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.

Purpose-Mammographic density (MD) is a strong risk factor for breast cancer, yet its relationship with tumor characteristics is not well established, particularly in Asian populations.Methods-MD was assessed from a total of 2001 Chinese breast cancer patients using Breast Imaging Reporting and Data System (BI-RADS) categories. Molecular subtypes were defined using immunohistochemical status on ER, PR, HER2, and Ki-67, as well as tumor grade. Multinomial logistic regression was used to test associations between MD and molecular subtype (luminal A = reference) adjusting for age, body mass index (BMI), menopausal status, parity, and nodal status.Results-The mean age at diagnosis was 51.7 years (SD = 10.7) and the average BMI was 24.7 kg/m 2 (SD = 3.8). The distribution of BI-RADS categories was 7.4% A = almost entirely fat, 24.2% B = scattered fibroglandular dense, 49.4% C = heterogeneously dense, and 19.0% D = extremely dense. Compared to women with BI-RADS = A/B, women with BI-RADS = D were more likely to have HER2-enriched tumors (OR = 1.81, 95% CI 1.08-3.06, p = 0.03), regardless of menopausal status. The association was only observed in women with normal (< 25 kg/m 2 ) BMI (OR = 2.43, 95% CI 1.24-4.76, p < 0.01), but not among overweight/obese women (OR: 0.98, 95% CI 0.38-2.52, p = 0.96).

Among individuals having perceived stigma with mental health disorders, Asian American active-duty personnel may be less likely to use mental health care when compared to non-Asian peers.

Disease heterogeneity of immune gene expression patterns of luminal breast cancer (BC) has not been well studied. We performed immune gene expression profiling of tumor and adjacent normal tissue in 92 Asian luminal BC patients and identified three distinct immune subtypes. Tumors in one subtype exhibited signs of T-cell activation, lower ESR1/ESR2 expression ratio and higher expression of immune checkpoint genes, nonsynonymous mutation burden, APOBEC-signature mutations, and increasing body mass index compared to other luminal tumors. Tumors in a second subtype were characterized by increased expression of interferonstimulated genes and enrichment for TP53 somatic mutations. The presence of three immune subtypes within luminal BC was replicated in cases drawn from The Cancer Genome Atlas and a Korean breast cancer study. Our 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.Introduction:

Chordoma is a rare bone tumor with genetic risk factors largely unknown. We conducted a whole‐exome sequencing (WES) analysis of germline DNA from 19 familial chordoma cases in five pedigrees and 137 sporadic chordoma patients and identified 17 rare germline variants in PALB2 and BRCA2, whose products play essential roles in homologous recombination (HR) and tumor suppression. One PALB2 variant showed disease cosegregation in a family with four affected people or obligate gene carrier. Chordoma cases had a significantly increased burden of rare variants in both genes when compared to population‐based controls. Four of the six PALB2 variants identified from chordoma patients modestly affected HR function and three of the 11 BRCA2 variants caused loss of function in experimental assays. These results, together with previous reports of abnormal morphology and Brachyury expression of the notochord in Palb2 knockout mouse embryos and genomic signatures associated with HR defect and HR gene mutations in advanced chordomas, suggest that germline mutations in PALB2 and BRCA2 may increase chordoma susceptibility. Our data shed light on the etiology of chordoma and support the previous finding that PARP‐1 inhibitors may be a potential therapy for some chordoma patients.

Purpose: Chordoma is a rare bone tumor with a high recurrence rate and limited treatment options. The aim of this study was to identify molecular subtypes of chordoma that may improve clinical management. Experimental Design: We conducted RNA sequencing in 48 tumors from Chinese skull-base chordoma patients and identified two major molecular subtypes. We then replicated the classification using a NanoString panel in 48 chordoma patients from North America. Results: Tumors in one subtype were more likely to have somatic mutations and reduced expression in chromatin remodeling genes, such as PBRM1 and SETD2, while the other subtype was characterized by the upregulation of genes in epithelial-mesenchymal transition and Sonic Hedgehog pathways. Immunohistochemical staining of top differentially expressed genes between the two subtypes in 312 Chinese chordoma patients with long-term follow-up data showed that the expression of some markers such as PTCH1 was significantly associated with survival outcomes. Conclusions: Our findings may improve the understanding of subtype-specific tumorigenesis of chordoma and inform clinical prognostication and targeted options.