On July 6, 2022, the research team led by Dr. Yu Wenqiang at the Research Institute of Fudan University affiliated with the Fudan University Shanghai Cancer Center, in collaboration with the team at the Airforce Medical University's Xijing Hospital, identified the third pan-cancer biomarker, SIX6. They revealed its applications in early detection, metastatic risk prediction, and assisting surgical margin assessment in various clinical scenarios of lung cancer, breast cancer, cervical cancer, endometrial cancer, and urinary tract epithelial cancer. Their findings were published in the Nature subjournal Signal Transduction and Targeted Therapy (IF=38.104).
Dr. Yu Wenqiang's team at Fudan University had previously published significant results related to pan-cancer biomarkers, including the first pan-cancer biomarker HIST1H4F in the official journal of the American Cancer Society, Cancer Research (IF=13.312) in 2019, the second pan-cancer biomarker PCDHGB7 in the well-known journal Clinical and Translational Medicine (IF=11.492) in 2021, and the use of PCDHGB7 in early screening for endometrial cancer in the international academic journal Frontiers in Molecular Biosciences (IF=6.113) in 2022. With a single biomarker detection, simple precision, and unlimited potential applications, pan-cancer biomarkers are immensely promising!
Early screening for cancer is a crucial step in overcoming the disease.
Cancer ranks as the second leading cause of death globally. In 2020, there were approximately 19.29 million new cancer cases worldwide, resulting in about 10 million cancer-related deaths. In China, cancer is the leading cause of death. In 2020, there were approximately 4.57 million new cancer cases and 3 million cancer-related deaths in China, accounting for 23.7% and 30.2% of global cancer incidence and mortality, respectively. The chances of survival for almost all cancers significantly increase if they are detected, diagnosed, and treated early. Yet, around 50% of cancer cases are diagnosed at an advanced stage due to inherent limitations of existing diagnostic and treatment methods, economic costs, and limited access to medical resources. Late-stage malignant tumors have lower survival rates. Therefore, early cancer screening and timely intervention can effectively arrest cancer progression and reduce incidence and mortality rates.Existing screening methods, such as imaging and endoscopic screening, are difficult to widely implement and often lag behind in detection timing. In recent years, molecular biomarker-based cancer early screening has gained more attention, but its actual clinical applications are few and far between. There is an urgent need to discover more effective molecular biomarkers. Furthermore, the vast majority of existing biomarkers are specific to certain types of cancer, and there are few reports on biomarkers that can be used for screening multiple cancer types. Dr. Yu Wenqiang's team at Fudan University has been deeply engaged in cancer biomarker research and has discovered a series of pan-cancer biomarkers, allowing a single biomarker to be used for detecting multiple cancers in various clinical scenarios, taking the research and application of cancer methylation biomarkers to new heights.
The third discovered pan-cancer biomarker, SIX6DNA methylation abnormalities are critical events in the development of cancer.
Extensive research has found low methylation of the entire genome sequence and abnormal high methylation at specific sites in tumors, which can be used for early cancer screening. DNA methylation also has inherent advantages in terms of stability and specificity in detection, but there are many barriers and bottlenecks in practical application due to sequencing technology and cost issues. Therefore, the research team at Fudan University previously built the Guide Positioning Sequencing (GPS) technology for whole-genome DNA methylation detection, achieving a significant breakthrough in accuracy and coverage. Applying this technology, the team discovered a site of high methylation, HIST1H4F, in multiple cancer types, proposed the concept of "pan-cancer biomarkers," and demonstrated the potential clinical utility of high methylation of HIST1H4F in lung cancer screening. Subsequently, through rigorous search, the team identified the second pan-cancer biomarker, PCDHGB7, and used it for early detection of cervical cancer. Remarkably, pan-cancer biomarkers can advance cervical cancer screening to the stage of high-grade lesion, truly achieving cancer prevention.In their continuous exploration of the potential applications of early pan-cancer biomarkers, the research team discovered another area of tumor cell differential methylation. The SIX6 gene attracted special attention. Apart from its traditional roles in tissue formation and organ development, the SIX6 gene also promotes epithelial-mesenchymal transition and metastasis, exerting tumor regulatory functions. The research team verified in 7,010 samples from 15 cancer types in the TCGA sample database that high methylation of the SIX6 site was universal in tumor samples. Furthermore, through the collection of 678 clinical samples from 10 common cancers, the team once again demonstrated that high methylation of SIX6 is a new pan-cancer biomarker.
Pan-cancer biomarkers position cancer detection at the pre-cancer stage, turning daydreams into reality.
An essential aspect of early cancer screening is the "early" detection of high methylation in SIX6. In the TCGA database samples with clear staging, the research team found that high methylation of SIX6 appeared in stage I (localized cancer) of 12 different tumors. Treatment at this stage corresponds to higher survival rates and better prognoses. Subsequently, it was confirmed in clinical samples that high methylation of SIX6 appeared in the early stages of lung, breast, and cervical cancer, and remained stable in the subsequent stages of cancer development. This indicates that SIX6 is suitable for comprehensive monitoring of multiple cancers.Given the long-term evolution of tumors, the research team further investigated whether high methylation of SIX6 occurred at an earlier stage in the tumor development timeline. For this, the research team selected samples of cervical and stomach cancer with characteristics of staged progression and found that compared to low-grade squamous intraepithelial lesions (LSIL), SIX6 in high-grade squamous intraepithelial lesions (HSIL) already exhibited significantly high methylation levels, similar to cervical cancer (CC). Similarly, samples at high stomach cancer risk (HGCR, including atrophic gastritis and HSIL) exhibited higher SIX6 methylation levels compared to low stomach cancer risk (LGCR, including chronic non-atrophic gastritis, gastritis, and superficial gastritis) samples. This indicates that high methylation of SIX6 is an extremely early event in tumor progression and may serve as an important characteristic of normal cells transforming into pre-cancer cells, with the potential to advance cancer prevention to the pre-cancer stage. To be more user-friendly for clinical screening applications, the research team selected non-invasive cervical swab and urine samples, and respectively verified the appearance of high methylation of SIX6 in the early stages of cervical cancer - HSIL, as well as its significant differentiation between endometrial cancer and benign endometrial disease (BED) and urinary tract epithelial cancer and benign urinary tract epithelial disease (BUD). It exhibited excellent sensitivity and specificity in clinical early screening, providing a significant time advantage and turning the daydream of cancer prevention at the pre-cancer stage into an opportunity to solve the problem, ultimately realizing the dream through efforts.
Catching the "thief" of cancer metastasis, and ensuring "no residue left under the operating room's invisible lamp".
Currently, 20%-30% of cancer cases are already in the advanced stage (regional cancer) when discovered, with cancer cells having spread to nearby lymph nodes, tissues, or organs. Metastasis becomes a critical factor influencing treatment strategy selection and prognosis. Preliminary verification found that high methylation of SIX6 appears earlier. Therefore, can the high methylation of SIX6 be used to "early" detect cancer metastasis? The research team found that in the potential metastatic stage of breast cancer, the lymph nodes of positive metastatic samples were also in a state of high methylation of SIX6, while there was a significant decrease in lymph nodes of negative metastatic samples. This indicates that the methylation detection of SIX6 has enormous potential and advantages in tracing the "early metastasis" of cancer, allowing the selection of a breast cancer treatment not to rely on experience but rely on precise scientific strategies. In addition, in clinical tumor resection surgery, ensuring a complete tumor removal under the invisible light is the common wish of every doctor and patient. The determination of the surgical margin in tumor resection directly determines the prognosis of the tumor, as no one hopes to "miss something under the tumor" during surgery. The analysis of surgical margin samples of gastric cancer by the research team showed that the methylation level of SIX6 in the surgical margin was still higher than that of the relatively normal samples, indicating that high methylation of SIX6 at the molecular level might be earlier and more sensitive in judgment than the current gold standard based on pathological judgment. In other words, tumor margin determination based on pan-cancer biomarkers might be more accurate, achieving the gold standard of determining tumor surgical margins at the epigenetic level, a significant direction for the efforts of the tumor surgery field in the next 10 years. The high methylation of SIX6 can serve as a precise indicator for surgical and prognosis predictions, with significant time and cost efficiency.Although tumors exhibit high heterogeneity, precision medicine based on tumor heterogeneity is currently timely, but the continuous expansion of common characteristics will undoubtedly help the scientific and medical communities better understand the whole picture of tumors. Pan-cancer research based on pan-cancer biomarkers will be an important direction for future cancer research. Simplifying complex problems is undoubtedly one of the essential approaches to solving them. The emergence of pan-cancer biomarkers allows the study of tumors to uncover the inherent nature of tumors through their heterogeneous appearances, and the research into common tumor characteristics will significantly advance tumor research, leading to simple and feasible tumor prevention and treatment strategies. The talk of cancer prevention at the pre-cancer stage should no longer be limited to theoretical discussions on paper, as lowering the cancer incidence is no longer a dream.
Post time: Jan-02-2024