Professor Zhang Kai of the Cancer Hospital, Chinese Academy of Medical Sciences: Germline Mutations Strongly Linked to Cancer Risk, Enabling Early Tumor Detection

On July 10, 2021, Genetron Health Research Institute, in collaboration with Suzhou BioBAY, jointly hosted the 5th Annual Conference on Tumor Gene Big Data. The conference brought together nearly 300 leading scholars from around the world, including Academician Cheng Shujun of the Chinese Academy of Engineering and Academician Yang Huanming of the Chinese Academy of Sciences. Under the theme “Multi-omics · New Opportunities in Genomics,” the event explored the new landscape enabled by multi-omics technologies and the boundless new opportunities arising from gene big data.

At the New Applications Forum on the afternoon of the 10th, Professor Zhang Kai, Deputy Director of the Department of Cancer Prevention at the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital of the Chinese Academy of Medical Sciences, delivered a presentation titled “Big Data-Driven Genetic Risk Assessment in the Chinese Population Empowers Precision Cancer Prevention.” He shared insights on the importance of germline mutations in cancer genetic risk assessment, future development directions, and research progress on germline mutations in the Chinese population. VCBeat has compiled his key viewpoints.

Is Cancer a Hereditary Disease? This Question Remains Unanswered to DateHowever, extensive research has demonstrated that individuals born with specific gene mutations (germline mutations) face a significantly increased risk of developing cancer. Most genes associated with hereditary cancer risk are tumor suppressor genes, which play critical roles in biological processes such as DNA damage repair and the cell cycle. Mutations in these tumor suppressor genes can lead to loss or reduction of function, thereby substantially elevating cancer risk in mutation carriers compared to the general population. For example, individuals carrying BRCA1 gene mutations have a markedly elevated risk of multiple cancers; specifically, women with this mutation have a 40%–80% lifetime risk of developing breast cancer and an 11%–40% lifetime risk of developing ovarian cancer.

Previously, scientists believed that hereditary familial tumors accounted for approximately 5% of all cancer cases. However, recent studies have revealed that the prevalence of germline mutations is significantly higher than previously thought. Therefore, when conducting health assessments for individuals at genetic risk of tumors, greater consideration should be given to germline mutations. Relying solely on traditional methods based on family and personal history to assess genetic cancer risk has several limitations, including high rates of missed diagnoses due to screening gaps, incomplete penetrance, and the need for prolonged follow-up.

Currently, multiple research projects on genetic risk assessment for cancer have been conducted worldwide based on genomics, demonstrating the value of germline mutations in genetic risk assessment.

Memorial Sloan Kettering Cancer Center analyzed 76 cancer susceptibility genes in 1,040 patients using dual-sample sequencing (somatic and germline), identifying 182 clinically significant mutations. If traditional methodologies relying solely on family history and phenotypic characteristics had been used, 101 patients without such histories or features would have been missed, resulting in false negatives.

Regarding individual cancer types, the Tulane Cancer Center at Tulane University enrolled 3,607 patients with prostate cancer, among whom the germline mutation carrier rate was 17.2%; BRCA1/2 gene mutations were more prevalent in individuals of Western ancestry, with a carrier rate of 30.7%. An international multicenter study enrolled 289 patients with pancreatic cancer and found a germline variant carrier rate of approximately 10%, with biallelic inactivation events occurring in 44.4% of patients carrying germline variants. The Dana-Farber Cancer Institute enrolled 306 cases of inflammatory breast cancer and identified a germline pathogenic mutation carrier rate of 14.4%.

Multiple studies cited above have shown that the prevalence of germline variants ranges from 10% to 20% across various common malignant cancers, significantly higher than the previously estimated 5%. This is particularly significant for pancreatic cancer, which currently lacks effective early screening methods; germline mutation testing plays a crucial role in the early detection of this disease.

To investigate the germline mutation carrier rate in the Chinese population and provide better guidance for cancer health management, Professor Zhang Kai’s team leveraged the Genetron Health database to report on the test results of nearly 30,000 large-panel samples. The study analyzed 94 tumor-associated genes and identified a total of 2,473 pathogenic or likely pathogenic mutations in 2,354 patients. Analysis of germline variants in common cancers revealed that germline mutations are widely distributed across various cancer types, predominantly in breast cancer, ovarian cancer, and colorectal cancer.

Germline mutations are also present in pancreatic cancer. Pancreatic cancer is associated with extremely high mortality, poor prognosis, significant challenges in early detection, and difficulty in defining high-risk populations. Establishing germline mutation testing as a reference standard for assessing hereditary risk in pancreatic cancer can facilitate early prevention, early detection, and early treatment. Professor Zhang Kai believes that germline mutations are likely to become a breakthrough point for the early prevention and screening of pancreatic cancer.

By analyzing common germline mutations in the Chinese population, such as those in BRCA, ATM, and MUTYH, Professor Zhang Kai found that colorectal cancer patients with MSH6 and PMS2 mutations had a later age of onset compared to other patients, while breast cancer patients with BRCA1 mutations developed the disease at a significantly earlier age than others.

International guidelines have recognized the impact of different mutations on the age of onset and provide varying recommended screening ages for individuals with specific mutations. Corresponding adjustments have also been made in Chinese guidelines. For instance, the guideline-recommended management plan for Lynch syndrome states that carriers of MLH1 or MSH2 mutations should begin colorectal cancer screening at age 20–25 years; if the youngest age at diagnosis of colorectal cancer in the family is under 30 years, screening should commence 2–5 years earlier than that age. Carriers of MSH6 or PMS2 mutations should begin colorectal cancer screening at age 25–30 years; if the youngest age at diagnosis of colorectal cancer in the family is under 30 years, screening should commence 2–5 years earlier than that age.

Furthermore, this study demonstrates that germline mutations lack well-defined hotspots, necessitating comprehensive testing. It also reveals that common somatic hotspots can harbor germline variants, thereby providing new insights and directions for the clinical management of cancer.

Leveraging the Chinese Population Germline Mutation Research Project, Professor Zhang Kai supervised the development of a genetic risk assessment mini-program. This tool focuses on four major hereditary syndromes: Hereditary Breast and Ovarian Cancer Syndrome, Li-Fraumeni Syndrome, Lynch Syndrome, and Gastrointestinal Polyposis Syndromes. These four syndromes encompass the most common germline mutations in the Chinese population. The mini-program enables one-click online assessment of hereditary cancer risk, automatically generates pedigree charts, and facilitates clinical genetic counseling by identifying individuals who should undergo genetic testing for hereditary cancer risk, thereby significantly improving efficiency.