Chordoma is a rare bone tumor with an unknown etiology and high recurrence rate. Here we conduct whole genome sequencing of 80 skull-base chordomas and identify PBRM1, a SWI/SNF (SWItch/Sucrose Non-Fermentable) complex subunit gene, as a significantly mutated driver gene. Genomic alterations in PBRM1 (12.5%) and homozygous deletions of the CDKN2A/2B locus are the most prevalent events. The combination of PBRM1 alterations and the chromosome 22q deletion, which involves another SWI/SNF gene (SMARCB1), shows strong associations with poor chordoma-specific survival (Hazard ratio [HR] = 10.55, 95% confidence interval [CI] = 2.81-39.64, p = 0.001) and recurrence-free survival (HR = 4.30, 95% CI = 2.34-7.91, p = 2.77 × 10−6). Despite the low mutation rate, extensive somatic copy number alterations frequently occur, most of which are clonal and showed highly concordant profiles between paired primary and recurrence/metastasis samples, indicating their importance in chordoma initiation. In this work, our findings provide important biological and clinical insights into skull-base chordoma.

BackgroundHeterogeneity of immune gene expression patterns of luminal breast cancer (BC), which is clinically heterogeneous and overall considered as low immunogenic, has not been well studied especially in non-European populations. Here, we aimed at characterizing the immune gene expression profile of luminal BC in an Asian population and associating it with patient characteristics and tumor genomic features.MethodsWe performed immune gene expression profiling of tumor and adjacent normal tissue in 92 luminal BC patients from Hong Kong using RNA-sequencing data and used unsupervised consensus clustering to stratify tumors. We then used luminal patients from The Cancer Genome Atlas (TCGA, N = 564) and a Korean breast cancer study (KBC, N = 112) as replication datasets.ResultsBased on the expression of 130 immune-related genes, luminal tumors were stratified into three distinct immune subtypes. Tumors in one subtype showed higher level of tumor-infiltrating lymphocytes (TILs), characterized by T cell gene activation, higher expression of immune checkpoint genes, higher nonsynonymous mutation burden, and higher APOBEC-signature mutations, compared with other luminal tumors. The high-TIL subtype was also associated with lower ESR1/ESR2 expression ratio and increasing body mass index. The comparison of the immune profile in tumor and matched normal tissue suggested a tumor-derived activation of specific immune responses, which was only seen in high-TIL patients. Tumors in a second subtype were characterized by increased expression of interferon-stimulated genes and enrichment for TP53 somatic mutations. The presence of three immune subtypes within luminal BC was replicated in TCGA and KBC, although the pattern was more similar in Asian populations. The germline APOBEC3B deletion polymorphism, which is prevalent in East Asian populations and was previously linked to immune activation, was not associated with immune subtypes in our study. This result does not support the hypothesis that the germline APOBEC3B deletion polymorphism is the driving force for immune activation in breast tumors in Asian populations.ConclusionOur findings suggest that immune gene expression and associated genomic features could be useful to further stratify luminal BC beyond the current luminal A/B classification and a subset of luminal BC patients may benefit from checkpoint immunotherapy, at least in Asian populations.

TP53 mutations are common in breast cancer and are typically associated with more aggressive tumor characteristics, but little is known about the clinicopathological and epidemiological relevance of p53 protein expression, a TP53 mutation surrogate, in breast cancer subtypes. In this study of 7226 Chinese women with invasive breast cancer, we defined breast cancer subtypes using immunohistochemical (IHC) measures of hormone receptors and HER2 in conjunction with histologic grade. p53 expression status was then used to further stratify subtypes into p53-positive and p53-negative. Odds ratios (ORs) and 95% confidence intervals (CIs) in case-only logistic regression analyses were used to examine heterogeneity across different subtypes. The frequency of p53 protein expression varied by breast cancer subtype, being lowest in the luminal A-like and highest in the triple-negative and HER2-enriched subtypes ( P -value < 0.01). In luminal A-like and B-like/HER2-negative subtypes, p53 positivity was associated with early-onset tumors, high grade, high proliferative index, and basal marker (CK5/6 and EGFR) expression. Further, compared with luminal A-like/p53-negative patients, A-like/p53-positive patients were more likely to be parous [adjusted OR parous vs. nulliparous = 2.67 (1.60, 4.51); P -value < 0.01] and to have breastfed [adjusted OR ever vs. never = 1.38 (1.03, 1.85); P -value = 0.03]. p53 positivity was not associated with examined clinical and risk factors in other tumor subtypes. Overall, these findings suggest that p53 expression, which is readily available in many settings, can be used to identify phenotypes of luminal A-like breast cancer with distinct clinical and epidemiological implications.