Investigating the prevalence of pathogenic variants in Saudi Arabian patients with familial cancer using a multigene next generation sequencing panel

Abstract

Family history is an important factor in determining hereditary cancer risk for many cancer types. The emergence of next-generation sequencing (NGS) has expedited the discovery of many hereditary cancer susceptibility genes and the development of rapid, affordable testing kits. Here, a 30-gene targeted NGS panel for hereditary cancer risk assessment was tested and validated in a Saudi Arabian population. A total of 310 subjects were screened, including 57 non-cancer patients, 110 index patients with cancer and 143 of the cancer patients' family members, 16 of which also had cancer. Of the 310 subjects, 119 (38.4%) were carriers of pathogenic or likely pathogenic variants (PVs) affecting one or more of the following genes: TP53, ATM, CHEK2, CDH1, CDKN2A, BRCA1, BRCA2, PALB2, BRIP1, RAD51D, APC, MLH1, MSH2, MSH6, PMS2, PTEN, NBN/NBS1 and MUTYH. Among 126 patients and relatives with a history of cancer, 49 (38.9%) were carriers of PVs or likely PVs. Two variants in particular were significantly associated with the occurrence of a specific cancer in this population (APC c.3920T>A - colorectal cancer/Lynch syndrome (p = 0.026); TP53 c.868C>T; - multiple colon polyposis (p = 0.048)). Diverse variants in BRCA2, the majority of which have not previously been reported as pathogenic, were found at higher frequency in those with a history of cancer than in the general patient population. There was a higher background prevalence of genetic variants linked to familial cancers in this cohort than expected based on prevalence in other populations.

Keywords: NGS; cancer; cancer screening; genetic counseling; hereditary cancer syndrome.

Figure 1. Age distributions across cohort subgroups.

Figure 2. Frequencies of PVs and likely PVs per gene, by subject group.

A list of all variants discovered in each patient group, along with any cancer types diagnosed in patients with these variants, can be found in the Supplementary Tables 1 and 4.

Figure 3. Locations of primary cancers.

Some patients have reported multiple cancer types on primary presentation, each patient is counted once.

Figure 4. Workflow diagram.

Subjects were stratified into three groups, their saliva samples were processed and sent for next generation sequencing. Family history was defined, in order to apply to all cancer subgroups, as having one or more relatives (parents, grandparents etc.) with any type of cancer. A breakdown of the relationships to the cancer patient subject demographic data for all subjects are available in Supplementary Table 1.