Impact of Patient Age on Molecular Alterations of Left-Sided Colorectal Tumors

Puccini, Alberto; Lenz, Heinz‐Josef; Marshall, John L.; Arguello, David; Korn, W. Michael; Weinberg, Benjamin A.; Poorman, Kelsey; Heeke, Arielle L.; Philip, Philip A.; Shields, Anthony F.; Goldberg, Richard M.; Salem, Mohamed E.

doi:10.1634/theoncologist.2018-0117

Cited by 41 publications

(30 citation statements)

References 49 publications

(72 reference statements)

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“…Furthermore, genes responsible for histone modification and chromatin remodeling, such as KMT2D and ARID1A, were more frequently mutated in RT compared with LT. Interestingly, in our previous analysis focused on the molecular characterization of left-sided CRC in AYA versus older adults, we highlighted an increased incidence of mutations in genes involved in histone modification in AYA compared with older patients with CRC, including KDM5C, KMT2A, KMT2C, KMT2D, and SETD2 [28]. Hence, disruption of the histone modification pathway appears to be a distinctive feature of CRC in AYA and to be more prominent in RT in our population.…”

Section: Protein Expression and Gene Amplificationmentioning

confidence: 72%

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Molecular Analyses of Left- and Right-Sided Tumors in Adolescents and Young Adults with Colorectal Cancer

et al. 2019

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Background. The incidence of colorectal cancer (CRC), particularly left-sided tumors (LT), in adolescents and young adults (AYA) is rising. Epigenetic events appear to play an important role in tumorigenesis and cancer progression, especially in younger patients. We compared molecular features of LT to right-sided tumors (RT) in AYA. Materials and Methods. A total of 246 LT and 56 RT were identified in a cohort of 612 AYA with primary CRC. Tumors were examined by next-generation sequencing (NGS), protein expression, and gene amplification. Tumor mutational burden (TMB) and microsatellite instability (MSI) were determined based on NGS data. Results. RT showed higher mutation rates compared with LT in several genes including BRAF (10.3% vs. 2.8%), KRAS (64.1% vs. 45.5%), PIK3CA (27% vs. 11.2%), and RNF43 (24.2% vs. 2.9%). Notably, additional mutations in distinct genes involved in histone modification and chromatin remodeling, as well as genes associated with DNA repair and cancer-predisposing syndromes, were characteristic of RT; most frequently KMT2D (27.8% vs. 3.4%), ARID1A (53.3% vs. 21.4%), MSH6 (11.1% vs. 2.3%), MLH1 (10.5% vs. 2.3%), MSH2 (10.5% vs. 1.2%), POLE (5.9% vs. 0.6%), PTEN (10.8% vs. 2.3%), and BRCA1 (5.4% vs. 0.6%). MSI was seen in 20.8% of RT versus 4.8% of LT. RT had a higher frequency of TMB-high regardless of MSI status. Conclusion. Molecular profiling of AYA CRC revealed different molecular characteristics in RT versus LT. Epigenetic mechanisms and alteration in DNA repair genes warrant further investigation and may be a promising treatment target for CRC in AYA. The Oncologist 2020;25:404-413 Implications for Practice: Colorectal cancer (CRC) in adolescents and young adults (AYA) comprises a distinct entity with different clinicopathologic features and prognosis compared with older patients. Molecular profiling of right-and left-sided tumors in AYA is needed to gain novel insight into CRC biology and to tailor targeted treatment in this age group. This study found that right-and leftsided CRC show distinct molecular features in AYA, overall and in subgroups based on microsatellite instability status. Alterations in DNA double-strand break repair and homologous recombination repair, as well as epigenetic mechanisms, appear to play a critical role. The present molecular profiling data may support the development of personalized treatment strategies in the AYA population.

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Section: Protein Expression and Gene Amplificationmentioning

confidence: 72%

“…There were also greater frequencies of MSI-high (MSI-H) status and high tumor mutational burden (TMB). Additionally, mutations in genes involved in histone modification were found to be significantly increased compared with older patients with CRC [28].…”

Section: Introductionmentioning

confidence: 99%

Molecular Analyses of Left- and Right-Sided Tumors in Adolescents and Young Adults with Colorectal Cancer

et al. 2019

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“…In this study tumour mutation burden was also evaluated by the authors . A high level of mutations (TMB-High>17 mutation/Mb) wass observed more often in patients with EOCRC (9.7% vs 2.8%, p<0.001) [3].…”

Section: Microsatellite Stable (Mss)-crc and Chromosome Unstable Waysmentioning

confidence: 88%

“…Whole-exome sequencing of tumour samples in different patient groups (under 45 years and older 65 years) did not reveal significant differences in the spectrum of genes with a high rate of mutations. In both cohorts, the rate of somatic mutations in the genes APC was 81.8%, TP53 -74.6%, KRAS -46.4%, ARID1A -19.4%, PIK3CA -13.4%, FBXW7 -11.2%, SMAD4 -10.1%, ATM -6.3%, NRAS -4.9%, BRAF -4.6%[3], while the somatic status of the genes responsible for hereditary CRC differed and was characterized by the prevalence of mutations in patients with EOCRC including the genes MSH6 (4.8% vs 1.2%, p=0.005), MSH2 (2.7% vs 0.0%, p=0.004), POLE (1.6% vs 0.0%, p=0.008), NF1 (5.9% vs 0.5%, p<0.001), SMAD4 (14.3% vs 8.3%, p=0.024), PTEN (4.3% vs 1.4%, p=0.03), TSC1 (1.1% vs 0.0%, p=0.031), TSC2 (1.6% vs 0.2%, p=0.048)[3].…”

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confidence: 98%

Molecular and Genetic Features of Colorectalcancer in Young Patients

Semyanikhina¹,

Pospekhova²

2019

MPSES

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The literature review represents the current state of research on molecular and genetic features of colorectal cancer in young patients. A steady increase in the incidence of colorectal cancer among young patients has been noted over recent years. Along with hereditary factors determining a high risk of colon tumours in patients who are carriers of germinal mutations in the genes responsible for the development of syndrome pathology (such as Lynch syndrome, familial adenomatous polyposis, Peutz-Jeghers syndrome, etc.), molecular and genetic changes in the cells of the colonic epithelium define the distinctive clinical and morphological features, prognosis, and response to specific therapy in young patients with colorectal cancer. To date, the main pathogenetic pathways involved in the promotion of carcinogenesis in the gut epithelium tissue have been identified: chromosomal instability, microsatellite instability, epigenetic abnormalities includinghyper-or hypomethylation of the tumour genome. Despite the well-studied molecular carcinogenesis of colorectal cancer, there are still many gaps in theunderstanding of the nature of such malignant neoplasms in patients with the disease diagnosed at an early age.

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“…But in the TCGA and Seshagiri dataset, higher correlations were observed (TCGA, R 2 =0.9978; Seshagiri, R 2 =0.9948), which indicated that include all point mutations in the calculation of TMB may even enhance the precision of the estimation to some extent. And there also is no agreed on the objective cut-points for TMB, so we defined TMB-high as ≥17 mut/Mbp [29,52] and ≥12 mut/Mbp [4,53] to investigate the molecular characteristics of patients with different TMB levels. Unexpectedly, similar molecular differences were found between the TMB-high and TMB-low group ( Supplementary Table S2 and Table S3).…”

Section: Discussionmentioning

confidence: 99%

An Exon Signature to Estimate the Tumor Mutational Burden of Right-sided Colon Cancer Patients

Guo¹,

Fu²,

Jin³

et al. 2020

J. Cancer

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The clinical applicability of the whole-exome sequencing (WES) in estimating tumor mutational burden (TMB) is currently limited by high cost, time-consuming and tissue availability. And given to the differences in the mutational landscapes among different types of cancer, we aimed to develop a cancer-specific signature to estimate TMB for right-sided colon cancer patients (RCC). Using WES data of 315 RCC patients, we identified the exons in which the number of mutational sites of the coding DNA sequences associated with TMB through linear regression analysis. Then, among these exons, we extracted a signature composed by 102 exons (~0.13 Mbp) through a heuristic selection procedure. The TMB estimated by the signature was highly correlated with those calculated by WES in the discovery dataset (R 2 =0.9869) and three independent validation datasets (R 2 =0.9351, R 2 =0.8063 and R 2 =0.9527, respectively). And the performance of the signature was superior to a colorectal-specific TMB estimation model contained 22 genes (~0.24 Mbp). Moreover, between TMB-high and TMB-low RCC patients, there were significantly differences in the frequencies of microsatellite instability status, CpG island methylator phenotype, BRAF, KRAS and POLE/POLD1 mutation status (p<0.01). However, the performances of the signature in other types of cancer were dramatically degraded (left-sided colon cancer, R 2 =0.7849 and 0.9407, respectively; rectum, R 2 =0.5955 and R 2 =0.965, respectively; breast cancer, R 2 =0.8444; lung cancer, R 2 =0.5963), suggesting that it was necessary to develop cancer-specific TMB estimated signatures to estimate precisely the TMB in different types of cancer. In summary, we developed an exon signature that can accurately estimate TMB in RCC patients, and the cost and time required for the assessment of TMB can be considerably decreased, making it more suitable for blood and/or biopsy samples.

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Impact of Patient Age on Molecular Alterations of Left-Sided Colorectal Tumors

Cited by 41 publications

References 49 publications

Molecular Analyses of Left- and Right-Sided Tumors in Adolescents and Young Adults with Colorectal Cancer

Molecular Analyses of Left- and Right-Sided Tumors in Adolescents and Young Adults with Colorectal Cancer

Molecular and Genetic Features of Colorectalcancer in Young Patients

An Exon Signature to Estimate the Tumor Mutational Burden of Right-sided Colon Cancer Patients

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