Pathogenic Variant Profile of Hereditary Cancer Syndromes in a Vietnamese Cohort

Abstract

Background: Hereditary cancer syndromes (HCS) are responsible for 5-10% of cancer cases. Genetic testing to identify pathogenic variants associated with cancer predisposition has not been routinely available in Vietnam. Consequently, the prevalence and genetic landscape of HCS remain unknown.

Methods: 1165 Vietnamese individuals enrolled in genetic testing at our laboratory in 2020. We performed analysis of germline mutations in 17 high- and moderate- penetrance genes associated with HCS by next generation sequencing.

Results: A total of 41 pathogenic variants in 11 genes were detected in 3.2% individuals. The carrier frequency was 4.2% in people with family or personal history of cancer and 2.6% in those without history. The percentage of mutation carriers for hereditary colorectal cancer syndromes was 1.3% and for hereditary breast and ovarian cancer syndrome was 1.6%. BRCA1 and BRCA2 mutations were the most prevalent with the positive rate of 1.3% in the general cohort and 5.1% in breast or ovarian cancer patients. Most of BRCA1 mutations located at the BRCA C-terminus domains and the top recurrent mutation was NM_007294.3:c.5251C>T (p.Arg1751Ter). One novel variant NM_000038.6(APC):c.6665C>A (p.Pro2222His) was found in a breast cancer patient with a strong family history of cancer. A case study of hereditary cancer syndrome was illustrated to highlight the importance of genetic testing.

Conclusion: This is the first largest analysis of carrier frequency and mutation spectrum of HCS in Vietnam. The findings demonstrate the clinical significance of multigene panel testing to identify carriers and their at-risk relatives for better cancer surveillance and management strategies.

Keywords: BRCA1; carrier frequency; genetic carrier screening; hereditary cancer syndrome; pathogenic variant.

Figure 1

Types and frequency of all pathogenic variants. (A) Percentage of participants positive for at least one pathogenic variant in the general cohort and in subgroups with or without history (Hx) of cancer. (B) Percentage of pathogenic variant carriers for individual gene. (C) Percentage of carriers (n=37) harboring 1, 2 or 3 pathogenic variants. (D) Distribution of molecular consequences (nonsense, missense and frameshift) among the 41 pathogenic variants. The frequency of different molecular consequences for each gene was illustrated.

Figure 2

Pathogenic variants associated with Hereditary Colorectal Cancer syndromes. (A) Percentage of participants positive for at least one pathogenic variant in the genes associated with Hereditary Colorectal Cancer Syndromes (HCCS): Lynch syndrome (MLH1, MSH2, MSH6, PMS2, EPCAM), familial adenomatous polyposis (FAP) (APC), MUTYH-associated adenomatous polypopsis (MAP) (MUTYH). The percentage of carriers by gender and number of variants was also illustrated. (B) Pie chart showing the distribution of pathogenic variants among the HCCS-associated genes. No variant was found in EPCAM and MSH2. (C) Lollipop plot reporting distribution of all pathogenic variants identified in MSH6. Protein domains shown include PWWP (Pro-Trp-Trp-Pro) and all Mutator S (MutS) domains.

Figure 3

Pathogenic variants associated with Hereditary Breast and Ovarian Cancer syndrome. (A) Percentage of participants positive for at least one pathogenic variant in the genes associated with the Hereditary Breast and Ovarian Cancer (HBOC) syndrome: BRCA1/2 and others: PALB2, TP53. No variant was identified in CDH1, STK11 and PTEN. (B) Percentage of participants with breast or ovarian cancer that harbored pathogenic variants in HBOC-associated genes. Apart from pathogenic variants, variants of uncertain significance (VUS) and a novel variant were identified in these patients. (C) Lollipop plot reporting distribution of all pathogenic variants identified in the BRCA1 and BRCA2 genes. Protein domains shown in BRCA1 include Zinc finger (ZF), Ethylene insensitive 3 (EIN3), BRCA1 C-Terminus domain 1 (CT1) and domain 2 (CT2). Protein domains shown in BRCA2 include BRC repeats (orange), helical domain, oligonucleotide/oligosaccharide-binding domain 1 (OB1) and domain 3 (OB3).

Figure 4

A cancer family pedigree with multiple affected members indicating hereditary cancer syndrome. The proband III.2 was diagnosed with gastric cancer at the age of 31 years old. Genetic testing revealed 2 pathogenic variants in the CDH1 and MUTYH genes. Other family members and relatives were labeled for the presence of cancer and mutation status.