Association between loss of Y chromosome and poor prognosis in male head and neck squamous cell carcinoma

Hollows, Robert; Wei, Wenbin; Cazier, Jean‐Baptiste; Mehanna, Hisham; Parry, G. G.; Halford, Graham; Murray, Paul G.

doi:10.1002/hed.25537

Cited by 27 publications

(34 citation statements)

References 51 publications

(102 reference statements)

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“…The Y chromosome evolved to retain genes with male-specific functions, as well as genes widely expressed involved in regulation of transcription, translation, and protein stability (36). Age-related loss of the Y chromosome in peripheral blood cells is a common somatic event in males and may be associated with higher risk of cancer, including leukemia, breast, and head and neck (37)(38)(39)(40).…”

Section: Sex Differences In Genetics Sex Chromosomesmentioning

confidence: 99%

Genome-Wide Sex and Gender Differences in Cancer

2020

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Despite their known importance in clinical medicine, differences based on sex and gender are among the least studied factors affecting cancer susceptibility, progression, survival, and therapeutic response. In particular, the molecular mechanisms driving sex differences are poorly understood and so most approaches to precision medicine use mutational or other genomic data to assign therapy without considering how the sex of the individual might influence therapeutic efficacy. The mandate by the National Institutes of Health that research studies include sex as a biological variable has begun to expand our understanding on its importance. Sex differences in cancer may arise due to a combination of environmental, genetic, and epigenetic factors, as well as differences in gene regulation, and expression. Extensive sex differences occur genome-wide, and ultimately influence cancer biology and outcomes. In this review, we summarize the current state of knowledge about sex-specific genetic and genome-wide influences in cancer, describe how differences in response to environmental exposures and genetic and epigenetic alterations alter the trajectory of the disease, and provide insights into the importance of integrative analyses in understanding the interplay of sex and genomics in cancer. In particular, we will explore some of the emerging analytical approaches, such as the use of network methods, that are providing a deeper understanding of the drivers of differences based on sex and gender. Better understanding these complex factors and their interactions will improve cancer prevention, treatment, and outcomes for all individuals.

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Section: Sex Differences In Genetics Sex Chromosomesmentioning

confidence: 99%

Genome-Wide Sex and Gender Differences in Cancer

2020

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“…Further, the extremely high frequency of >50% of LoY suggests that there is a fitness advantage. To our knowledge, EAC represents the highest rate of LoY among solid tumors [ 15 , 24 , 25 , 26 ]. Cestari et al found LoY in high grade dysplastic Barrett’s mucosa but not yet in low grade dysplastic or normal Barrett’s mucosa.…”

Section: Discussionmentioning

confidence: 99%

Y Chromosome Loss Is a Frequent Event in Barrett’s Adenocarcinoma and Associated with Poor Outcome

Löser

Wölwer

Alakus

et al. 2020

Cancers

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Background: The loss of the Y chromosome in various malignant diseases has been described previously. There are no reliable information on the actual frequency, significance and homogeneity of Y chromosome loss (LoY) in esophageal adenocarcinoma (EAC). Methods: 400 male EAC including lymph-node metastases were analyzed with commercially available Y chromosome specific fluorescence in-situ probes. The results were correlated with molecular and immunohistochemical markers and clinicopathological aspects. Results: The entire cohort (n = 400) showed a singular LoY of one chromosome arm in 1.0% (q-arm) and 2.8% (p-arm), complete LoY in 52.5%. LoY was strongly associated with shortened overall-survival (OS). Patients with preserved Y chromosome had a median OS of 58.8 months, patients with LoY an OS of 19.4 months (p < 0.001). Multivariate analysis showed LoY as an independent prognostic marker with a hazard ratio of 1.835 (95% CI 1.233–2.725). LoY correlated with TP53 mutations (p = 0.003), KRAS amplification (p = 0.004), loss of ARID1a (p = 0.045) and presence of LAG3 (p = 0.018). Conclusions: Loss of the Y chromosome is a very common phenomenon in EAC. The LoY is heterogeneously distributed within the tumor, but corresponding lymph node metastases frequently show homogeneous LoY, indicating a selection and metastasizing advantage with poor prognosis. To date, the male predominance of EAC (7–9:1) is unclear, so genetic explanatory models are favored. The LoY in EAC may be biologically and functionally relevant and additional genomic or functional analyses are needed.

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“…DNA FISH in cell lines was performed and quantified by the WVU Cytogenetics Laboratory. DNA FISH for the tissue arrays was performed as described previously with the following modifications (21). Slides were first baked at 60 C before proceeding through the protocol.…”

Section: Dna Fish and Tissue Array Analysismentioning

confidence: 99%

“…21, 34-41). LOY involves the loss of the entire Y chromosome and occurs in human male tissues as a consequence of aging; however, only recent studies have begun validating a correlation between LOY and cancer biology (18,21,(36)(37)(38)(40)(41)(42)(43)(44). Using DNA-FISH, we investigated the sex chromosome status of our panel of cell lines.…”

Section: Loss Of the Linc-spry3 Transcripts In The Radioresistant Celmentioning

confidence: 99%

Y Chromosome LncRNA Are Involved in Radiation Response of Male Non–Small Cell Lung Cancer Cells

et al. 2020

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Numerous studies have implicated changes in the Y chromosome in male cancers, yet few have investigated the biological importance of Y chromosome noncoding RNA. Here we identify a group of Y chromosome-expressed long noncoding RNA (lncRNA) that are involved in male non-small cell lung cancer (NSCLC) radiation sensitivity. Radiosensitive male NSCLC cell lines demonstrated a dose-dependent induction of linc-SPRY3-2/3/4 following irradiation, which was not observed in radioresistant male NSCLC cell lines. Cytogenetics revealed the loss of chromosome Y (LOY) in the radioresistant male NSCLC cell lines. Gain-and loss-of-function experiments indicated that linc-SPRY3-2/3/4 transcripts affect cell viability and apoptosis. Computational prediction of RNA binding proteins (RBP) motifs and UV-cross-linking and immunoprecipitation (CLIP) assays identified IGF2BP3, an RBP involved in mRNA stability, as a binding partner for linc-SPRY3-2/3/4 RNA. The presence of linc-SPRY3-2/3/4 reduced the half-life of known IGF2BP3 binding mRNA, such as the antiapoptotic HMGA2 mRNA, as well as the oncogenic c-MYC mRNA. Assessment of Y chromosome in NSCLC tissue microarrays and expression of linc-SPRY3-2/3/4 in NSCLC RNA-seq and microarray data revealed a negative correlation between the loss of the Y chromosome or linc-SPRY3-2/3/4 and overall survival. Thus, linc-SPRY3-2/3/4 expression and LOY could represent an important marker of radiotherapy in NSCLC. Significance: This study describes previously unknown Y chromosome-expressed lncRNA regulators of radiation response in male NSCLC and show a correlation between loss of chromosome Y and radioresistance.

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Association between loss of Y chromosome and poor prognosis in male head and neck squamous cell carcinoma

Cited by 27 publications

References 51 publications

Genome-Wide Sex and Gender Differences in Cancer

Genome-Wide Sex and Gender Differences in Cancer

Y Chromosome Loss Is a Frequent Event in Barrett’s Adenocarcinoma and Associated with Poor Outcome

Y Chromosome LncRNA Are Involved in Radiation Response of Male Non–Small Cell Lung Cancer Cells

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