Heterogeneity 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.
We 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.
Based 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.
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 and a subset of luminal BC patients may benefit from checkpoint immunotherapy, at least in Asian populations.
Phyllodes tumor (PT) of the breast is a rare but clinically important fibroepithelial tumor with potential risks of recurrence and metastasis. Recent studies identified recurrent TERT promoter ...mutations in PTs. However, the clinical significance of this alteration has not been fully examined. Two hundred and seven PTs from two intuitions were included. All cases were subjected to immunohistochemical analysis for TERT expression. Analysis of TERT promoter mutations was further performed by Sanger sequencing targeting the hotspot mutation region on cases from one of the involved institutions. The expression of TERT was correlated with clinicopathologic features, mutation status and recurrence. There was an association of TERT expression and its promoter mutation. Both stromal TERT expression and its promoter mutation correlated with PT grading and older patient age. Recurrence free survival (RFS) of PT patients with high stromal TERT expression was shorter if the excision margin was positive. Our findings suggested a possible pathogenic role of TERT alteration in PT malignancy. Currently there is no consensus for re-excision for PT patients with positive surgical margin, particularly for low grade cases. Stromal TERT expression could be potentially useful to guide management patients with benign PTs.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Breast cancer is the leading cause of cancer morbidity among Shanghai and Hong Kong women, which contributes to 20-25% of new female cancer incidents. This study aimed to describe the temporal trend ...of breast cancer and interpret the potential effects on the observed secular trends.
Cancer incident data were obtained from the cancer registries. Age-standardized incidence rate was computed by the direct method using the World population of 2000. Average annual percentage change (AAPC) in incidence rate was estimated by the Joinpoint regression. Age, period and cohort effects were assessed by using a log-linear model with Poisson regression.
During 1976-2009, an increasing trend of breast cancer incidence was observed, with an AAPC of 1.73 95% confidence interval (CI): 1.54-1.92) for women in Hong Kong and 2.83 (95% CI, 2.26-3.40) in Shanghai. Greater upward trends were revealed in Shanghai women aged 50 years old or above (AAPC = 3.09; 95% CI, 1.48-4.73). Using age at 50 years old as cut-point, strong birth cohort effects were shown in both pre- and post-menopausal women, though a more remarkable effect was suggested in Shanghai post-menopausal women. No evidence for a period effect was indicated.
Incidence rate of breast cancer has been more speedy in Shanghai post-menopausal women than that of the Hong Kong women over the past 30 years. Decreased birth rate and increasing environmental exposures (e.g., light-at-night) over successive generations may have constituted major impacts on the birth cohort effects, especially for the post-menopausal breast cancer; further analytic studies are warranted.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Few studies have examined epigenetic age acceleration (AA), the difference between DNA methylation (DNAm) predicted age and chronological age, in relation to somatic genomic features in paired cancer ...and normal tissue, with less work done in non-European populations. In this study, we aimed to examine DNAm age and its associations with breast cancer risk factors, subtypes, somatic genomic profiles including mutation and copy number alterations and other aging markers in breast tissue of Chinese breast cancer (BC) patients from Hong Kong.
We performed genome-wide DNA methylation profiling of 196 tumor and 188 paired adjacent normal tissue collected from Chinese BC patients in Hong Kong (HKBC) using Illumina MethylationEPIC array. The DNAm age was calculated using Horvath's pan-tissue clock model. Somatic genomic features were based on data from RNA sequencing (RNASeq), whole-exome sequencing (WES), and whole-genome sequencing (WGS). Pearson's correlation (r), Kruskal-Wallis test, and regression models were used to estimate associations of DNAm AA with somatic features and breast cancer risk factors.
DNAm age showed a stronger correlation with chronological age in normal (Pearson r = 0.78, P < 2.2e-16) than in tumor tissue (Pearson r = 0.31, P = 7.8e-06). Although overall DNAm age or AA did not vary significantly by tissue within the same individual, luminal A tumors exhibited increased DNAm AA (P = 0.004) while HER2-enriched/basal-like tumors exhibited markedly lower DNAm AA (P = < .0001) compared with paired normal tissue. Consistent with the subtype association, tumor DNAm AA was positively correlated with ESR1 (Pearson r = 0.39, P = 6.3e-06) and PGR (Pearson r = 0.36, P = 2.4e-05) gene expression. In line with this, we found that increasing DNAm AA was associated with higher body mass index (P = 0.039) and earlier age at menarche (P = 0.035), factors that are related to cumulative exposure to estrogen. In contrast, variables indicating extensive genomic instability, such as TP53 somatic mutations, high tumor mutation/copy number alteration burden, and homologous repair deficiency were associated with lower DNAm AA.
Our findings provide additional insights into the complexity of breast tissue aging that is associated with the interaction of hormonal, genomic, and epigenetic mechanisms in an East Asian population.
The role of family history to the risk of breast cancer was analyzed by incorporating menopausal status in Hong Kong Chinese women, with a particular respect to the estrogen receptor-positive (ER+) ...type.
Seven hundred and forty seven breast cancer incident cases and 781 hospital controls who had completed information on family cancer history in first-degree relatives (nature father, mother, and siblings) were recruited. Odds ratio for breast cancer were calculated by unconditional multiple logistic regression, stratified by menopausal status (a surrogate of endogenous female sex hormone level and age) and type of relative affected with the disease. Further subgroup analysis by tumor type according to ER status was investigated.
Altogether 52 (6.96%) breast cancer cases and 23 (2.95%) controls was found that the patients' one or more first-degree relatives had a history of breast cancer, showing an adjusted odds ratio (OR) of 2.41 (95%CI: 1.45-4.02). An excess risk of breast cancer was restricted to the ER+ tumor (OR = 2.43, 95% CI: 1.38-4.28), with a relatively higher risk associated with an affected mother (OR = 3.97, 95%CI: 1.46-10.79) than an affected sister (OR = 2.06, 95%CI: 1.07-3.97), while the relative risk was more prominent in the subgroup of pre-menopausal women. Compared with the breast cancer overall, the familial risks to the ER+ tumor increased progressively with the number of affected first-degree relatives.
This study provides new insights on a relationship between family breast cancer history, menopausal status, and the ER+ breast cancer. A separate risk prediction model for ER+ tumor in Asian population is desired.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Recent genomic studies suggest that Asian breast cancer (BC) may have distinct somatic features; however, most comparisons of BC genomic features across populations did not account for differences in ...age, subtype, and sequencing methods. In this study, we analyzed whole-exome sequencing (WES) data to characterize somatic copy number alterations (SCNAs) and mutation profiles in 98 Hong Kong BC (HKBC) patients and compared with those from The Cancer Genome Atlas of European ancestry (TCGA-EA, N = 686), which had similar distributions of age at diagnosis and PAM50 subtypes as in HKBC. We developed a two-sample Poisson model to compare driver gene selection pressure, which reflects the effect sizes of cancer driver genes, while accounting for differences in sample size, sequencing platforms, depths, and mutation calling methods. We found that somatic mutation and SCNA profiles were overall very similar between HKBC and TCGA-EA. The selection pressure for small insertions and deletions (indels) in GATA3 (false discovery rate (FDR) corrected p < 0.01) and single-nucleotide variants (SNVs) in TP53 (nominal p = 0.02, FDR corrected p = 0.28) was lower in HKBC than in TCGA-EA. Among the 13 signatures of single-base substitutions (SBS) that are common in BC, we found a suggestively higher contribution of SBS18 and a lower contribution of SBS1 in HKBC than in TCGA-EA, while the two APOBEC-induced signatures showed similar prevalence. Our results suggest that the genomic landscape of BC was largely very similar between HKBC and TCGA-EA, despite suggestive differences in some driver genes and mutational signatures that warrant future investigations in large and diverse Asian populations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
T cell antigen receptor (TCR)β V(D)J variable region exon assembly is ordered, with Dβ to Jβ rearrangements occurring before joining of Vβs to a DJβ complex. Germ-line V(D)J segments are flanked by ...recombination signal (RS) sequences, which consist of heptamers and nonamers separated by a spacer of 12 (12-RS) or 23 (23-RS) bp. V(D)J recombination is restricted by the 12/23 rule; joining occurs only between gene segments flanked by 12-RSs and 23-RSs. Vβ segments have 23-RSs and Jβ segments 12-RSs, which based on the 12/23 rule should allow direct joining. However, Vβ segments rearrange only to DJβ complexes and not Jβ segments, because of restrictions beyond 12/23 (B12/23) that make the Vβ23-RS incompatible with the Jβ12-RS. To determine whether direct Vβ to Jβ joining occurs if flanking RSs are B12/23 compatible, we generated mice whose lymphocytes contained replacement of the Vβ1412-RS with the 3′Dβ112-RS on a TCRβ allele lacking Dβ segments (the ${\rm J}\beta 1^{{\rm M}6}$ allele). Mice heterozygous for the ${\rm J}\beta 1^{{\rm M}6}$ allele had dramatically increased Vβ14⁺ thymocyte and T cell numbers and decreased numbers of cells expressing other Vβs. This altered Vβ repertoire resulted from direct Vβ14 to Jβ1 rearrangements on the ${\rm J}\beta 1^{{\rm M}6}$ allele. Mice harboring lymphocytes homozygous for ${\rm J}\beta 1^{{\rm M}6}$ allele developed normal thymocyte and T cell numbers with all expressing Vβ14. Our findings show that selective RS modifications enforce rearrangement of a specific Vβ gene segment and demonstrate the importance of B12/23 mechanisms for ensuring generation of diverse TCRβ repertoires.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
V(D)J recombination is targeted by short recombination signal (RS) sequences that are relatively conserved but exhibit natural sequence variations. To evaluate the potential of RS sequence variations ...to determine the primary and peripheral TCRβ repertoire, we generated mice containing specific replacement of the endogenous Vβ14 RS with the 3′Dβ1 RS (Vβ14/3′DβRS). These mice exhibited a dramatic increase in Vβ14
+ thymocyte numbers at the expense of thymocytes expressing other Vβs. In addition, the percentage of peripheral Vβ14
+ αβ T lymphocytes was similarly increased. Strikingly, this altered Vβ repertoire resulted predominantly from a higher relative level of primary Vβ14/3′DβRS rearrangement to DβJβ complexes, despite the ability of the 3′Dβ1 RS to break B12/23 restriction and allow direct rearrangement of Vβ14/3′DβRS to Jβ segments.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
Phyllodes tumors (PTs) of the breast are uncommon fibroepithelial neoplasms. Most behave in a benign fashion but they also have the potential to recur locally or to metastasize.
Methods
In ...the current study involving 290 PTs (181 benign, 76 borderline, and 33 malignant) from three hospitals over an 11-year period, we assessed the relationship between histologic parameters (including histologic features affecting grade and surgical margin status), postoperative adjuvant treatment, and local recurrences and distant metastases.
Results
An involved surgical margin was the only factor associated with increased risk of local recurrences (hazard ratio HR 4.673,
p
= 0.003), but not for distant metastases. For local recurrences, a wider margin did not confer additional benefits. None of the histologic factors were predictive for local recurrences. In contrast, distant metastases were correlated with histologic parameters, particularly an infiltrative border (HR 10.935,
p
= 0.012) and the presence of necrosis (HR 15.311,
p
= 0.007). In this series, all local recurrences were found in patients without radiotherapy, regardless of surgical margin status.
Conclusion
A negative surgical margin is mandatory for the effective local control of PT recurrence, and a minimal margin clearance may be sufficient. For distant metastases, the inherent characteristics of PTs are important, thus it may be prudent to evaluate additional histologic features, including necrosis, for patients’ prognostication.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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