Association between iodine nutrition and cervical lymph node metastasis of papillary thyroid microcarcinoma.

We aimed to investigate the association between iodine intake and nodal metastasis stratified by central lymph node metastasis (CLNM) and lateral lymph node metastasis (LLNM) of papillary thyroid microcarcinoma (PTMC). Urinary iodine concentration (UIC) and clinicopathological characteristics were used to identify factors associated with CLNM and LLNM using logistic regression analysis. A sum of 3,858 PTMC patients were enrolled. The median UIC (MUI) of patients with CLNM or LLNM was not statistically different from those without nodal metastasis. Male patients had a higher MUI than females (183.4 µg/L vs. 173.6 µg/L). Female patients with extracapsular extension had a higher MUI than those without it (210.0 µg/L vs. 172.1 µg/L). Male patients with LLNM had a significantly lower MUI than those without LLNM (134.7 µg/L vs. 187.9 µg/L). Female patients with more than adequate iodine intake were more likely to present with CLNM and extrathyroidal extension than those with adequate iodine intake with an odds ratio (95% confidence interval) of 1.23 (1.01-1.51) and 1.59 (1.09-2.32) after adjustment. Iodine nutrition was not found to be associated with LLNM. In addition, patients with a younger age, larger tumors, extrathyroidal extension, and intrathyroidal spread were more likely to be CLNM, whereas nodular goiter presented with a protective factor; CLNM was the only factor associated with LLNM of PTMC in both genders. In conclusion, iodine nutrition has a much closer association with female than male patients, and high iodine intake may be associated with CLNM and extrathyroidal extension in female PTMC patients.

Visual Volatile-Compound Fingerprint Based on Headspace Gas Chromatography-Ion Mobility Spectrometry Combined with Chemometrics Analysis and Exploration in the Authentic Identification of Lonicerae japonicae flos.

Headspace gas chromatography-ion mobility spectrometric (HS-GC-IMS) fingerprint of volatile organic compounds (VOCs) in Lonicerae japonicae flos (LJF, Jinyinhua in Chinese) was developed. This method, combined with chemometrics analysis, was explored in the identification of authentic LJF. Seventy VOCs were identified from LJF, including aldehydes, ketones, esters, etc. The developed volatile-compound fingerprint based on HS-GC-IMS coupled with PCA analysis can successfully discriminate LJF from its adulterant: Lonicerae japonicae(LJ, called Shanyinhua in China) and can equally discriminate the LJF samples from different geographical origins of China. Total of four (compound 120, compound 184, 2-heptanone and 2-heptanone#2) and nine VOCs (styrene, compound 41, 3z-hexenol, methylpyrazine, hexanal#2, compound 78, compound 110, compound 124 and compound 180) were exploited, which might serve as the chemical markers for the difference of LJF, LJ and LJF from different regions of China. The result showed that the fingerprint based on HS-GC-IMS combined with PCA exhibited distinct advantages, such as rapid, intuitive and powerful selectivity, which demonstrated great application potential in the authentic identification of LJF.

Whole-genome bisulfite sequencing analysis of circulating tumour DNA for the detection and molecular classification of cancer.

BACKGROUND: Cancer cell-specific variation and circulating tumour DNA (ctDNA) methylation are promising biomarkers for non-invasive cancer detection and molecular classification. Nevertheless, the applications of ctDNA to the early detection and screening of cancer remain highly challenging due to the scarcity of cancer cell-specific ctDNA, the low signal-to-noise ratio of DNA variation, and the lack of non-locus-specific DNA methylation technologies. METHODS: We enrolled three cohorts of breast cancer (BC) patients from two hospitals in China (BC: n = 123; healthy controls: n = 40). We developed a ctDNA whole-genome bisulfite sequencing technology employing robust trace ctDNA capture from up to 200 µL plasma, mini-input (1 ng) library preparation, unbiased genome-wide coverage and comprehensive computational methods. RESULTS: A diagnostic signature comprising 15 ctDNA methylation markers exhibited high accuracy in the early (area under the curve [AUC] of 0.967) and advanced (AUC of 0.971) BC stages in multicentre patient cohorts. Furthermore, we revealed a ctDNA methylation signature that discriminates estrogen receptor status (Training set: AUC of 0.984 and Test set: AUC of 0.780). Different cancer types, including hepatocellular carcinoma and lung cancer, could also be well distinguished. CONCLUSIONS: Our study provides a toolset to generate unbiased whole-genome ctDNA methylomes with a minimal amount of plasma to develop highly specific and sensitive biomarkers for the early diagnosis and molecular subtyping of cancer.

Radioactive iodine in low- to intermediate-risk papillary thyroid cancer.

It remains controversial whether papillary thyroid cancer (PTC) patients with low- to intermediate-risk disease should receive radioactive iodine (RAI) after total thyroidectomy (TT). We aim to identify those who might benefit from RAI treatment in PTC patients with cervical nodal metastasis after TT. Patients were divided into TT and TT+RAI groups from the Surveillance, Epidemiology, and End Results (SEER) database (2004-2018). Overall survival (OS) and cancer-specific survival (CSS) were compared, and propensity score matching (PSM) was performed between groups. A total of 15,179 patients were enrolled, including 3,387 (22.3%) who underwent TT and 11,792 (77.7%) who received TT+RAI. The following characteristics were more likely to present in the TT+RAI group: multifocality, capsular extension, T3, N1b, and more metastatic cervical lymph nodes. RAI was associated with better OS in low- to intermediate-risk PTC patients in the multivariate Cox regression model. The subgroup analysis showed that RAI predicted better OS in patients ≥55 years, American Joint Committee on Cancer (AJCC) stage II, and capsular extension with a hazard ratio (HR) (95% CI) of 0.57 (0.45-0.72), 0.57 (0.45-0.72), and 0.68 (0.51-0.91), respectively. However, RAI failed to improve the prognoses of patients with age <55 years, AJCC stage I, PTC ≤1 cm, and capsular invasion. In the PSM cohort with 3,385 paired patients, TT+RAI treatment predicted better OS compared with TT alone. In addition, TT+RAI predicted better OS in patients with metastatic cervical lymph nodes ≥2, multifocality, extracapsular extension, and American Thyroid Association (ATA) intermediate risk. In conclusion, RAI was associated with better OS in low- to intermediate-risk PTC patients with age ≥55 years, multifocality, extrathyroidal extension, and ATA intermediate risk. However, the survival benefit from RAI may be limited in patients with AJCC stage I, PTC ≤1 cm, unifocality, capsular invasion, and ATA low-risk diseases; these patients even showed pathological cervical lymph node metastasis.

Rapid authentication of Chaenomeles species by visual volatile components fingerprints based on headspace gas chromatography-ion mobility spectrometry combined with chemometric analysis.

INTRODUCTION: Chaenomeles, including Chaenomeles speciosa (ZP), Chaenomeles sinensis (GP), Chaenomeles tibetica (XZ), and Chaenomeles japonica (RB), has been widely used as food in China for thousands of years. However, only ZP, was recorded to be the authentic medicinal Chaenomeles. Therefore, the rapid and accurate method for the authenticity identification of Chaenomeles species is urgently needed. OBJECTIVE: To develop a method for rapid differentiation of Chaenomeles species. METHODS: The visual volatile components fingerprints based on headspace gas chromatography-ion mobility spectrometry (HS-GC-IMS) combined with chemometric analysis, including principal component analysis (PCA), linear discriminant analysis (LDA) and partial least-squares discriminant analysis (PLS-DA), were utilised for the authentication of Chaenomeles species. RESULTS: The visual volatile components fingerprints by the GC-IMS intuitively showed the distribution features of the volatile components for different Chaenomeles samples. The LDA and PLS-DA models successfully discriminated Chaenomeles species with original discrimination accuracy of 100%. Fifteen volatile compounds (VOCs) (peaks 9, 12, 13, 19, 23, 24, 35, 48, 57, 65, 67, 76, 79, 80, 83) were selected as the potential species-specific markers of Chaenomeles via variable importance of projection (VIP > 1.2) and one-way analysis of variance (P < 0.05). CONCLUSIONS: This study showed that the visual volatile components fingerprints by HS-GC-IMS combined with chemometric analysis is a meaningful method in the Chaenomeles species authentication.

Exome-wide Analysis of De Novo and Rare Genetic Variants in Patients With Brain Arteriovenous Malformation.

BACKGROUND AND OBJECTIVES: Brain arteriovenous malformation (bAVM) is a congenital disorder and a leading cause of hemorrhagic stroke. Germline genetic variants play an essential role in the pathogenesis of bAVM. However, the biological relevance of disease-associated genes identified in previous studies is elusive. In this study, we aim to systematically investigate the contribution of germline variants to bAVM and explore the critical molecular pathways underlying the pathogenesis of bAVM. METHODS: Probands with sporadic bAVM were consecutively recruited into this study from November 2015 to November 2018 and underwent exome sequencing. The controls were aggregated from individuals who were not known to have vascular malformation and underwent exome sequencing for clinical or research purposes. The retained control dataset included 4,609 individuals, including 251 individuals with parental samples sequenced. We first analyzed de novo variants in cases and controls and performed a pathway enrichment analysis. A gene-based rare variant association analysis was then performed to identify genes whose variants were significantly enriched in cases. RESULTS: We collected an exome-sequenced bAVM cohort consisting of 152 trios and 40 singletons. By first focusing on de novo variants, we observed a significant mutational burden of likely gene-disrupting variants in cases vs controls. By performing a pathway enrichment analysis of all nonsynonymous de novo variants identified in cases, we found the angiopoietin-like protein 8 (ANGPTL8) regulatory pathway to be significantly enriched in patients with bAVM. Through an exome-wide rare variant association analysis utilizing 4,394 in-house exome data as controls, we identified SLC19A3 as a disease-associated gene for bAVM. In addition, we found that the SLC19A3 variants in cases are preferably located at the N' side of the SLC19A3 protein. These findings implicate a phenotypic expansion of SLC19A3-related disorders with a domain-specific effect. DISCUSSION: This study provides insights into the biological basis of bAVM by identifying novel molecular pathways and candidate genes.

DrABC: deep learning accurately predicts germline pathogenic mutation status in breast cancer patients based on phenotype data.

BACKGROUND: Identifying breast cancer patients with DNA repair pathway-related germline pathogenic variants (GPVs) is important for effectively employing systemic treatment strategies and risk-reducing interventions. However, current criteria and risk prediction models for prioritizing genetic testing among breast cancer patients do not meet the demands of clinical practice due to insufficient accuracy. METHODS: The study population comprised 3041 breast cancer patients enrolled from seven hospitals between October 2017 and 11 August 2019, who underwent germline genetic testing of 50 cancer predisposition genes (CPGs). Associations among GPVs in different CPGs and endophenotypes were evaluated using a case-control analysis. A phenotype-based GPV risk prediction model named DNA-repair Associated Breast Cancer (DrABC) was developed based on hierarchical neural network architecture and validated in an independent multicenter cohort. The predictive performance of DrABC was compared with currently used models including BRCAPRO, BOADICEA, Myriad, PENN II, and the NCCN criteria. RESULTS: In total, 332 (11.3%) patients harbored GPVs in CPGs, including 134 (4.6%) in BRCA2, 131 (4.5%) in BRCA1, 33 (1.1%) in PALB2, and 37 (1.3%) in other CPGs. GPVs in CPGs were associated with distinct endophenotypes including the age at diagnosis, cancer history, family cancer history, and pathological characteristics. We developed a DrABC model to predict the risk of GPV carrier status in BRCA1/2 and other important CPGs. In predicting GPVs in BRCA1/2, the performance of DrABC (AUC = 0.79 [95% CI, 0.74-0.85], sensitivity = 82.1%, specificity = 63.1% in the independent validation cohort) was better than that of previous models (AUC range = 0.57-0.70). In predicting GPVs in any CPG, DrABC (AUC = 0.74 [95% CI, 0.69-0.79], sensitivity = 83.8%, specificity = 51.3% in the independent validation cohort) was also superior to previous models in their current versions (AUC range = 0.55-0.65). After training these previous models with the Chinese-specific dataset, DrABC still outperformed all other methods except for BOADICEA, which was the only previous model with the inclusion of pathological features. The DrABC model also showed higher sensitivity and specificity than the NCCN criteria in the multi-center validation cohort (83.8% and 51.3% vs. 78.8% and 31.2%, respectively, in predicting GPVs in any CPG). The DrABC model implementation is available online at http://gifts.bio-data.cn/ . CONCLUSIONS: By considering the distinct endophenotypes associated with different CPGs in breast cancer patients, a phenotype-driven prediction model based on hierarchical neural network architecture was created for identification of hereditary breast cancer. The model achieved superior performance in identifying GPV carriers among Chinese breast cancer patients.

Multi-omic characterization of genome-wide abnormal DNA methylation reveals diagnostic and prognostic markers for esophageal squamous-cell carcinoma.

This study investigates aberrant DNA methylations as potential diagnosis and prognosis markers for esophageal squamous-cell carcinoma (ESCC), which if diagnosed at advanced stages has <30% five-year survival rate. Comparing genome-wide methylation sites of 91 ESCC and matched adjacent normal tissues, we identified 35,577 differentially methylated CpG sites (DMCs) and characterized their distribution patterns. Integrating whole-genome DNA and RNA-sequencing data of the same samples, we found multiple dysregulated transcription factors and ESCC-specific genomic correlates of identified DMCs. Using featured DMCs, we developed a 12-marker diagnostic panel with high accuracy in our dataset and the TCGA ESCC dataset, and a 4-marker prognostic panel distinguishing high-risk patients. In-vitro experiments validated the functions of 4 marker host genes. Together these results provide additional evidence for the important roles of aberrant DNA methylations in ESCC development and progression. Our DMC-based diagnostic and prognostic panels have potential values for clinical care of ESCC, laying foundations for developing targeted methylation assays for future non-invasive cancer detection methods.

Repair of Breast Defect by Transfer of a Contralateral Internal Mammary Artery Perforator Flap.

This is a case report of a patient with a borderline phyllodes tumor in the left breast. Seventeen months after the resection of the phyllodes tumor from the patient's left breast, the tumor occurred again 5 months ago in the surgical region. A large defect was generated after the extended resection of the left breast mass, and it was repaired with a contralateral internal mammary artery perforator flap. After the operation, bilateral breast symmetry was good, and the patient was satisfied with the shape of the breast. Postoperative follow-up was performed for 15 months, and no local recurrence was observed.

The Distinct Performances of Ultrasound, Mammograms, and MRI in Detecting Breast Cancer in Patients With Germline Pathogenic Variants in Cancer Predisposition Genes.

A proportion of up to 10% of breast cancer resulted from hereditary germline pathogenic variants (GPVs) in cancer predisposition genes (CPGs), which been demonstrated distinct clinical features and imaging manifestations. However, the performance of imaging modalities for breast cancer surveillance in CPG mutation-carriers is still unclear, especially in Asian women. A population of 3002 breast cancer patients who received germline genetic testing of CPGs was enrolled from three hospitals in China. In total, 343 (11.6%) patients were found to harbor GPVs in CPGs, including 137 (4.6%) in BRCA1 and 135 (4.6%) in BRCA2. We compared the performances of ultrasound, mammograms, MRI, and the combining strategies in CPG mutation carriers and non-carriers. As a result, the ultrasound showed a higher detection rate compared with mammograms regardless of the mutation status. However, its detection rate was lower in CPG mutation carriers than in non-carriers (93.2% vs 98.0%, P=2.1×10-4), especially in the BRCA1 mutation carriers (90.9% vs 98.0%, P=2.0×10-4). MRI presented the highest sensitivity (98.5%) and the lowest underestimation rate (14.5%) in CPG mutation carriers among ultrasound, mammograms, and their combination. Supplemental ultrasound or mammograms would add no significant value to MRI for detecting breast cancer (P>0.05). In multivariate logistic regression analysis, the family or personal cancer history could not replace the mutation status as the impact factor for the false-negative result and underestimation. In summary, clinicians and radiologists should be aware of the atypical imaging presentation of breast cancer in patients with GPVs in CPGs.

Extent of Surgery and the Prognosis of Unilateral Papillary Thyroid Microcarcinoma.

It remains controversial whether patients with papillary thyroid microcarcinoma (PTMC) benefit from total thyroidectomy (TT) or thyroid lobectomy (TL). We aimed to investigate the impact of extent of surgery on the prognosis of patients with unilateral PTMC. Patients were obtained from the Surveillance, Epidemiology, and End Results database from 2004 to 2015. Cancer-specific survival (CSS) and overall survival (OS) were evaluated by Cox regression and Kaplan-Meier curves with propensity score matching. Of 31167 PTMC patients enrolled, 22.2% and 77.8% of which underwent TL and TT, respectively. Patients with TT were more likely to be younger, females, present tumors of multifocality, extrathyroidal extension, cervical lymph node metastasis (CLNM), distant metastasis, and receive radioactive iodine (RAI) compared with those receiving TL. The multivariate Cox regression model showed that TT was not associated with an improved CSS and OS compared with TL with hazard ratio (HR) and 95% confidence interval (CI) of 0.53 (0.25-1.12) and 0.86 (0.72-1.04), respectively. In addition, the Kaplan-Meier curves further confirmed the similar survival between TL and TT after propensity score matching. The subgroup analysis showed that TT was associated with better CSS for patients < 55 years, those with tumors of gross extrathyroidal extension, CLNM (N1b), and cases not receiving RAI with HR 95% CI of 0.13 (0.02-0.81), 0.12 (0.02-0.66), 0.11 (0.02-0.64) and 0.36 (0.13-0.90), respectively. TT predicted a trend of better OS for patients with N1b and distant metastasis after adjustment. In addition, TT was associated with better CSS than TL for patients with risk factors like N1b combined with gross extrathyroidal extension, and/or multifocality after matching. In conclusion, TL may be enough for low-risk PTMC patients. TT may improve the prognosis of unilateral PTMC patients with 2 or more risk clinicopathologic factors like CLNM, multifocality, extrathyroidal extension and a younger age compared with TL.

The Prognosis of Single Hormone Receptor-Positive Breast Cancer Stratified by HER2 Status.

Single estrogen receptor (ER)+ and progesterone receptor (PR)+ tumors account for about10% of all breast cancers. However, the prognosis of these single hormone receptor-positive (HR+) tumor remains unclear. We aimed to investigate the characteristics of single HR+ breast tumors according to HER2 status in order to improve the treatment of patients with single HR+. Patients from the SEER program (2010-2016) were divided into ER+PR-, ER-PR+, ER+PR+ and ER-PR- molecular subtypes stratified by HER2 status. Overall survival (OS) and breast cancer-specific survival (BCSS) were compared by Kaplan-Meier curves after propensity score matching (PSM). A total of 203,406 patients were enrolled. Single ER+ and PR+ tumors account for 11.9% of the total population. For HER2- subtype, patients with ER+PR- (n = 16906 pairs) and ER-PR+ (n = 1395 pairs) had worse prognoses than those with ER+PR+ with hazard ratio (HR) and 95% confidence interval (CI) of 1.52 (1.41-1.64) and 2.25 (1.76-2.88) for OS; and 1.94 (1.76-2.14) and 2.57 (1.94-3.40) for BCSS, respectively; ER+PR- showed a better prognosis than ER-PR+ (n = 1394 pairs) and ER-PR- (n = 9626 pairs) with HR (95% CI) of 1.32 (1.06-1.65) and 1.44 (1.33-1.55) for OS, and 1.32 (1.03-1.69) and 1.46 (1.34-1.60) for BCSS, respectively; ER-PR+ had a similar prognosis relative to ER-PR- (n = 1395 pairs) after PSM. For HER2+ subtype, patients with ER-PR+, ER+PR-, and ER-PR- had similar OS and BCSS; ER+PR+ showed a similar prognosis compare with ER-PR+ (n = 535 pairs), but had better OS and BCSS than ER+PR- (n = 5376 pairs) and ER-PR- (n = 8143 pairs) after PSM. In addition, ER+PR+HER2+ showed similar OS and better BCSS compared with ER+PR+HER2- after PSM. In conclusion, single PR+ patients experienced poorer prognoses than single ER+ patients, and may be treated as ER-PR- patients in HER2- subtype. In HER2+ patients, both single ER+ and single PR+ cases showed similar prognoses compared with ER-PR- cases, and may be treated as ER-PR- patients.

Circulating exosomal miR-363-5p inhibits lymph node metastasis by downregulating PDGFB and serves as a potential noninvasive biomarker for breast cancer.

Sentinel lymph node (LN) biopsy is currently the standard procedure for clinical LN-negative breast cancer (BC) patients but it is prone to false-negative results and complications. Thus, an accurate noninvasive approach for LN staging is urgently needed in clinical practice. Here, circulating exosomal microRNA (miRNA) expression profiles in peripheral blood from BC patients and age-matched healthy women were obtained and analyzed. We identified an exosomal miRNA, miR-363-5p, that was significantly downregulated in exosomes from plasma of BC patients with LN metastasis which exhibited a consistent decreasing trend in tissue samples from multiple independent datasets. Plasma exosomal miR-363-5p achieved high diagnostic performance in distinguishing LN-positive patients from LN-negative patients. The high miR-363-5p expression level was significantly correlated with improved overall survival. Functional assays demonstrated that exosomal miR-363-5p modulates platelet-derived growth factor (PDGF) signaling activity by targeting PDGFB to inhibit cell proliferation and migration. Our study revealed, for the first time, plasma exosomal miR-363-5p plays a tumor suppressor role in BC and has the potential for noninvasive LN staging and prognosis prediction of BC.

Genome-wide cell-free DNA methylation analyses improve accuracy of non-invasive diagnostic imaging for early-stage breast cancer.

Early detection is crucial to improve breast cancer (BC) patients' outcomes and survival. Mammogram and ultrasound adopting the Breast Imaging Reporting and Data System (BI-RADS) categorization are widely used for BC early detection, while suffering high false-positive rate leading to unnecessary biopsy, especially in BI-RADS category-4 patients. Plasma cell-free DNA (cfDNA) carrying on DNA methylation information has emerged as a non-invasive approach for cancer detection. Here we present a prospective multi-center study with whole-genome bisulfite sequencing data to address the clinical utility of cfDNA methylation markers from 203 female patients with breast lesions suspected for malignancy. The cfDNA is enriched with hypo-methylated genomic regions. A practical computational framework was devised to excavate optimal cfDNA-rich DNA methylation markers, which significantly improved the early diagnosis of BI-RADS category-4 patients (AUC from 0.78-0.79 to 0.93-0.94). As a proof-of-concept study, we performed the first blood-based whole-genome DNA methylation study for detecting early-stage breast cancer from benign tumors at single-base resolution, which suggests that combining the liquid biopsy with the traditional diagnostic imaging can improve the current clinical practice, by reducing the false-positive rate and avoiding unnecessary harms.

Mechanistically derived patient-level framework for precision medicine identifies a personalized immune prognostic signature in high-grade serous ovarian cancer.

An accurate prognosis assessment for cancer patients could aid in guiding clinical decision-making. Reliance on traditional clinical features alone in a complex clinical environment is challenging and unsatisfactory in the era of precision medicine; thus, reliable prognostic biomarkers are urgently required to improve a patient staging system. In this study, we proposed a patient-level computational framework from mechanistic and translational perspectives to establish a personalized prognostic signature (named PLPPS) in high-grade serous ovarian carcinoma (HGSOC). The PLPPS composed of 68 immune genes achieved accurate prognostic risk stratification for 1190 patients in the meta-training cohort and was rigorously validated in multiple cross-platform independent cohorts comprising 792 HGSOC patients. Furthermore, the PLPPS was shown to be the better prognostic factor compared with clinical parameters in the univariate analysis and retained a significant independent association with prognosis after adjusting for clinical parameters in the multivariate analysis. In benchmark comparisons, the performance of PLPPS (hazard ratio (HR), 1.371; concordance index (C-index), 0.604 and area under the curve (AUC), 0.637) is comparable to or better than other published gene signatures (HR, 0.972 to 1.340; C-index, 0.495 to 0.592 and AUC, 0.48-0.624). With further validation in prospective clinical trials, we hope that the PLPPS might become a promising genomic tool to guide personalized management and decision-making of HGSOC in clinical practice.

The prognosis of invasive ductal carcinoma, lobular carcinoma and mixed ductal and lobular carcinoma according to molecular subtypes of the breast.

BACKGROUND: To investigate the prognosis of females with invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), and mixed invasive ductal and lobular carcinoma (IDLC) according to hormone receptor (HR) and HER2 status. METHODS: Data of 171,881 patients from the SEER database were analyzed. Propensity score matching was used to balance the covariates. Breast cancer-specific survival (BCSS) and overall survival (OS) of IDC, ILC, and IDLC were investigated. RESULTS: Patients with ILC were older, had lower tumor grade, higher tumor stage, larger tumor size, more nodal metastasis, higher estrogen receptor(+), lower HER2(-), and less likely to receive partial mastectomy and chemotherapy compared with IDC and IDLC. ILC and IDLC showed better prognosis than IDC after matching by Kaplan-Meier curves. Multivariate Cox regression showed better OS of ILC and IDLC compared with IDC with hazard ratio and a 95% confidence interval of 0.84 (0.77-0.90) and 0.91 (0.83-1.00), respectively. For HR(+)HER2(-) subgroup, ILC showed better OS than IDC; IDC showed worse BCSS and OS than IDLC. For HR(+)HER2(+); ILC showed better OS compared with IDLC; there were no survival differences of IDC, ILC, and IDLC for HER2(+). For HR(-)HER2(-), ILC and IDC showed better BCSS and OS compared with IDLC by multivariate analysis. CONCLUSIONS: The prognoses of female patients with IDC, ILC or IDLC were associated with the molecular subtypes of breast carcinoma. Management decisions should be based on pathological types and molecular subtypes.

Decreased level of peripheral CD8+CD28+ T cells is associated with lymph node metastasis in patients with breast cancer.

Background: Lymph node metastasis (LNM) is an independent risk factor for prognosis in patients with early breast cancer (EBC). Here we explored whether peripheral lymphocyte subtypes could be used as surrogate markers for LNM in patients with EBC. Materials & methods: The lymphocyte subpopulations in peripheral blood were measured in 152 EBC patients and 43 patients with benign breast tumors. Results: The cytotoxic T cell count was significantly lower in patients with EBC than in patients with benign tumors (244.17 ± 105.83 vs 289.97 ± 121.72; p = 0.02), especially in patients with LNM (218.36 ± 86.21; p = 0.04). Conclusion: A decreased level of peripheral CD8+CD28+ T lymphocytes is associated with LNM in patients with EBC and could be used as a potential therapeutic target for breast cancer.

Mutational landscape and genetic signatures of cell-free DNA in tumour-induced osteomalacia.

Tumour-induced osteomalacia (TIO) is a very rare paraneoplastic syndrome with bone pain, fractures and muscle weakness, which is mostly caused by phosphaturic mesenchymal tumours (PMTs). Cell-free DNA (cfDNA) has been regarded as a non-invasive liquid biopsy for many malignant tumours. However, it has not been studied in benign tumours, which prompted us to adopt the targeted next-generation sequencing approach to compare cfDNAs of 4 TIO patients, four patients with bone metastasis (BM) and 10 healthy controls. The mutational landscapes of cfDNA in TIO and BM groups were similar in the spectrum of allele frequencies and mutation types. Markedly, deleterious missense mutations in FGFR1 and loss-of-function mutations in MED12 were found in 3/4 TIO patients but none of BM patients. The gene ontology analysis strongly supported that these mutated genes found in TIOs would play a potential role in PMTs' process. The genetic signatures and corresponding change in expression of FGFR1 and FGF23 were further validated in PMT tissues from a test cohort of another three TIO patients. In summary, we reported the first study of the mutational landscape and genetic signatures of cfDNA in TIO/PMTs.

CFEA: a cell-free epigenome atlas in human diseases.

Epigenetic alterations, including 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC) and nucleosome positioning (NP), in cell-free DNA (cfDNA) have been widely observed in human diseases, and many available cfDNA-based epigenome-wide profiles exhibit high sensitivity and specificity in disease detection and classification. However, due to the lack of efficient collection, standardized quality control, and analysis procedures, efficiently integrating and reusing these data remain considerable challenges. Here, we introduce CFEA (http://www.bio-data.cn/CFEA), a cell-free epigenome database dedicated to three types of widely adopted epigenetic modifications (5mC, 5hmC and NP) involved in 27 human diseases. We developed bioinformatic pipelines for quality control and standard data processing and an easy-to-use web interface to facilitate the query, visualization and download of these cell-free epigenome data. We also manually curated related biological and clinical information for each profile, allowing users to better browse and compare cfDNA epigenomes at a specific stage (such as early- or metastasis-stage) of cancer development. CFEA provides a comprehensive and timely resource to the scientific community and supports the development of liquid biopsy-based biomarkers for various human diseases.

Computational identification of mutator-derived lncRNA signatures of genome instability for improving the clinical outcome of cancers: a case study in breast cancer.

Emerging evidence revealed the critical roles of long non-coding RNAs (lncRNAs) in maintaining genomic instability. However, identification of genome instability-associated lncRNAs and their clinical significance in cancers remain largely unexplored. Here, we developed a mutator hypothesis-derived computational frame combining lncRNA expression profiles and somatic mutation profiles in a tumor genome and identified 128 novel genomic instability-associated lncRNAs in breast cancer as a case study. We then identified a genome instability-derived two lncRNA-based gene signature (GILncSig) that stratified patients into high- and low-risk groups with significantly different outcome and was further validated in multiple independent patient cohorts. Furthermore, the GILncSig correlated with genomic mutation rate in both ovarian cancer and breast cancer, indicating its potential as a measurement of the degree of genome instability. The GILncSig was able to divide TP53 wide-type patients into two risk groups, with the low-risk group showing significantly improved outcome and the high-risk group showing no significant difference compared with those with TP53 mutation. In summary, this study provided a critical approach and resource for further studies examining the role of lncRNAs in genome instability and introduced a potential new avenue for identifying genomic instability-associated cancer biomarkers.