TangentXY: Improved copy-number estimation of sex chromosomes reveals features associated with aneuploidies in chromosomes X and Y across cancers
- 1Dana-Farber Cancer Institute
Abstract
Signal-to-noise ratios in copy-number estimates across genomic loci improve with the use of large panels of germline reference data. However, in the case of sex chromosomes, germline samples differ between males and females (males have one X chromosome (chrX) and one Y chromosome (chrY), while females have two chrXs), limiting the size of the reference sets to those that match the sex of the index sample. Frequent mosaic loss of chrY in normal male tissue also leads to biases when not accounted for. Here we report TangentXY, a copy-number normalization method that uses both male and female reference samples, correcting for sex differences in chrX and accounting for chrY mosaicism, to assess sex chromosome copy numbers for samples of either sex. We show that TangentXY maintains sex-specific differences in chrX and chrY while minimizing noise. We also used TangentXY to analyze associations between copy-number alterations in sex chromosomes and cancer characteristics, and found that losses in the chrX but not chrY are correlated with TP53 mutation, that gain of chrX can predict patient prognosis in certain tumor types, and that the vast majority of gains of chrX in males remain active, whereas gains of chrX in females are divided approximately equally between active and inactive chrXs. We also found that loss of chrY correlates with inactivating driver mutations in escape genes in chrX, suggesting a mechanism by which its frequent loss promotes cancers in males.
Related
- Karyotypic complexity and mutated TP53 are associated with myeloid neoplasms with ring chromosomes.
- Preserved CETP Activity and Early Serum Amyloid A are Associated with Improved Outcomes in Sepsis-Associated ARDS
- Cancer type-specific profiling of chromatin regulator mutations identifies recurrent and co-occurring gene sets associated with improved survival following immune checkpoint therapy
- Myocardial extracellular volume reduction is associated with improved cardiac function after SGLT2 inhibitor therapy in HFpEF
- 962 Immune related hepatitis is associated with improved survival in patients with melanoma and liver metastases
BibTeX
@misc{enomoto2026tangentxy,
title = {{TangentXY: Improved copy-number estimation of sex chromosomes reveals features associated with aneuploidies in chromosomes X and Y across cancers}},
author = {K. Enomoto and S. Sarmashghi and S. Misek and S. Lee and G. Raskind and S. Hoyt and G. Gao and D. Deng and X. Zhang and J. Kalfon and G. Saksena and A. Cherniack and R. Beroukhim},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.01.755972},
url = {https://www.biorxiv.org/content/10.64898/2026.10.01.755972v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - TangentXY: Improved copy-number estimation of sex chromosomes reveals features associated with aneuploidies in chromosomes X and Y across cancers
AU - K. Enomoto
AU - S. Sarmashghi
AU - S. Misek
AU - S. Lee
AU - G. Raskind
AU - S. Hoyt
AU - G. Gao
AU - D. Deng
AU - X. Zhang
AU - J. Kalfon
AU - G. Saksena
AU - A. Cherniack
AU - R. Beroukhim
PY - 2026
DA - 2026/10/01
PB - bioRxiv
DO - 10.64898/2026.10.01.755972
UR - https://www.biorxiv.org/content/10.64898/2026.10.01.755972v1
AB - Signal-to-noise ratios in copy-number estimates across genomic loci improve with the use of large panels of germline reference data. However, in the case of sex chromosomes, germline samples differ between males and females (males have one X chromosome (chrX) and one Y chromosome (chrY), while females have two chrXs), limiting the size of the reference sets to those that match the sex of the index sample. Frequent mosaic loss of chrY in normal male tissue also leads to biases when not accounted for. Here we report TangentXY, a copy-number normalization method that uses both male and female reference samples, correcting for sex differences in chrX and accounting for chrY mosaicism, to assess sex chromosome copy numbers for samples of either sex. We show that TangentXY maintains sex-specific differences in chrX and chrY while minimizing noise. We also used TangentXY to analyze associations between copy-number alterations in sex chromosomes and cancer characteristics, and found that losses in the chrX but not chrY are correlated with TP53 mutation, that gain of chrX can predict patient prognosis in certain tumor types, and that the vast majority of gains of chrX in males remain active, whereas gains of chrX in females are divided approximately equally between active and inactive chrXs. We also found that loss of chrY correlates with inactivating driver mutations in escape genes in chrX, suggesting a mechanism by which its frequent loss promotes cancers in males.
ER -