Dataset Information

The Genomic Landscape of Colorectal Cancer in the Saudi Arabian Population Using a Comprehensive Genomic Panel.

ABSTRACT:

Purpose

Next-generation sequencing (NGS) technology detects specific mutations that can provide treatment opportunities for colorectal cancer (CRC) patients.

Patients and methods

We analyzed the mutation frequencies of common actionable genes and their association with clinicopathological characteristics and oncologic outcomes using targeted NGS in 107 Saudi Arabian patients without a family history of CRC.

Results

Approximately 98% of patients had genetic alterations. Frequent mutations were observed in BRCA2 (79%), CHEK1 (78%), ATM (76%), PMS2 (76%), ATR (74%), and MYCL (73%). The APC gene was not included in the panel. Statistical analysis using the Cox proportional hazards model revealed an unusual positive association between poorly differentiated tumors and survival rates (p = 0.025). Although no significant univariate associations between specific mutations or overall mutation rate and overall survival were found, our preliminary analysis of the molecular markers for CRC in a predominantly Arab population can provide insights into the molecular pathways that play a significant role in the underlying disease progression.

Conclusions

These results may help optimize personalized therapy when drugs specific to a patient's mutation profile have already been developed.

SUBMITTER: Alsolme E

PROVIDER: S-EPMC10527739 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Publications

The Genomic Landscape of Colorectal Cancer in the Saudi Arabian Population Using a Comprehensive Genomic Panel.

Alsolme Ebtehal E Alqahtani Saleh S Fageeh Musa M Barakeh Duna D Sharma Nitesh K NK Mangul Serghei S Robinson Heather A HA Fathaddin Amany A Hauser Charlotte A E CAE Abedalthagafi Malak M

Diagnostics (Basel, Switzerland) 20230919 18

<h4>Purpose</h4>Next-generation sequencing (NGS) technology detects specific mutations that can provide treatment opportunities for colorectal cancer (CRC) patients.<h4>Patients and methods</h4>We analyzed the mutation frequencies of common actionable genes and their association with clinicopathological characteristics and oncologic outcomes using targeted NGS in 107 Saudi Arabian patients without a family history of CRC.<h4>Results</h4>Approximately 98% of patients had genetic alterations. Freq ...[more]

PMID: 37761360

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Project description:BackgroundColorectal cancer (CRC) is a prevalent malignancy with diverse molecular characteristics. The NGS-based approach enhances our comprehension of genomic landscape of CRC and may guide future advancements in precision oncology for CRC patients.MethodIn this research, we conducted an analysis using Next-Generation Sequencing (NGS) on samples collected from 111 individuals who had been diagnosed with CRC. We identified somatic and germline mutations and structural variants across the tumor genomes through comprehensive genomic profiling. Furthermore, we investigated the landscape of driver mutations and their potential clinical implications.ResultsOur findings underscore the intricate heterogeneity of genetic alterations within CRC. Notably, BRAF, ARID2, KMT2C, and GNAQ were associated with CRC prognosis. Patients harboring BRAF, ARID2, or KMT2C mutations exhibited shorter progression-free survival (PFS), whereas those with BRAF, ARID2, or GNAQ mutations experienced worse overall survival (OS). We unveiled 80 co-occurring and three mutually exclusive significant gene pairs, enriched primarily in pathways such as TP53, HIPPO, RTK/RAS, NOTCH, WNT, TGF-Beta, MYC, and PI3K. Notably, co-mutations of BRAF/ALK, BRAF/NOTCH2, BRAF/CREBBP, and BRAF/FAT1 correlated with worse PFS. Furthermore, germline AR mutations were identified in 37 (33.33%) CRC patients, and carriers of these variants displayed diminished PFS and OS. Decreased AR protein expression was observed in cases with AR germline mutations. A four-gene mutation signature was established, incorporating the aforementioned prognostic genes, which emerged as an independent prognostic determinant in CRC via univariate and multivariate Cox regression analyses. Noteworthy BRAF and ARID2 protein expression decreases detected in patients with their respective mutations.ConclusionThe integration of our analyses furnishes crucial insights into CRC's molecular characteristics, drug responsiveness, and the construction of a four-gene mutation signature for predicting CRC prognosis.

Project description:The Arabian Peninsula is considered the initial site of historic human migration out of Africa. The modern-day indigenous Arabians are believed to be the descendants who remained from the ancient split of the migrants into Eurasia. Here, we investigated how the population history and cultural practices such as endogamy have shaped the genetic variation of the Saudi Arabians. We genotyped 3,352 individuals and identified twelve genetic sub-clusters that corresponded to the geographical distribution of different tribal regions, differentiated by distinct components of ancestry based on comparisons to modern and ancient DNA references. These sub-clusters also showed variation across ranges of the genome covered in runs of homozygosity, as well as differences in population size changes over time. Using 25,488,981 variants found in whole genome sequencing data (WGS) from 302 individuals, we found that the Saudi tend to show proportionally more deleterious alleles than neutral alleles when compared to Africans/African Americans from gnomAD (e.g. a 13% increase of deleterious alleles annotated by AlphaMissense between 0.5 - 5% frequency in Saudi, compared to 7% decrease of the benign alleles; P < 0.001). Saudi sub-clusters with greater inbreeding and lower effective population sizes showed greater enrichment of deleterious alleles as well. Additionally, we found that approximately 10% of the variants discovered in our WGS data are not observed in gnomAD; these variants are also enriched with deleterious annotations. To accelerate studying the population-enriched deleterious alleles and their health consequences in this population, we made available the allele frequency estimates of 25,488,981 variants discovered in our samples. Taken together, our results suggest that Saudi's population history impacts its pattern of genetic variation with potential consequences to the population health. It further highlights the need to sequence diverse and unique populations so to provide a foundation on which to interpret medical- and pharmaco- genomic findings from these populations.

Dataset Information

The Genomic Landscape of Colorectal Cancer in the Saudi Arabian Population Using a Comprehensive Genomic Panel.

Purpose

Patients and methods

Results

Conclusions

Publications

The Genomic Landscape of Colorectal Cancer in the Saudi Arabian Population Using a Comprehensive Genomic Panel.

Similar Datasets

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