Comprehensive germline and somatic profiling of high-risk Thai breast cancer via next-generation sequencing

Abstract

Breast cancer genomic landscapes differ across ethnic groups, yet the somatic profile of Thai breast tumours has remained uncharacterised. This study analysed 1676 high-hereditary-risk Thai breast cancer patients, identified according to National Comprehensive Cancer Network (NCCN) guideline. Germline alterations were assessed in 1370 cases using a custom 36-core cancer panel. Somatic mutations were characterised in formalin-fixed, paraffin-embedded tumour tissues from 180 of the 1676 patients using the 501-gene Oncomine Comprehensive Assay Plus panel. Pathogenic or likely pathogenic (P/LP) variants were detected in 13% of the 1370 germline analyses, with BRCA1 and BRCA2 being the most frequently altered genes. The prevalence of P/LP variants in BRCA1, BRCA2, and PALB2 differed from that observed in other ethnic cohorts. In somatic profiling, TP53 emerged as the most frequently mutated gene, especially in HER2 and TNBC tumours, whereas MAP3K1 and GATA3 were the most frequently mutated genes in the HR+/HER2- tumours. Moreover, hormone-receptor-positive (HR+) tumours showed distinct mutation patterns compared with other ethnicities. Notably, germline carriers exhibited lower PIK3CA mutation rates than non-carriers. These findings advance our understanding of Thai breast cancer genomics and underscore the importance of ethnic diversity in cancer research, offering insights into tailored screening and therapeutic approaches.

Keywords: Breast cancer; Genomic landscape; Next-generation sequencing; Somatic mutation.

Fig. 1

Germline mutation landscape in Thai breast cancer patients and comparison with other ethnicities. (A) Landscape of pathogenic/likely pathogenic variants in 1370 Thai breast cancer patients. (B) Comparison of the 10 most frequently mutated genes (high- and moderate-penetrance genes) in Thai patients with those in high-risk Caucasian and Chinese cohorts.

Fig. 2

Somatic landscape and characterisation of Thai breast tumours. (A) Somatic mutation landscape of 180 Thai breast tumours, classified by molecular subtype. The first column of percentage frequencies represents the frequency of mutated genes in the overall sample set. (B) Clinically relevant subtype-specific mutated genes. Asterisks indicate somatic mutations associated with molecular subtypes. (C) Co-occurrence and mutual exclusivity of somatic mutations in 180 Thai breast tumours. Co-occurrence refers to cases in which two genes tend to be mutated together in the same sample. (D) Landscape of somatic copy number variations (CNVs) in 170 formalin-fixed, paraffin-embedded (FFPE) breast tumour tissues, classified by molecular subtype.

Fig. 3

Somatic alterations in oncogenic signalling pathways. (A) Somatic alterations in oncogenic signalling pathways in 180 FFPE breast tumour tissues from Thai breast cancer patients, classified by molecular subtype. The first column of percentage frequencies represents the prevalence of pathway mutations in the overall sample set. (B) Significant enrichment of oncogenic pathway mutations in different molecular subtypes (P < 0.05; FDR < 0.25). Significant associations with subtype were identified using two-tailed Fisher’s exact tests. ‘Rest’ refers to all other subtypes.

Fig. 4

Population-specific somatic mutations in Thai breast cancer patients compared with other ethnic cohorts. (A) Comparison of the prevalence of mutations in major breast cancer driver genes in Thai patients and Caucasian cohorts (TCGA), classified by ER+/HER2−, HER2, and TNBC status. (B) Comparison with Caucasian (METABRIC) and Malaysian cohorts, classified by ER + and ER − status. (C) Comparison of PIK3CA mutation rates in non-germline carriers and other ethnic cohorts. Significance was determined using two-tailed Fisher’s exact tests.

Fig. 5

Clinical impact and germline–somatic mutation interactions in Thai breast tumours. (A) Kaplan‒Meier survival curve for Thai breast tumours harbouring co-mutations in TP53 and PTEN. (B) Comparison of somatic mutation prevalence across all mutated genes in tumours from carriers with and without germline mutations (* P = 0.03; ** P = 0.004). (C) Oncoplot illustrating somatic mutation profiles in tumours with and without germline mutations. Asterisks (*) indicate significant differences in mutation frequency between the two groups. (D) Somatic mutation landscape of tumours harbouring germline BRCA1/2 mutations.