A panel of DNA methylation markers for the classification of consensus molecular subtypes 2 and 3 in patients with colorectal cancer

Consensus molecular subtypes (CMSs) can guide precision treatment of colorectal cancer (CRC). We aim to identify methylation markers to distinguish between CMS2 and CMS3 in patients with CRC, for which an easy test is currently lacking. To this aim, fresh‐frozen tumor tissue of 239 patients with stage I‐III CRC was analyzed. Methylation profiles were obtained using the Infinium HumanMethylation450 BeadChip. We performed adaptive group‐regularized logistic ridge regression with post hoc group‐weighted elastic net marker selection to build prediction models for classification of CMS2 and CMS3. The Cancer Genome Atlas (TCGA) data were used for validation. Group regularization of the probes was done based on their location either relative to a CpG island or relative to a gene present in the CMS classifier, resulting in two different prediction models and subsequently different marker panels. For both panels, even when using only five markers, accuracies were > 90% in our cohort and in the TCGA validation set. Our methylation marker panel accurately distinguishes between CMS2 and CMS3. This enables development of a targeted assay to provide a robust and clinically relevant classification tool for CRC patients.     

Development of miRNA‐based therapeutic approaches for cancer patients

Over the past few decades, siRNA and miRNA have attracted a great deal of attention from researchers and clinicians. These molecules have been extensively studied from the standpoint of developing biopharmaceuticals against various diseases, including heart disease, diabetes and cancers. siRNA suppresses only a single target, whereas each miRNA regulates the expression of multiple target genes. More importantly, because miRNA are also secreted from cancer cells, and their aberrant expression is associated with tumor development and progression, they represent not only therapeutic targets but also promising biomarkers for diagnosis and prognosis. Therefore, miRNA may be more effective tools against cancers, in which multiple signal pathways are dysregulated. In this review, we summarize recent progress in the development of miRNA therapeutics for the treatment of cancer patients, and describe delivery systems for oligonucleotide therapeutics.     

Mammographic density and molecular subtypes of breast cancer

Background:

Gene expression profiling has led to a subclassification of breast cancers independent of established clinical parameters, such as the Sorlie–Perou subtypes. Mammographic density (MD) is one of the strongest risk factors for breast cancer, but it is unknown if MD is associated with molecular subtypes of this carcinoma.

Methods:

We investigated whether MD was associated with breast cancer subtypes in 110 women with breast cancer, operated in Stockholm, Sweden, during 1994 to 1996. Subtypes were defined using expression data from HGU133A+B chips. The MD of the unaffected breast was measured using the Cumulus software. We used multinomial logistic models to investigate the relationship between MD and Sorlie–Perou subtypes.

Results:

Although the distribution of molecular subtypes differed in women with high vs low MD, this was statistically non-significant (P=0.249), and further analyses revealed no association between the MD and Sorlie–Perou subtypes as a whole, nor with individual subtypes.

Conclusion:

These findings suggest that although MD is one of the strongest risk factors for breast cancer, it does not seem to be differentially associated with breast cancer molecular subtypes. However, larger studies with more comprehensive covariate information are needed to confirm these results.     

新疆乳腺癌分子分型的临床病理学意义

目的:回顾性分析新疆维吾尔自治区人民医院病理科确诊的乳腺癌病理资料,探讨新疆地区不同分子分型乳腺癌的临床病理意义.方法:收集2011 年 1 月至2014 年 12 月就诊于新疆维吾尔自治区人民医院并行改良根治手术的 406 例乳腺癌患者的临床病理资料,根据雌激素受体ER、孕激素受体PR、人表皮生长因子受体-2 (HER-2)和 Ki-67 增殖指数进行分子分型,比较不同分子亚型乳腺癌患者的临床病理特征.结果:luminal A型中组织学分级I级最常见,luminal B型发病年龄较luminal A型年轻、但组织学分级更高,淋巴结转移更常见,HER-2过表达型淋巴结转移率最高,三阴性型组织学分级III级比例最高.不同分子分型乳腺癌在肿块大小、组织学分级方面的差异均显示统计学意义(P<0.05).结论:新疆地区luminal B 型乳腺癌更常见,HER-2 过表达型比例最低.联合组织学分类和分子分型,更有助于指导乳腺癌的诊断和治疗.     

A novel cell‐free DNA methylation‐based model improves the early detection of colorectal cancer

Screening for early‐stage disease is vital for reducing colorectal cancer (CRC)‐related mortality. Methylation of circulating tumor DNA has been previously used for various types of cancer screening. A novel cell‐free DNA (cfDNA) methylation‐based model which can improve the early detection of CRC is warranted. For our study, we collected 313 tissue and 577 plasma samples from patients with CRC, advanced adenoma (AA), non‐AA and healthy controls. After quality control, 187 tissue DNA samples (91 non‐malignant tissue from CRC patients, 26 AA and 70 CRC) and 489 plasma cfDNA samples were selected for targeted DNA methylation sequencing. We further developed a cfDNA methylation model based on 11 methylation biomarkers for CRC detection in the training cohort (area under curve [AUC] = 0.90 (0.85–0.94]) and verified the model in the validation cohort (AUC = 0.92 [0.88–0.96]). The cfDNA methylation model robustly detected patients pre‐diagnosed with early‐stage CRC (AUC = 0.90 [0.86–0.95]) or AA (AUC = 0.85 [0.78–0.91]). Here we established and validated a non‐invasive cfDNA methylation model based on 11 DNA methylation biomarkers for the detection of early‐stage CRC and AA. The utilization of the model in clinical practice may contribute to the early diagnosis of CRC.     

Meat subtypes and their association with colorectal cancer: Systematic review and meta‐analysis

Associations between specific red meat subtypes and risk of colorectal cancer (CRC) have been investigated in a number of epidemiological studies. However, no publication to date has summarised the overall epidemiological evidence. We conducted a systematic review and meta‐analysis of prospective studies (cohort, nested case‐control or case‐cohort studies), which reported relative risk (RR) estimates and 95% confidence intervals (CI) for the association between intake of meat subtypes with colorectal, colon or rectal cancer or colorectal adenoma risk. PubMed and ISI Web of Science were searched up until August 1, 2014. Nineteen studies examined meat subtypes (5 beef, 5 pork, 2 lamb, 1 veal and 19 poultry) and associations with colorectal, colon or rectal cancer risk and 4 studies examined associations with adenoma risk (1 beef and 4 poultry). Comparing highest versus lowest intake, beef consumption was associated with an increased risk of CRC (RR = 1.11, 95% CI = 1.01 to 1.22) and colon cancer (RR = 1.24, 95% CI = 1.07 to 1.44), but no association was found with rectal cancer (RR = 0.95, 95% CI = 0.78 to 1.16). Higher consumption of lamb was also associated with increased risk of CRC (RR = 1.24, 95% CI = 1.08 to 1.44). No association was observed for pork (RR = 1.07, 95% CI = 0.90 to 1.27), but some between study heterogeneity was observed. No association was observed for poultry consumption and risk of colorectal adenomas or cancer. This meta‐analysis suggests that red meat subtypes differ in their association with CRC and its sub sites. Further analysis of data from prospective cohort studies is warranted, especially regarding the role of pork.     

基于分子成像的结直肠癌精准诊疗

分子成像是指借助分子成像探针,运用影像学技术反映活体状态下生物体内细胞及分子水平上特定分子的变化,并对其进行定性、定量、定时研究的无创手段.分子成像主要着眼于生物的变化过程,而不是这些变化导致的解剖变化、最终结果.由于分子成像具有上述特征,所以可以动态观察结直肠癌发生发展过程中的生物学行为,能很好克服直肠癌传统成像的不...     

Colorectal cancer intrinsic subtypes predict chemotherapy benefit,deficient mismatch repair and epithelial‐to‐mesenchymal transition

In most colorectal cancer (CRC) patients, outcome cannot be predicted because tumors with similar clinicopathological features can have differences in disease progression and treatment response. Therefore, a better understanding of the CRC biology is required to identify those patients who will benefit from chemotherapy and to find a more tailored therapy plan for other patients. Based on unsupervised classification of whole genome data from 188 stages I–IV CRC patients, a molecular classification was developed that consist of at least three major intrinsic subtypes (A‐, B‐ and C‐type). The subtypes were validated in 543 stages II and III patients and were associated with prognosis and benefit from chemotherapy. The heterogeneity of the intrinsic subtypes is largely based on three biological hallmarks of the tumor: epithelial‐to‐mesenchymal transition, deficiency in mismatch repair genes that result in high mutation frequency associated with microsatellite instability and cellular proliferation. A‐type tumors, observed in 22% of the patients, have the best prognosis, have frequent BRAF mutations and a deficient DNA mismatch repair system. C‐type patients (16%) have the worst outcome, a mesenchymal gene expression phenotype and show no benefit from adjuvant chemotherapy treatment. Both A‐type and B‐type tumors have a more proliferative and epithelial phenotype and B‐types benefit from adjuvant chemotherapy. B‐type tumors (62%) show a low overall mutation frequency consistent with the absence of DNA mismatch repair deficiency. Classification based on molecular subtypes made it possible to expand and improve CRC classification beyond standard molecular and immunohistochemical assessment and might help in the future to guide treatment in CRC patients.     

Epigenetic changes in colorectal cancer

Epigenetic changes frequently occur in human colorectal cancer.Genomic global hypomethylation,gene promoter region hypermethylation,histone modifications,and alteration of miRNA patterns are major epigenetic changes in colorectal cancer.Loss of imprinting(LOI) is associated with colorectal neoplasia.Folate deficiency may cause colorectal carcinogenesis by inducing gene-specific hypermethylation and genomic global hypomethylation.HDAC inhibitors and demethylating agents have been approved by the FDA for myelodysplastic syndrome and leukemia treatment.Non-coding RNA is regarded as another kind of epigenetic marker in colorectal cancer.This review is mainly focused on DNA methylation,histone modification,and microRNA changes in colorectal cancer.     

High‐throughput and multi‐phases identification of autoantibodies in diagnosing early‐stage breast cancer and subtypes

Autoantibodies (AAbs) targeted tumor‐associated antigens (TAAs) have the potential for early detection of breast cancer. Here, 574 early‐stage breast cancer (ES‐BC) patients containing 4 subtypes (Luminal A, Luminal B, HER2+, TN), 126 benign breast disease (BBD) patients, and 199 normal healthy controls (NHC) were separated into three‐phases to discover, verify, and validate AAbs. In discovery phase using high‐throughput protein microarray, 37 AAbs with sensitivity of 31.25%‐86.25% and specificity over 73% in ES‐BC, and 40 AAbs with different positive rates between subtypes were identified as candidates. In verification phase, 18 AAbs were significantly increased compared with the Control (BBD and NHC) in focused array. Ten out of 18 AAbs exhibited a significant difference between subtypes (P < .05). In ELISA validation phase, 5 novel AAbs (anti‐{"type":"entrez-nucleotide","attrs":{"text":"KJ901215","term_id":"649134855","term_text":"KJ901215"}}KJ901215, ‐FAM49B, ‐HYI, ‐GARS, ‐CRLF3) exhibited significantly higher levels in ES‐BC compared with BBD/NHC (P < .05). The sensitivities of individual AAb and a 5‐AAbs panel were 20.41%‐28.57% and 38.78%, whereas the specificities were over 90% and 85.94%. Simultaneously, 4 AAbs except anti‐GARS differed significantly between TN and non‐TN subtype (P < .05). We constructed 3 random forest classifier models based on AAbs to discriminant ES‐BC from Control or BBD, and to discern TN subtype, which yielded an area under the curve of 0.870, 0.860, and 0.875, respectively. Biological interaction analysis revealed 4 TAAs, except for {"type":"entrez-nucleotide","attrs":{"text":"KJ901215","term_id":"649134855","term_text":"KJ901215"}}KJ901215, that were associated with well known proteins of BC. This study discovered and stepwise validated 5 novel AAbs with the potential to diagnose ES‐BC and discern TN subtype, indicating easy‐to‐detect and minimally invasive diagnostic value of serum AAbs ahead of biopsy for future application.     

不同分子亚型乳腺癌的MR表现

目的 探讨不同分子亚型的乳腺癌磁共振（magnetic resonance,MR）表现的差异性。方法 回顾性分析经病理证实的69例乳腺癌患者的术前乳腺MR资料,通过分析MR形态学特征、早期强化率、时间信号强度曲线（time-signal intensity curve,TIC）以及表观扩散系数（apparent diffusion coefficient,ADC）值,对病变进行联合评价。结果 69例乳腺癌患者中,共有62例患者（76个病灶）呈肿块样强化病变,其中Luminal A型乳腺癌8例（11个病灶）,Luminal B型乳腺癌35例（44个病灶）,HER-2过表达型乳腺癌9例（11个病灶）,三阴性乳腺癌10例（10个病灶）。肿块样强化病变中,不同分子亚型乳腺癌的形态差异有统计学意义（χ²=17.006,P=0.002）,其中三阴性乳腺癌形态表现为圆形的比例明显大于其他三组乳腺癌（40.00% vs 10.61%,χ²=6.390,P=0.033）;不同分子亚型乳腺癌的边缘差异亦有统计学意义（χ²=25.502,P=0.001）,其中三阴性乳腺癌边缘清晰比例显著大于其他三组乳腺癌（60.00% vs 10.61%,χ²=14.942,P=0.001）;不同分子亚型乳腺癌的内部强化方式、早期强化率、TIC类型及ADC值的差异无统计学意义（P＞0.05）。。结论 不同分子亚型乳腺癌MR表现上有一定区别,可能有助于区分三阴性乳腺癌和非三阴性乳腺癌,但目前尚不能依据MR表现乳腺癌分子亚型直接预测。     

Pembrolizumab in Asian patients with microsatellite‐instability‐high/mismatch‐repair‐deficient colorectal cancer

The phase 3 KEYNOTE‐177 study evaluated pembrolizumab versus chemotherapy with or without bevacizumab or cetuximab in patients with newly diagnosed, microsatellite‐instability‐high (MSI‐H)/mismatch‐repair‐deficient (dMMR) metastatic colorectal cancer (mCRC). Primary endpoints were progression‐free survival (PFS) per RECIST v1.1 by blinded independent central review (BICR) and overall survival (OS). Secondary endpoints were overall response rate (ORR) per RECIST v1.1 by BICR and safety. Here, we report results from the post hoc analysis of patients who were enrolled in Asia from the final analysis (FA) of KEYNOTE‐177. A total of 48 patients from Japan, Korea, Singapore, and Taiwan (pembrolizumab, n = 22; chemotherapy, n = 26) were included. At FA, median time from randomization to data cutoff (February 19, 2021) was 45.3 (range 38.1–57.8) months with pembrolizumab and 43.9 (range 36.6–55.1) months with chemotherapy. Median PFS was not reached (NR; 95% confidence interval [CI] 1.9 months–NR) with pembrolizumab versus 10.4 (95% CI 6.3–22.0) months with chemotherapy (hazard ratio [HR] 0.56, 95% CI 0.26–1.20). Median OS was NR (range 13.8 months–NR) versus 30.0 (14.7–NR) months (HR 0.65, 95% CI 0.27–1.55) and ORR was 50% (95% CI 28–72) versus 46% (95% CI 27–67). Grade 3/4 treatment‐related adverse events (TRAEs) were reported by two patients (9%) in the pembrolizumab arm and 20 (80%) in the chemotherapy arm. Immune‐mediated adverse events or infusion reactions were reported by six patients (27%) and 10 patients (40%), respectively. No deaths due to TRAEs occurred. These data support first‐line pembrolizumab as a standard of care for patients from Asia with MSI‐H/dMMR mCRC. ClinicalTrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT02563002","term_id":"NCT02563002"}}NCT02563002.