Targeted exome sequencing reveals distinct pathogenic variants in Iranians with colorectal cancer

Abstract

PURPOSENext Generation Sequencing (NGS) is currently used to establish mutational profiles in many multigene diseases such as colorectal cancer (CRC), which is on the rise in many parts of the developing World including, Iran. Little is known about its genetic hallmarks in these populations.AIMTo identify variants in 15 CRC-associated genes in patients of Iranian descent.RESULTSThere were 51 validated variants distributed on 12 genes: 22% MSH3 (n = 11/51), 10% MSH6 (n = 5/51), 8% AMER1 (n = 4/51), 20% APC (n = 10/51), 2% BRAF (n = 1/51), 2% KRAS (n = 1/51), 12% PIK3CA (n = 6/51), 8% TGFβR2A (n = 4/51), 2% SMAD4 (n = 1/51), 4% SOX9 (n = 2/51), 6% TCF7L2 (n = 3/51), and 6% TP53 (n = 3/51). Most known and distinct variants were in mismatch repair genes (MMR, 32%) and APC (20%). Among oncogenes, PIK3CA was the top target (12%).MATERIALS AND METHODSCRC specimens from 63 Shirazi patients were used to establish the variant' profile on an Ion Torrent platform by targeted exome sequencing. To rule-out technical artifacts, the variants were validated in 13 of these samples using an Illumina NGS platform. Validated variants were annotated and compared to variants from publically available databases. An in-silico functional analysis was performed. MSI status of the analyzed samples was established.CONCLUSIONThese results illustrate for the first time CRC mutational profile in Iranian patients. MSH3, MSH6, APC and PIK3CA genes seem to play a bigger role in the path to cancer in this population. These findings will potentially lead to informed genetic diagnosis protocol and targeted therapeutic strategies.

Molecular characterization of colorectal cancer using whole‐exome sequencing in a Taiwanese population

“…Ashktorab et al analyzed 63 Iranian patients using targeted exome sequencing and found higher mutation rates of MSH3 , MSH6 , APC , and PIK3CA and hypothesized a larger role for these genes in CRC. They suggested the adoption of a specific informed genetic diagnostic protocol and tailored therapy in this population . Because patients with RAS wild‐type CRC can be non‐responders to EGFR‐targeted therapy, Geibler et al analyzed cell lines and tumor specimens to identify prediction markers by NGS, EGFR methylation and expression, and E‐cadherin expression.…”

“…They suggested the adoption of a specific informed genetic diagnostic protocol and tailored therapy in this population. 7 Because patients with RAS wild-type CRC can be non-responders to EGFR-targeted therapy, Geibler et al analyzed cell lines and tumor specimens to identify prediction markers by NGS, EGFR methylation and expression, and E-cadherin expression. The authors revealed ATM mutations and low E-cadherin expression as novel supportive predictive markers.…”

Genetics and genomic medicine in Iran

“…It is higher than in the European population (Hasanzad et al., ). A high prevalence (39.3%) of subjects (respectively, 24.3% homozygous T/T CYP2D6*10 and 15% heterozygous C/T CYP2D6*10 as poor and intermediate metabolizers) among Iranians; therefore, the harmful effects of drugs are relatively common (Bagheri et al., ). An ABCD1 mutation (c.253dup leading to p.Arg85Profs*110) was identified in 35 affected individuals (out of 96 pedigree members) among an expanded pedigree among Lurs. Therefore, the prevalence of X‐ALD is expected to be higher among consanguineous Lurs ethnicity (Mehrpour et al., ). ) MSH3, MSH6, APC, and PIK3CA genes are predicted to play a bigger role in the pathogenesis of colon cancer in Iranian population (Ashktorab et al., ). In a pilot study of Persian nephropathic cystinosis population, the common 57‐kb deletion was not observed; however, at least 50% of mutations were observed in exons 6 and 7 of CTNS (Ghazi et al., ). In another pilot study, the role of kidney anion exchanger 1 gene (AE1) mutations is highlighted in Iranian children with distal renal tubular acidosis (dRTA); moreover a novel mutation pattern of AE) has been reported in patients with distal renal tubular acidosis in Iran (Hooman et al., ). Among all Iranian patients with cystic fibrosis, just 16.6% has shown a delta F508 mutation in CFTR (either homozygote or heterozygote) (Najafi et al., ), which is different from many other populations around the world.…”

“…6. )MSH3, MSH6, APC, and PIK3CA genes are predicted to play a bigger role in the pathogenesis of colon cancer in Iranian population (Ashktorab et al, 2017). 7.…”

The landscape of somatic mutation in sporadic Chinese colorectal cancer

“…Whole exome sequencing (WES) study on American-African patients discovered significant different somatic mutation genes, indicating alternative disease mechanisms in patients with different ethnic background [7]. Moreover, investigations on Iranian and Japanese patients uncover different somatic gene mutations and alternative mutation frequencies than Caucasian counterparts [8,9]. Therefore, a whole exome sequencing of Chinese patients is essential for novel somatic gene mutation spectrums characterization, which may consequently change our understanding of disease etiology and precision medicine management.…”