Beijing Geneplus Technology Co., Ltd.

The differences in the clinical features, prognosis and genetic mutations in Chinese patients with malignant melanoma (MM) and additional primary tumours remain unclear.

A retrospective analysis was conducted on patients with malignancies in Fujian Cancer Hospital from January 2007 to September 2022, end follow-up in September 2023. Clinical data were gathered, survival analysis was performed, and genetic mutations were detected.

There were 58 of 1223 melanoma patients with melanoma and additional primary tumours, an incidence of 4.74%. Acral MM was the most common subtype (26/58), 23 (39.66%) patients had concomitant digestive tumours. Patients who had MM as their first primary tumour (MMFP) had shorter tumour occurrence intervals (9.93 vs. 57.78 months, p = .008) but longer melanoma survival (MM-OS) than the non-MMFP group (100.43 vs. 18.93 months, p = .015). Patients with cancer family histories were more likely to have pathogenic and likely pathogenic (P/LP) mutations (2/5 vs. 4/25). The somatic BRAF gene mutation was frequently observed in MM tissue (8/19, 42.11%). Three patients had whole-genome doubling and microsatellite instability-high (MSI-H). The COSMIC2 signature 3 was significantly higher in the P/LP group.

The frequency of MM and additional primary tumours is about 5% in Chinese populations. Patients with melanoma diagnosed first have longer melanoma survival. Digestive system tumours were the most concomitant; a digestive examination is advisable, especially for those with an expected overall survival (OS) greater than 10 months. Meanwhile, patient's family cancer history should be followed up in detail, along with completion of germline P/LP mutation and somatic mutation testing, all of which may provide valuable support for further treatment.

Colorectal cancer (CRC) genetic testing of regions beyond clinical guidelines has revealed a substantial number of likely pathogenic germline mutations (GMs). It remains largely undetermined whether and how these GMs, typically located in non-mismatch repair (non-MMR) genes, are associated with the tumorigenesis of CRC. This study aimed to identify CRC-predisposing GMs among 93 cancer susceptibility genes and investigate their potential influences on CRC somatic mutational features. We secondarily aimed to investigate whether somatic ERBB2 amplification contributes to identifying GM carriers. This study incorporated a total of 3,240 Chinese CRC patients and 10,588 control individuals. CRC patients were subjected to paired tumor-normal sequencing with a 1,021-gene panel. A case-control analysis was conducted to profile the GM-associated CRC risk. A comprehensive germline-somatic association analysis was performed among 2,405 patients, with key findings subsequently validated in an independent 835-patient cohort and the TCGA CRC cohort. The case-control results supported CRC-predisposing effects of GMs in certain homologous recombination repair (HRR) and DNA damage checkpoint factor (CPF) genes, such as BRCA1/2, RecQ helicase genes, ATM, and CHEK2. HRR GMs were associated with an increased copy number alteration burden, more TP53 clonal mutations, and a higher probability of carrying somatic ERBB2 amplification. CPF GMs were inferred to have synergistic effects with ARID1A and KDM6A somatic mutations in CRC tumorigenesis. Among patients with onset age ≥55 years, stable microsatellites, and no cancer family history, ERBB2 amplification was significantly predictive of GM carriers. Our findings elucidate different germline tumorigenic patterns not driven by deficient MMR. Somatic ERBB2 amplification in CRC can serve as an indicator for germline genetic testing when traditional risk features are absent.

Background: This study aimed to investigate glycogen metabolism in gastric cancer (GC) and develop a glycogen-based riskScore model for predicting GC prognosis. Methods: Patients' expression profiles for 33 tumor types were retrieved from TCGA. Four GC bulk and one single-cell sequencing datasets were obtained from GEO database. This study also enrolled a bladder urothelial carcinoma immunotherapeutic IMvigor210 cohort. The ssGSEA method was conducted to assess glycogen biosynthesis and degradation level. Consensus clustering analysis was conducted to identify different clusters. A glycogen riskScore signature was developed to evaluate prognostic value across different cohorts. Besides, in vitro experiments were conducted to further evaluate the role of glycogen metabolism related genes in GC. Results: Both glycogen biosynthesis and degradation were significantly associated with worse overall survival and were also related with malignant phenotype in GC at both bulk and single-cell levels. Differential outcomes and immune functions were verified in the three identified clusters. The constructed glycogen riskScore model accurately classified GC patients with different outcomes, genomic and immune landscape, and performed well in predicting prognosis through external validation, immunotherapy and pan-cancer cohorts. Furthermore, the riskScore could predict response to chemotherapy and immunotherapy. Functional analyses revealed the signature's connection to pro-tumor and immunosuppression related pathways across pan-cancer. Additionally, glycogen metabolism related genes were found to regulate the malignant phenotypes of GC cells. Conclusion: This study revealed important roles of glycogen metabolism in promoting progression of GC and presented a glycogen riskScore model as a novel tool for predicting prognosis and treatment response.