NEW YORK – Researchers at the Dana-Farber Cancer Institute, Harvard Medical School, and elsewhere have teased out the rearrangements underlying Xp11 translocation renal cell carcinoma (tRCC), an aggressive, rare kidney cancer subtype involving fusions between the TFE3 enhancer-coding gene on the X chromosome and sequences from the X chromosome or autosomal chromosomes.
"Our results highlight how X chromosome genetics constrains somatic [X chromosome] alterations and underlies cancer sex differences," senior and co-corresponding author Srinivas Viswanathan, a medical oncology researcher affiliated with Dana-Farber, Harvard, the Broad Institute, and Brigham and Women's Hospital, and his colleagues wrote in Cell on Tuesday.
In contrast to other kidney cancers, which tend to be more common in men, the tRCC form is about twice as common in females than men, given the X chromosome involvement. Even so, prior studies had not untangled the specific rearrangements and X chromosomes involved.
For their new analysis, the researchers performed whole-genome sequencing and RNA sequencing on matched tumor-germline samples from five male and 10 female patients with tRCC, including 11 frozen or formalin-fixed paraffin-embedded samples collected prior to treatment and 18 samples collected after systemic treatment.
The collection included 10 primary tumor samples and seven metastatic tumor samples, along with normal, primary tumor, and metastatic tumor samples collected at rapid autopsy. Together, the team's results suggested that tRCC tends to contain reciprocal and balanced rearrangements leading to TFE3 driver fusions.
Together, the results pointed to the role of reciprocal translocations in tRCC, including TFE3 fusions that included sequences from inactive X chromosomes or autosomal chromosomes, accounting for the overrepresentation of tRCC in women — rearrangement patterns that appeared to alter the silencing or activation of genes in these regions.
"Females have two X chromosomes while males have one," Viswanathan explained in an email. "However, to achieve dosage compensation between the sexes, one of the two female X chromosomes is epigenetically silenced ('inactive X,' Xi) and most transcription occurs off of the other X homolog ('active X,' Xa)."
"We showed that both the Xi and Xa could be accessed for TFE3 rearrangements in females, explaining why this cancer is twice as common in females as males," he added, noting that "when TFE3 rearrangements occur from the Xi, this results in reactivation of genes that were previously silenced; it can also lead to the silencing of previously expressed genes on autosomes."
By performing single-nucleus RNA-seq on 4,290 individual cells from one of the primary tumors containing a translocation involving sequences from an inactive X chromosome and chromosome 1, along with bulk RNA-seq on primary tumor and metastatic liver tumor samples, the team found further evidence for the partial reactivation of sequences on the inactive X chromosome.
"Given the distinct features of chrXi, including its epigenetic state, chromatin ultrastructure, physical location, and DNA replication timing, it is also conceivable that somatic chrXi rearrangements may evince selective dependencies," the authors wrote, noting that "somatic rearrangements involving chrXi may underlie sex-specific transcriptional differences in other cancers."
More broadly, Viswanathan suggested the study "could have implications for our understanding of the genetic basis of sex bias in other cancers, and for uncovering sex-specific cancer vulnerabilities in future studies."