Therefore, the loss of specific Y chromosome genes in LOY cancer cells could potentially contribute to immune evasion and worsen the prognosis for certain types of cancer. ²⁸ , ⁵⁵ Two Y chromosome genes, KDM5D and UTY, are of particular interest due to their involvement in epigenetic regulation. ²⁸ KDM5D, in previous studies, has been linked to inhibiting the growth and progression of prostate cancer and gastric cancer. ⁴⁵ , ⁴⁶ , ⁵⁶ KDM5D does this by demethylating H3K4me3 marks, which leads to the suppression of matrix metalloproteinases' expression, known to be involved in tumor cell invasion. When KDM5D expression is reduced, H3K4me3 levels at target gene promoters increase, resulting in a more aggressive phenotype and metastasis. ⁵⁶

UTY is another member of the chromosome Y chromosome‐specific histone demethylase family, and it has been reported that UTY deficiency can promote the development of bladder cancer. ⁴⁷ , ⁵⁷ Although its demethylase activity for H3K27 is less potent than that of its paralog UTX, recent investigations have highlighted the ability of UTY to modulate epigenetic processes through alternative mechanisms, such as phase separation‐mediated regulation of gene expression. ⁵⁸ This suggests that UTY may inhibit cancer progression in a methylase activity‐independent manner. Importantly, both UTY‐disrupted and KDM5D‐disrupted bladder cancer cells exhibited an immune evasion phenotype similar to that observed in Y chromosome‐depleted cells. ²⁸ Therefore, it is plausible that deficiency of UTY and/or KDM5D in LOY cancer cells could potentially contribute to an immunosuppressive phenotype by upregulating immune checkpoint molecules through epigenetic mechanisms. In addition, a previous study in mice demonstrated that the loss of Kdm5d partially resembled LOY in HSPCs, contributing to the clonal expansion of HSPCs and the progression of acute myeloid leukemia (AML). ³⁷ This finding provides further insights into the complex mechanism by which mLOY influences cancer progression, with a particular focus on the significance of Kdm5d deficiency.

However, the narrative that mLOY in mouse bladder cancer, resulting in the loss of Uty and Kdm5d genes, leads to the upregulation of immune checkpoint molecules, enabling them to evade immune cell attacks, seems to conflict with another study involving colorectal cancers (CRC). ⁵⁵ In a mouse model of CRC engineered with KRAS ^G12G (KRAS*), Apc‐KO, and Trp53‐KO triple transgenic mutations, it was observed that KRAS* CRC exhibited higher metastasis and worse outcomes compared with CRC with wild‐type KRAS due to the activation of KRAS*‐STAT4‐KDM5D signaling. Mechanistically, KDM5D epigenetically inhibits tight junctions and downregulates the expression of MHC‐I. Deletion of Kdm5d in CRC cells improved tight junction integrity and rendered them susceptible to immune attack by CD8⁺ T cells. In contrast, overexpression of Kdm5d in CRC cells resulted in a more invasive phenotype. ⁵⁵ While the direct impact of mLOY on CRC has not been investigated, these findings indicate that the effects of mLOY may differ based on the specific cancer type or cell type under consideration. The intricate interaction among these molecular pathways emphasizes the importance of gaining a thorough understanding of mLOY in various cancer contexts.

7. CURRENT CHALLENGES AND FUTURE DIRECTIONS

Studies on the impact of hematopoietic mLOY and cancer mLOY on cancer progression are still in their infancy. A growing body of evidence suggests that both types of mLOY could worsen cancer prognosis. This may primarily occur through immune‐mediated mechanisms, where mLOY renders cancer cells less susceptible to attacks from the immune system. This intersection of mLOY with oncoimmunology offers a fresh perspective for tailored cancer immunotherapy strategies.

One important aspect is the potential interaction with anti‐PD‐1 ICB therapy. This therapy has the capacity to rejuvenate exhausted T cells, restoring their function. Intriguingly, mLOY in cancers has been observed to enhance their response to anti‐PD‐1 ICB therapy when compared with non‐mLOY cancers. These findings pave the way for future clinical practices that can aid in identifying cancer patients who are most suitable for anti‐PD‐1 ICB therapy. Furthermore, there is potential for targeted inhibition of UTY and/or KDM5D to serve as a novel therapeutic strategy aimed at improving the sensitivity of ICB therapy in non‐mLOY cancer patients.

However, numerous questions remain unanswered. It is not yet clear how LOY cancer cells modulate T cell function and facilitate the creation of immunosuppressive microenvironments that ultimately accelerate cancer progression. Further investigation is also required to uncover potential interactions between LOY cancer cells and LOY tumor‐infiltrating immune cells within the context of cancer progression. The relationship between LOY, or the deletion of the Y chromosome gene KDM5D, and aggressive cancer characteristics has generated controversy in studies involving bladder cancer and CRC. This suggests that the impact of mLOY on cancer may be highly context dependent. Therefore, further research is warranted to investigate the role of mLOY across different cancer types.

In addition, a significant methodological challenge lies in the accurate detection of mLOY in various clinical samples. Current mLOY detection methods include DNA microarrays, WGS, and droplet digital polymerase chain reaction (ddPCR), among others. Unfortunately, these techniques are often labor intensive and lack the desired sensitivity and resolution. This limitation obstructs our comprehensive understanding of the biological and clinical significance of hematopoietic and cancer mLOY. Therefore, there exists an urgent need to develop easier, more sensitive detection methods to enhance our understanding of the role of mLOY in cancer pathology.

AUTHOR CONTRIBUTIONS

Ying Wang: Funding acquisition; writing – original draft. Soichi Sano: Funding acquisition; writing – original draft; writing – review and editing.

FUNDING INFORMATION

This work was supported by National Natural Science Foundation of China (No. 82100218), Chongqing Doctoral Research Fund (No. CSTB2022BSXM‐JCX0023), and Young Doctoral Talent Program (2022YQB009) to Y.W. and Grant‐in‐Aid for Scientific Research C (22K08162), Grant for Basic Research of the Japanese Heart Failure Society, Grant for Basic Research of the Japanese Circulation Society, Research Grant of the Japan Cardiovascular Research Foundation, Research Grant of the SENSHIN Medical Research Foundation, Research Grant of the MSD Life Science Foundation, The Novartis Research Grant, Research Grant of the Kondou Kinen Medical Foundation, Research Grant of the Mochida Memorial Foundation for Medical and Pharmaceutical Research, and The Bayer Scholarship for Cardiovascular Research to S.S.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

ETHICS STATEMENT

Approval of the research protocol by an Institutional Review Board: N/A.

Informed Consent: N/A.

Registry and the Registration No. of the study/trial: N/A.

Animal Studies: N/A.

Wang Y, Sano S. Why Y matters? The implication of loss of Y chromosome in blood and cancer. Cancer Sci. 2024;115:706‐714. doi: 10.1111/cas.16072