Specific Molecular Subtypes Research Articles

Copper Chaperone for Superoxide Dismutase Subtypes as a Prognostic Marker in Luminal B Breast Cancer.

Copper chaperone for superoxide dismutase (CCS) is an essential component of the oxidation-reduction system. In breast cancer cells, CCS expression is highly up-regulated, which contributes to cellular proliferation and migration. Breast cancer is a multifaceted disease with different tumor prognoses and responses to clinical treatments, which may be associated with multiple molecular subtypes of CCS. The CCS expression patterns in breast cancer were investigated by TNMplot, cBioPortal, and HPA network database. The correlation of CCS expression with clinicopathological parameters was analyzed using the UALCAN database. The Cancer Genome Atlas (TCGA) data set was used to analyze the Clinical characteristics of CCS in luminal B patients. The bc-GenExMiner database was used to analyze the effects of BReast-CAncer susceptibility gene (BRCA)1/2, TP53 mutation status, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER) expression on CCS expression. The survival curves and prognostic value of CCS in luminal B breast cancer were performed through Kaplan-Meier curves, univariate and multivariate Cox regression using the PrognoScan, bc-GenExMiner, and Clinical bioinformatics analysis platform. We found that CCS expression was associated with patient age, race, ER, and PR status. We also discovered that BRCA1/2 mutations had an effect on CCS expression. The luminal B subtype had the highest CCS expression, which was linked to poor survival compared with other subtypes. In addition, Kaplan-Meier curve analysis showed that luminal B patients with high CCS mRNA expression showed a poor survival and the CCS gene is an independent predictor of outcome in patients with luminal B breast cancer by univariate and multivariate Cox regression. Our findings emphasize the significant expression of CCS in luminal B breast cancer and its potential as an autonomous prognostic determinant for this specific molecular subtype. These findings suggest that CCS holds promise as a prospective marker for the treatment of luminal B breast cancer.

The Role of Serum Nestin in Diagnosis and Prognosis of Breast Cancer: A Prospective Observational Study.

The molecular classification of breast cancer has enabled targeted therapy for specific molecular subtypes. Nestin, which has been studied for its role in oncogenesis, could contribute to this direction. This study aimed to investigate the differences between serum nestin levels and molecular profiling, as well as histopathological tumor types, in women who underwent surgery for breast cancer. Women who underwent surgery for breast cancer at the Breast Unit of the 1st Propaedeutic Department of Surgery, Hippocration General Hospital, National and Kapodistrian University of Athens were prospectively included. Patients' demographic data were recorded and serum nestin levels were measured. Molecular biomarker analysis was performed, as well as histopathologic assessment. Seventy patients were included in the analysis. Among patients with breast cancer, 93% were estrogen receptor (ER) positive, 91% were progesterone receptor (PR) positive, and 43% were human epidermal growth factor receptor 2 (HER2) positive. Ki67 was expressed in 16% of patients and p53 was expressed in 32% of patients. Invasive ductal carcinoma was diagnosed in 80% of patients, with 44% of tumors classified as T1 and 46% as T2. Additionally, 43% were G1 and 56% were N0, while 34% were N1. No statistically significant difference was observed between serum nestin levels and ER, PR, HER2, Ki67, and p53 expression. Furthermore, no difference was observed between serum nestin levels and breast cancer histological type, size, N-stage, and grading. The diagnostic and prognostic role of circulating nestin for breast cancer was not confirmed and no correlation with immunohistochemistry results was observed. Thus, the necessity of larger prospective studies is enhanced.

Characterization of ligand-receptor pair in acute myeloid leukemia: a scoring model for prognosis, therapeutic response, and T cell dysfunction.

The significance of ligand-receptor (LR) pair interactions in the progression of acute myeloid leukemia (AML) has been the focus of numerous studies. However, the relationship between LR pairs and the prognosis of AML, as well as their impact on treatment outcomes, is not fully elucidated. Leveraging data from the TCGA-LAML cohort, we mapped out the LR pair interactions and distinguished specific molecular subtypes, with each displaying distinct biological characteristics. These subtypes exhibited varying mutation landscapes, pathway characteristics, and immune infiltration levels. Further insight into the immune microenvironment among these subtypes revealed disparities in immune cell abundance. Notably, one subtype showed a higher prevalence of CD8 T cells and plasma cells, suggesting increased adaptive immune activities. Leveraging a multivariate Lasso regression, we formulated an LR pair-based scoring model, termed "LR.score," to classify patients based on prognostic risk. Our findings underscored the association between elevated LR scores and T-cell dysfunction in AML. This connection highlights the LR score's potential as both a prognostic marker and a guide for personalized therapeutic interventions. Moreover, our LR.score revealed substantial survival prediction capacities in an independent AML cohort. We highlighted CLEC11A, ICAM4, ITGA4, and AVP as notably AML-specific. qRT-PCR analysis on AML versus normal bone marrow samples confirmed the significant downregulation of CLEC11A, ITGA4, ICAM4, and AVP in AML, suggesting their inverse biomarker potential in AML. In summary, this study illuminates the significance of the LR pair network in predicting AML prognosis, offering avenues for more precise treatment strategies tailored to individual patient profiles.

The correlation between clinical outcomes and genomic analysis with high risk factors for the progression of osteosarcoma.

Osteosarcoma (OS) is a rare but aggressive malignancy. Despite previous reports, molecular characterization of this disease is not well understood, and little is known regarding OS in Chinese patients. Herein, we analyzed the genomic signatures of 73 Chinese OS cases. TP53, NCOR1, LRP1B, ATRX, RB1, and TFE3 were the most frequently mutated gene in our OS cohort. In addition, the genomic analysis of Western OS patients was performed. Notably, there were remarkable disparities in mutational landscape, base substitution pattern, and tumor mutational burden between the Chinese and Western OS cohorts. Specific molecular mechanisms, including DNA damage repair (DDR) gene mutations, copy number variation (CNV) presence, aneuploidy, and intratumoral heterogeneity, were associated with disease progression. Additionally, 30.1% of OS patients carried clinically actionable alterations, which were mainly enriched in PI3K, MAPK, DDR, and RTK signaling pathways. A specific molecular subtype incorporating DDR alterations and CNVs was significantly correlated with distant metastasis-free survival and event-free survival, and this correlation was observed in all subgroups with different characteristics. These findings comprehensively elucidated the genomic profile and revealed novel prognostic factors in OS, which would contribute to understanding this disease and promoting precision medicine of this population.

Genetic Alterations in Glioblastoma and Their Clinical Implications – A Comprehensive Review

Glioblastoma (GBM) is the most aggressive primary brain tumor with limited treatment options and poor prognosis. In recent years, molecular research has provided valuable insights into the underlying mechanisms of GBM, uncovering key molecular alterations and signaling pathways that drive tumor development and progression. Driver mutations play a critical role in the pathogenesis of glioblastoma (GBM), influencing tumor initiation, growth, and therapeutic response. Among the key driver mutations identified in GBM, the prominent example is the mutation of the epidermal growth factor receptor (EGFR) gene. Dysregulated signaling pathways, including the PI3K/Akt/mTOR, the Ras/Raf/MEK/ERK, and the NOTCH pathway play a critical role in cell proliferation, survival, and invasion in GBM. Epigenetic modifications contribute to tumor initiation, repression of the tumor suppressor genes, and therapy resistance. Global DNA hypomethylation, site-specific hypermethylation, histone deacetylase, microRNAs (miRNAs), and long non-coding RNAs (lncRNAs) are the most common epigenetic modifications. Immune checkpoints, such as programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are upregulated, leading to T-cell exhaustion and impaired antitumor immune responses. The molecular classification systems have provided a more refined understanding of GBM biology, have important implications for personalized treatment strategies, play a role in guiding clinical trials designed to specifically target and evaluate novel therapies in patients with specific molecular subtypes, and hold promise for predicting treatment response. The identification of molecular subtypes can be associated with different treatment decisions.

Synchronous Endometrial and Ovarian Carcinomas: Pathologic and Molecular Analysis Highlights the Monoclonal Origin of the Lesions.

The diagnosis of synchronous carcinomas, involving both the endometrium and ovaries, is not a rare finding in gynecologic pathology and represents a challenge with implications on tumor staging and therapeutic decision-making. A mono-institutional series of 11 metastatic and 6 paired synchronous endometrial and ovarian carcinomas were reviewed by 2 expert pathologists based on previously published histopathologic criteria. The series was investigated for DNA mismatch repair proteins, p53, and POLE status and was subject to DNA-based next-generation sequencing targeting 67 cancer-related genes. Out of 17 pairs, 16 featured the same histotype (10 endometrioid, 4 serous high-grade, and 2 clear cells). By using WHO 2020 criteria, 11 couples of tumors were confirmed as metastatic and 6 couples were confirmed as independent. Based on next-generation sequencing analysis, 16 of 17 cases (11 metastatic and 5 independent) of our series showed evidence of a clonal relationship between endometrial and ovarian carcinomas. In metastatic cases, the adverse outcome was associated with nonendometrioid/high-grade endometrioid histotype and with the p53-abnormal molecular subtype. Four cases originally fulfilling clinicopathological criteria of independent endometrial and ovarian carcinomas were clonally related, low-grade endometrioid histotype and POLE -mut, mismatch repair deficient, and no specific molecular profile molecular subtypes; no adverse event was recorded in this group. In summary, the molecular characterization of synchronous gynecologic carcinomas confirms their clonal origin in most cases. However, the results of our study point out that the clinical behavior of these tumors seems to be determined by the presence of high-risk WHO 2020 histologic criteria and molecular features (i.e. p53-abnormal), rather than the monoclonal origin.

Prognostic and therapeutic implications of iron-related cell death pathways in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a blood cancer that is diverse in terms of its molecular abnormalities and clinical outcomes. Iron homeostasis and cell death pathways play crucial roles in cancer pathogenesis, including AML. The objective of this study was to examine the clinical significance of genes involved in iron-related cell death and apoptotic pathways in AML, with the intention of providing insights that could have prognostic implications and facilitate the development of targeted therapeutic interventions. Gene expression profiles, clinical information, and molecular alterations were integrated from multiple datasets, including TCGA-LAML and GSE71014. Our analysis identified specific molecular subtypes of acute myeloid leukemia (AML) displaying varying outcomes, patterns of immune cell infiltration, and profiles of drug sensitivity for targeted therapies based on the expression of genes involved in iron-related apoptotic and cell death pathways. We further developed a risk model based on four genes, which demonstrated promising prognostic value in both the training and validation cohorts, indicating the potential of this model for clinical decision-making and risk stratification in AML. Subsequently, Western blot analysis showed that the expression levels of C-Myc and CyclinD1 were significantly reduced after CD4 expression levels were knocked down. The findings underscore the potential of iron-related cell death pathways as prognostic biomarkers and therapeutic targets in AML, paving the way for further research aimed at understanding the molecular mechanisms underlying the correlation between iron balance, apoptosis regulation, and immune modulation in the bone marrow microenvironment.

Different prognostic values of KRAS exon 2 submutations and BRAF V600E mutation in microsatellite stable (MSS) and unstable (MSI) stage III colon cancer: an ACCENT/IDEA pooled analysis of seven trials

The prognostic value of KRAS and BRAFV600E mutations in stage III colon cancer (CC) remains controversial and has never been clearly analyzed in patients with microsatellite instability-high (MSI-H) tumors due to sample size limitations. Data are also lacking for KRAS submutations and prognosis. We examined clinicopathological variables and prognosis in patients with surgically resected stage III CC who participated in seven clinical trials from the ACCENT/IDEA databases. Associations between KRAS exon 2 and BRAFV600E mutations and time to recurrence (TTR), overall survival (OS), and survival after recurrence (SAR) were assessed using a Cox model. We also analyzed the prognostic value of KRAS exon 2 submutations. Among 8460 patients, 11.4% had MSI-H status. In the MSI-H group, BRAFV600E, KRAS exon 2 mutants, and double-wild-type statuses were detected in 40.6%, 18.1%, and 41.3%, respectively, whereas and in the microsatellite stable (MSS) group, these were detected in 7.7%, 38.6%, and 53.8%, respectively. In the MSS group, 5-year TTR rates of 61.8%, 66.3%, and 72.9% were observed among patients with BRAFV600E, KRAS exon 2 mutants, and those who were DWT, respectively [adjusted hazard ratio (HR)= 1.58 and 1.31, both P < 0.001]. In the MSI-H group, 5-year TTR rates did not differ significantly among the mutated subgroups. Similar results were found for OS. However, survival after relapse was significantly shorter in the KRAS exon 2- and BRAFV600E-mutated patients in both MSS (adjusted HR= 2.06 and 1.15; both P < 0.05) and MSI-H (adjusted HR= 1.99 and 1.81; both P < 0.05) groups. In the MSS group, KRAS exon 2 mutations were associated with TTR, but only p.G12C, p.G12D, and p.G13D were associated with poor outcomes after disease recurrence. Testing for both KRAS and BRAFV600E mutations in stage III patients should be considered as they can better define individual patient prognosis, and may also enable patient selection for (neo)adjuvant trials dedicated to specific molecular subtypes with poor prognosis.

Drug-induced interstitial lung disease caused by olaparib: three case reports and review of the Japanese Adverse Drug Event Report database and literature

BackgroundOlaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has demonstrated effectiveness in treating ovarian, breast, and other cancers, particularly those with specific molecular subtypes including, but not limited to, BRCA1/2 mutations. Consequently, its utilization is expected to increase in the future. For this reason, it is important to acknowledge the potential for adverse events associated with olaparib, including the relatively rare but significant risk of drug-induced interstitial lung disease (DIILD). Since DIILD can lead to fatal outcomes, its early detection is crucial. The dissemination of knowledge regarding DIILD can be facilitated through case reports; however, specific reports of DIILD caused by olaparib have only been published in Japanese. To the best of our knowledge, this is the first report in English of our experience with three cases of DIILD caused by olaparib.Case presentationCases 1, 2, and 3 involved Japanese women with ovarian cancer who had been receiving olaparib at a dose of 600 mg/day. Case 1, a 72-year-old woman who had been on olaparib for 4 months, and case 2, a 51-year-old woman who had been on olaparib for 8 months, reported fever and general malaise. Chest computed tomography (CT) revealed pale ground glass opacity (GGO) similar to hypersensitivity pneumonitis. The severity grade was 2 in both cases. Case 3, a 78-year-old woman who had been on olaparib for 3 weeks, presented with cough and reported dyspnea on exertion. Chest CT revealed non-specific interstitial pneumonia and organizing pneumonia-like shadows. The severity grade was 4. Olaparib was discontinued in all cases. Case 1 received 0.6 mg/kg of prednisolone due to mild hypoxia, while prednisolone was not administered in case 2 due to the absence of hypoxia. Case 3 received steroid pulse therapy due to severe hypoxia. Olaparib administration was not resumed in any patient.ConclusionDIILD caused by olaparib in Japan, including the present three cases, commonly presents with GGO, similar to hypersensitivity pneumonitis on chest CT. The prognosis for the majority of patients is favorable; however, there have been instances of severe cases. Early recognition of drug-induced lung injury and further accumulation of cases is important.

Characterization of stem cell subtypes and prognostic signature in hepatocellular carcinoma.

Cancer stem cells (CSCs) were linked to cancer aggressiveness and poor prognosis in patients with hepatocellular carcinoma (HCC). We integrated two external HCC cohorts to develop the stem cell subtypes according to unsupervised clustering with 26 stem cell gene sets. Between the subtypes, differences in prognosis, clinical characteristics, recognized HCC subtypes, metabolic profile, immune-related features, somatic mutation, and drug sensitivity were examined. The prognostic signature was created, and validated by numerous cohorts, and used to assess the efficacy of immunotherapy and transcatheter arterial chemoembolization (TACE) treatment. The nomogram was developed based on the signature and clinical features. We further examined the function of KIF20A in HCC and proved that KIF20A had the potential to regulate the stemness of HCC cells through western blot. Low stem cell patterns, a good prognosis, positive clinical features, specific molecular subtypes, low metastatic characteristics, and an abundance of metabolic and immunological aspects were associated with Cluster 1, whereas Cluster 2 was the reverse. Chemotherapy and immunotherapy were more effective in Cluster 1. Cluster 1 and CTNNB1 and ALB mutation were more closely. Additionally, the prognosis, immunotherapeutic, and TACE therapy responses were all worse in the high-risk group. The nomogram could predict the survival probability of HCC patients. KIF20A was discovered to be overexpressed in HCC and was revealed to be connected to the stemness of the HepG2 cell line. Two stem cell subgroups with different prognoses, metabolic, and immunological characteristics in HCC patients were identified. We also created a 7-gene prognostic signature and a nomogram to estimate the survival probability. The function of KIF20A in HCC stemness was initially examined.

Exploring the human microbiome - A step forward for precision medicine in breast cancer.

The second most frequent cancer in the world and the most common malignancy in women is breast cancer. Breast cancer is a significant health concern in India with a high mortality-to-incidence ratio and presentation at a younger age. Recent studies have identified gut microbiota as a significant factor that can have an influence on the development, treatment, and prognosis of breast cancer. This review article aims to describe the influence of microbial dysbiosis on breast cancer occurrence and the possible interactions between oncobiome and specific breast cancer molecular subtypes. The review further also discusses the role of epigenetics and diet/nutrition in the regulation of the gut and breast microbiome and its association with breast cancer prevention, therapy, and recurrence. Additionally, the recent technological advances in microbiome research, including next-generation sequencing (NGS) technologies, genome sequencing, single-cell sequencing, and microbial metabolomics along with recent advances in artificial intelligence (AI) have also been reviewed. This is an attempt to present a comprehensive status of the microbiome as a key cancer biomarker. We believe that correlating microbiome and carcinogenesis is important as it can provide insights into the mechanisms by which microbial dysbiosis can influence cancer development and progression, leading to the potential use of the microbiome as a tool for prognostication and personalized therapy.

Association of Polygenic Score With Tumor Molecular Subtypes in Papillary Thyroid Carcinoma.

Genome-wide association studies have identified germline variants associated with elevated PTC risk. It is also known that somatic driver mutations contribute to PTC development and as such PTCs can be further categorized into different molecular subtypes based on their somatic alterations. However, it remains unknown whether identified germline variants predictive of PTC risk are associated with specific molecular subtypes. The primary goal of the present study is to determine whether germline genetic risk, as assessed using a polygenic score (PGS) is associated with molecular subtypes of papillary thyroid carcinoma (PTC), defined based on tumor driver mutation status. This study was carried out using data from The Cancer Genome Atlas (TCGA) thyroid cancer study. A previously validated 10-single-nucleotide variation PGS for PTC derived from genome-wide association study hits was calculated to ascertain germline genetic risk. The primary molecular subtypes of interest were defined by tumor driver mutation status (BRAFV600E-mutated vs RAS-mutated vs "other"). We also explored associations between PGS and molecular subtypes defined by messenger RNA (mRNA) expression, microRNA expression, and DNA methylation patterns. Polytomous logistic regression analysis was used to assess the association between PGS and PTC molecular subtype with and without adjustment for clinical variables. Odds ratios (ORs) with their 95% CIs were estimated. A total of 359 patients were included in the study. PGS was significantly associated specific tumor molecular subtypes defined by tumor driver mutation status. Increasing germline risk was associated with having a higher odd of BRAFV600E-mutated PTC compared to PTCs without driver mutations in the "other" category. No significant difference was detected in terms of PGS tumor categorization in the RAS subtype compared to BRAFV600E. In exploratory analyses, PGS was also associated with mRNA-, microRNA-, and DNA methylation-defined molecular subtypes, as defined by the TCGA PTC study. PGS has molecular subtype-specific associations in PTC, which has implications for their use in risk prediction.

Smoking and risk of colorectal cancer according to KRAS and BRAF mutation status in a Japanese prospective Study.

Although smoking is a major modifiable risk factor for many types of cancer, evidence for colorectal cancer is equivocal in Asian populations. Recent Western studies have proposed that the association between smoking and colorectal cancer is restricted to specific tumor molecular subtypes. However, no studies have evaluated the association according to tumor molecular subtypes in Asian populations. In a Japanese prospective population-based cohort study of 18 773 participants, we collected tumor tissues from incident colorectal cancer cases and evaluated KRAS (Kirsten rat sarcoma viral oncogene homolog) and BRAF (v-raf murine sarcoma viral oncogene homolog B) mutation status using target sequencing. Multivariable-adjusted Cox proportional hazard model was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for associations of smoking with the risk of overall colorectal cancer and its subtypes defined by KRAS and BRAF mutation status. Among 339 cases, KRAS and BRAF mutations were identified in 164 (48.4%) and 16 (4.7%) cases, respectively. The multivariable-adjusted HR for ever smoking compared with never smoking was 1.24 [95% CI: 0.93-1.66], 1.75 [1.14-2.68], 0.87 [0.59-1.29], 1.24 [0.93-1.67] and 1.22 [0.38-3.93] for overall, KRAS wild-type, KRAS-mutated, BRAF wild-type and BRAF-mutated colorectal cancer, respectively. The statistically significant heterogeneity was indicated between KRAS mutation status (Pheterogeneity = 0.01) but not between BRAF mutation status. This study is the first to demonstrate that smokers have an approximately 2-fold higher risk of KRAS wild-type colorectal cancer than never smokers in an Asian population. Our findings support that smoking is a risk factor for colorectal cancer, especially for its subtype without KRAS mutations, in Asian populations.

FIGO staging of endometrial cancer: 2023.

Many advances in the understanding of the pathologic and molecular features of endometrial cancer have occurred since the FIGO staging was last updated in 2009. Substantially more outcome and biological behavior data are now available regarding the several histological types. Molecular and genetic findings have accelerated since the publication of The Cancer Genome Atlas (TCGA) data and provide improved clarity on the diverse biological nature of this collection of endometrial cancers and their differing prognostic outcomes. The goals of the new staging system are to better define these prognostic groups and create substages that indicate more appropriate surgical, radiation, and systemic therapies. The FIGO Women's Cancer Committee appointed a Subcommittee on Endometrial Cancer Staging in October 2021, represented by the authors. Since then, the committee members have met frequently and reviewed new and established evidence on the treatment, prognosis, and survival of endometrial cancer. Based on these data, opportunities for improvements in the categorization and stratification of these factors were identified in each of the four stages. Data and analyses from the molecular and histological classifications performed and published in the recently developed ESGO/ESTRO/ESP guidelines were used as a template for adding the new subclassifications to the proposed molecular and histological staging system. Based on the existing evidence, the substages were defined as follows: Stage I (IA1): non-aggressive histological type of endometrial carcinoma limited to a polyp or confined to the endometrium; (IA2) non-aggressive histological types of endometrium involving less than 50% of the myometrium with no or focal lymphovascular space invasion (LVSI) as defined by WHO criteria; (IA3) low-grade endometrioid carcinomas limited to the uterus with simultaneous low-grade endometrioid ovarian involvement; (IB) non-aggressive histological types involving 50% or more of the myometrium with no LVSI or focal LVSI; (IC) aggressive histological types, i.e. serous, high-grade endometrioid, clear cell, carcinosarcomas, undifferentiated, mixed, and other unusual types without any myometrial invasion. Stage II (IIA): non-aggressive histological types that infiltrate the cervical stroma; (IIB) non-aggressive histological types that have substantial LVSI; or (IIC) aggressive histological types with any myometrial invasion. Stage III (IIIA): differentiating between adnexal versus uterine serosa infiltration; (IIIB) infiltration of vagina/parametria and pelvic peritoneal metastasis; and (IIIC) refinements for lymph node metastasis to pelvic and para-aortic lymph nodes, including micrometastasis and macrometastasis. Stage IV (IVA): locally advanced disease infiltrating the bladder or rectal mucosa; (IVB) extrapelvic peritoneal metastasis; and (IVC) distant metastasis. The performance of complete molecular classification (POLEmut, MMRd, NSMP, p53abn) is encouraged in all endometrial cancers. If the molecular subtype is known, this is recorded in the FIGO stage by the addition of "m" for molecular classification, and a subscript indicating the specific molecular subtype. When molecular classification reveals p53abn or POLEmut status in Stages I and II, this results in upstaging or downstaging of the disease (IICmp53abn or IAmPOLEmut ). The updated 2023 staging of endometrial cancer includes the various histological types, tumor patterns, and molecular classification to better reflect the improved understanding of the complex nature of the several types of endometrial carcinoma and their underlying biologic behavior. The changes incorporated in the 2023 staging system should provide a more evidence-based context for treatment recommendations and for the more refined future collection of outcome and survival data.

New Biomarkers and Treatment Advances in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a specific subtype of breast cancer lacking hormone receptor expression and HER2 gene amplification. TNBC represents a heterogeneous subtype of breast cancer, characterized by poor prognosis, high invasiveness, high metastatic potential, and a tendency to relapse. In this review, the specific molecular subtypes and pathological aspects of triple-negative breast cancer are illustrated, with particular attention to the biomarker characteristics of TNBC, namely: regulators of cell proliferation and migration and angiogenesis, apoptosis-regulating proteins, regulators of DNA damage response, immune checkpoints, and epigenetic modifications. This paper also focuses on omics approaches to exploring TNBC, such as genomics to identify cancer-specific mutations, epigenomics to identify altered epigenetic landscapes in cancer cells, and transcriptomics to explore differential mRNA and protein expression. Moreover, updated neoadjuvant treatments for TNBC are also mentioned, underlining the role of immunotherapy and novel and targeted agents in the treatment of TNBC.

The relationship between the change with neoadjuvant chemotherapy in the tumor-infiltrating lymphocyte (TIL) expressions and pathological response in breast cancer patients.

3114 Background: Many prognostic biomarkers for survival have been studied in the neoadjuvant setting for locally advanced breast cancer (LABC). Our study assessed the correlation between the change in tumour-infiltrating lymphocytes (TIL) before and after neoadjuvant chemotherapy (NAC) in breast tissue and its impact on survival in patients with LABC. Methods: Eighty-four LACB patients were retrospectively analysed in this study. TIL was assessed by means of immunohystochemistry (Eclipse Ni, Nikon, Japan) in paraffin-embedded blocks obtained by core-needle biopsy or surgical specimen with respect to the 'TIL working group' criteria. Results: TIL scores were grouped as 0%, &lt;10%, 10-50%, and &gt;50%, the median TIL percentage was 17.5% before NAC and 5% after NAC, and the difference was statistically significant (p&lt;0.001). Postop-Ki-67 (p=0.005), molecular subtype (p=0.027), pre-NAC TIL score (p=0.006), post-NAC TIL score (p&lt;0.001), postop-Ki-67 (p=0.005) and preoperative residual cancer burden tumour-infiltrating lymphocyte (RCB-TIL) (p&lt;0.001) were significantly correlated with pCR. Higher TIL scores were significantly associated with higher PCR rates. Univariate analysis for disease-free survival (DFS) and overall survival (OS) revealed that postop-Ki-67 level and presence of pCR and postoperative ki-67 score (p=0.031) were significant prognostic factors, respectively. The independent prognostic factor for DFS were postop-Ki-67 score (p=0.012, RR: 6.16, 95% CI: 1.48-9.12), post-NAC TIL score (p=0.041, RR: 0.42, 95% CI: 0.16-1.06) and the presence of pCR (p=0.038, RR: 0.10, 95% CI: 0.01-0.87). Logistic regression analysis showed that a preoperative ki-67 score greater than 14% (p=0.001, OR: 4.55; 95% CI: 0.11-1.49), a postoperative ki-67 score equal to or lower than 14% (p=0.011, OR: 1.10; 95% CI: 0.42-2.29), preop-grade 3 (p=0.01, OR: 2.65; 95% CI: 0.85-3.14), low postop-TIL score (p&lt;0.001, OR: 3.14; 95% CI: 0.79-4.11) were significant predictive factors for pCR. Conclusions: Our study confirms the hypothesis that TIL expressions may be therapeutic targets, especially in specific molecular breast cancer subtypes.

PIM1 GENETIC ALTERATIONS ASSOCIATED WITH DISTINCT MOLECULAR PROFILES, PHENOTYPES AND DRUG RESPONSES IN DIFFUSE LARGE B‐CELL LYMPHOMA

Background: PIM1 is one of somatic hypermutation genes in diffuse large B-cell lymphoma (DLBCL). Characterization of a specific molecular subtype with PIM1 genetic alterations is warranted in order to design better personalized therapy for this inferior prognosis patients. The study aims to explore PIM1 genetic alterations and its value in identifying high risk patients and guiding individualized treatment strategies. Methods: NGS targeted sequencing was performed on 162 samples from 2008 to 2018 at Tianjin Medical University Cancer Institute&Hospital to detect 307 lymphoma-related gene mutations. All patients' genomic landscape, PIM1 mutation type and gene mutual exclusivity and co-occurrence were analysed. Transcriptome sequencing was performed on 140 DLBCL patients and differential gene expression analysis, protein-protein interaction analysis, Gene Ontology (GO) and Kyoto Encyclopedia of Genesand Genomes (KEGG) analyses were also performed. Besides, a PIM1 mutation-related gene signature was established and predicted the therapeutic response of common chemotherapeutic and targeted drugs. Results: We observed that PIM1 mutations characterized by predominant missense and nonsense mutations and frameshift deletions mainly occurred in protein kinases domain, leading to a deleterious event, and uncovered that SETD1B, CD79B, MYD88 and PRDM1 mutations were enriched and SPEN mutation excluded with PIM1 mutations. Besides, PIM1-mutated DLBCL conferring a typical mutational signature involved in disorder the tumor microenvironment, JAK-STAT and NF-κB signaling pathways. Patients with PIM1 mutations were characterized by higher IPI scores, more frequent disease relapse and testis and/or CNS involvement, as well as inferior progression-free survival and overall survival. A novel PIM1 mutation-related gene signature indicated distinct phenotypes and served as a promising biomarker for risk stratification. Patients with high-risk score had higher response to TGFβ receptor inhibitors (SB525334, SB505124), Lenalidomide, NF-κB inhibitors (Parthenolide, TPCA-1) and JAK inhibitors (Ruxolitinib, TG101348). Conclusions: Taken together, our findings provide novel insights into the pathogenic role of PIM1 mutations and highlights personalized therapy strategies for treatment of PIM1-mutated DLBCL patients. Keywords: aggressive B-cell non-Hodgkin lymphoma, bioinformatics, computational and systems biology, diagnostic and prognostic biomarkers No conflicts of interests pertinent to the abstract.

“Surface epithelial slackening” pattern in endometrioid carcinoma: A morphological feature for differentiating the POLE mutation-subtype from the no specific molecular profile subtype

Endometrial cancers are classified into mismatch repair (MMR) deficient- (MMRd), p53 mutation- (p53mut), DNA polymerase epsilon (POLE) mutation (POLEmut), and no specific molecular profile (NSMP) subtypes according to The Cancer Genome Atlas (TCGA). The distinction between POLEmut and NSMP subtypes is made on the basis of molecular analysis because the specific histological and immunohistochemical features of these two subtypes are still unknown. In this study, we analyzed histological features by scoring the presence of a mucinous pool, giant cells, clear cells, keratinization, neutrophilic abscess, and surface proliferating pattern in 82 cases of endometrial cancers in which an integrative diagnosis was confirmed by immunohistochemistry and genomic profiles showing POLE mutations, tumor mutation burden, and microsatellite instability. In contrast to the hierarchical branching of micropapillary proliferation observed in serous carcinoma, POLEmut-subtype endometrioid carcinomas often showed a surface epithelial slackening (SES) pattern in the tumor cells facing the uterine surface. The POLEmut subtype exhibited higher scores for clear cells and SES patterns than the other three subtypes. The scores for giant cells, clear cells, and the SES pattern were significantly higher in the POLEmut subtype than in the NSMP subtype, suggesting that these morphometric parameters are useful for differentiating POLEmut- and NSMP-subtype endometrioid carcinomas, although genomic profiling is still necessary for a definite molecular diagnosis.

Short Tandem Repeat DNA Profiling Using Perylene-Oligonucleotide Fluorescence Assay.

We report an amplification-free genotyping method to determine the number of human short tandem repeats (STRs). DNA-based STR profiling is a robust method for genetic identification purposes such as forensics and biobanking and for identifying specific molecular subtypes of cancer. STR detection requires polymerase amplification, which introduces errors that obscure the correct genotype. We developed a new method that requires no polymerase. First, we synthesized perylene-nucleoside reagents and incorporated them into oligonucleotide probes that recognize five common human STRs. Using these probes and a bead-based hybridization approach, accurate STR detection was achieved in only 1.5 h, including DNA preparation steps, with up to a 1000-fold target DNA enrichment. This method was comparable to PCR-based assays. Using standard fluorometry, the limit of detection was 2.00 ± 0.07 pM for a given target. We used this assay to accurately identify STRs from 50 human subjects, achieving >98% consensus with sequencing data for STR genotyping.

Multimodal ultrasound features of breast cancers: correlation with molecular subtypes

ObjectivesTo investigate whether multimodal intratumour and peritumour ultrasound features correlate with specific breast cancer molecular subtypes.MethodsFrom March to November 2021, a total of 85 patients with histologically proven breast cancer underwent B-mode, real-time elastography (RTE), colour Doppler flow imaging (CDFI) and contrast-enhanced ultrasound (CEUS). The time intensity curve (TIC) of CEUS was obtained, and the peak and time to peak (TTP) were analysed. Chi-square and binary logistic regression were used to analyse the connection between multimodal ultrasound imaging features and breast cancer molecular subtype.ResultsAmong 85 breast cancers, the subtypes were as follows: luminal A (36 cases, 42.4%), luminal B (20 cases, 23.5%), human epidermal growth factor receptor-2 positive (HER2+) (16 cases, 18.8%), and triple negative breast cancer (TNBC) (13 cases, 15.3%). Binary logistic regression models showed that RTE (P < 0.001) and CDFI (P = 0.036) were associated with the luminal A cancer subtype (C-index: 0.741), RTE (P = 0.016) and the peak ratio between intratumour and corpus mamma (P = 0.036) were related to the luminal B cancer subtype (C-index: 0.788). The peak ratio between peritumour and intratumour (P = 0.039) was related to the HER2 + cancer subtype (C-index: 0.859), and CDFI (P = 0.002) was associated with the TNBC subtype (C-index: 0.847).ConclusionsMultimodal ultrasound features could be powerful predictors of specific breast cancer molecular subtypes. The intra- and peritumour CEUS features play assignable roles in separating luminal B and HER2 + breast cancer subtypes.