Comprehensive characterization of RAS mutations in colon and rectal cancers in old and young patients

Serebriiskii, Ilya G.; Connelly, Caitlin; Frampton, Garrett M.; Newberg, Justin Y.; Cooke, Matthew; Miller, V. A.; Ali, Siraj M.; Ross, Jeffrey S.; Handorf, Elizabeth A.; Arora, Sanjeevani; Lieu, Christopher H.; Golemis, Erica A.; Meyer, Joshua E.

doi:10.1038/s41467-019-11530-0

Cited by 154 publications

(146 citation statements)

References 53 publications

(67 reference statements)

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“…( 23 ) It is, however, important to note that the false negative rate for KRAS immunohistochemistry has not been documented and current mCRC biomarker testing guidelines have not approved its clinical use. To date, the largest published cohort of RAS -amplified mCRCs is by Serebriiskii et al( 13 ) The authors retrospectively reviewed Foundation Medicine’s NGS database of 13,336 mCRCs and, consistent with our findings, determined the prevalence of RAS amplification was 2%. However, this database contains minimal clinicopathologic data.…”

Section: Discussionsupporting

confidence: 77%

KRAS amplification in metastatic colon cancer is associated with a history of inflammatory bowel disease and may confer resistance to anti-EGFR therapy

et al. 2020

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Mutations in RAS occur in 30–50% of metastatic colorectal carcinomas (mCRCs) and correlate with resistance to anti-EGFR therapy. Consequently, mCRC biomarker guidelines state RAS mutational testing should be performed when considering EGFR inhibitor treatment. However, a small subset of mCRCs are reported to harbor RAS amplification. In order to elucidate the clinicopathologic features and anti-EGFR treatment response associated with RAS amplification, we retrospectively reviewed a large cohort of mCRC patients that underwent targeted next-generation sequencing and copy number analysis for KRAS , NRAS , HRAS , BRAF and PIK3CA . Molecular testing was performed on 1,286 consecutive mCRC from 1,271 patients as part of routine clinical care, and results were correlated with clinicopathologic findings, mismatch repair (MMR) status and follow-up. RAS amplification was detected in 22 (2%) mCRCs and included: KRAS , NRAS and HRAS for 15, 5 and 2 cases, respectively (6 to 21 gene copies). Patients with a KRAS -amplified mCRC were more likely to report a history of inflammatory bowel disease (p < 0.001). In contrast, mutations in KRAS were associated with older patient age, right-sided colonic origin, low-grade differentiation, mucinous histology and MMR proficiency (p ≤ 0.017). Four patients with a KRAS -amplified mCRC and no concomitant RAS / BRAF / PIK3CA mutations received EGFR inhibitor-based therapy, and none demonstrated a clinicoradiographic response. The therapeutic impact of RAS amplification was further evaluated using a separate, multi-institutional cohort of 23 patients. Eight of 23 patients with KRAS -amplified mCRC received anti-EGFR therapy and all 8 patients exhibited disease progression on treatment. Although the number of KRAS -amplified mCRCs is limited, our data suggests the clinicopathologic features associated with mCRC harboring a KRAS amplification are distinct from those associated with a KRAS mutation. However, both alterations seem to confer EGFR inhibitor resistance and, therefore, RAS testing to include copy number analyses may be of consideration in the treatment of mCRC.

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Section: Discussionsupporting

confidence: 77%

KRAS amplification in metastatic colon cancer is associated with a history of inflammatory bowel disease and may confer resistance to anti-EGFR therapy

et al. 2020

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“…Interestingly, non-V600E BRAF mutations showed no differences across age groups, and recently reported data suggest that patients that harbor non-V600E BRAF mutations have a distinct and improved prognosis (27). In a previously published study, we performed a detailed characterization of RAS mutational profiles in colon and rectal cancer in young and older patients (28), finding an association of specific mismatch substitutions with age and tumor site. Age-and site-related differences in alteration rates for specific mutations in the other genes reported here have not been described in great detail, and clearly bear greater scrutiny.…”

Section: Discussionmentioning

confidence: 88%

Comprehensive Genomic Landscapes in Early and Later Onset Colorectal Cancer

Lieu

Golemis

Serebriiskii

et al. 2019

Clinical Cancer Research

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Purpose: The incidence rates of colorectal cancers are increasing in young adults. The objective of this study was to investigate genomic differences between tumor samples collected from younger and older patients with colorectal cancer.Experimental Design: DNA was extracted from 18,218 clinical specimens, followed by hybridization capture of 3,769 exons from 403 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer. Genomic alterations (GA) were determined, and association with patient age and microsatellite stable/microsatellite instability high (MSS/MSI-H) status established.Results: Overall genomic alteration rates in the younger (<40) and older (!50) cohorts were similar in the majority of the genes analyzed. Gene alteration rates in the microsatellite stable (MSS) younger and older cohorts were largely similar, with several notable differences. In particular, TP53(FDR < 0.01) and CTNNB1 (FDR ¼ 0.01) alterations were more common in younger patients with colorectal cancer, and APC (FDR < 0.01), KRAS (FDR < 0.01), BRAF (FDR < 0.01), and FAM123B (FDR < 0.01) were more commonly altered in older patients with colorectal cancer. In the MSI-H cohort, the majority of genes showed similar rate of alterations in all age groups, but with significant differences seen in APC (FDR < 0.01), BRAF (FDR < 0.01), and KRAS (FDR < 0.01).Conclusions: Tumors from younger and older patients with colorectal cancer demonstrated similar overall rates of genomic alteration. However, differences were noted in several genes relevant to biology and response to therapy. Further study will need to be conducted to determine whether the differences in gene alteration rates can be leveraged to provide personalized therapies for young patients with early-onset sporadic colorectal cancer. Figure 5. Differing rates of specific BRAF and RNF43 mutations by age showing a clear distinction between BRAF V600E mutations versus other BRAF mutations as well as a difference in RNF43 659_660 mutations and RNF43 117 mutations.Genomic Landscape Young-Onset CRC www.aacrjournals.org

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“…The frequencies of 40-45% suggested by the other datasets are based on small sample sizes of fewer than 500. Notably however, the private Foundation Medicine (FM) dataset comprising 13,336 colorectal samples reports a KRAS mutation frequency of ~50% (40). This may be due to higher sensitivity of the recent genetic screening methods employed by FM versus the long-term aggregate data in COSMIC.…”

Section: Ras Patterns Across Datasetsmentioning

confidence: 99%

“…of the National Cancer Institute, MSKCC, ICGC, the Sanger Centre and others for generating the cancer genetics databases that made this work possible. (40,41,44). Mutation frequencies are applied to the most recent American Cancer Society data on cancer incidence (total patients) to estimate new cancer cases per year in the USA.…”

Section: Concluding Remarks and Future Directionsmentioning

confidence: 99%

The Frequency of Ras Mutations in Cancer

2020

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Ras is frequently mutated in cancer; however, there is a lack of consensus in the literature regarding the cancer mutation frequency of Ras, with quoted values varying from 10-30%. This variability is at least in part due to the selective aggregation of data from different databases and the dominant influence of particular cancer types and particular Ras isoforms within these datasets. In order to provide a more definitive figure for Ras mutation frequency in cancer, we cross-referenced the data in all major publicly accessible cancer mutation databases to determine reliable mutation frequency values for each Ras isoform in all major cancer types. These percentages were then applied to current US cancer incidence statistics to estimate the number of new patients each year that have Ras-mutant cancers. We find that ~19% of cancer patients harbor Ras mutations; equivalent to ~3.4 million new cases per year worldwide. We discuss the Ras isoform and mutation-specific trends evident within the datasets that are relevant to current Ras-targeted therapies. Research.

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Comprehensive characterization of RAS mutations in colon and rectal cancers in old and young patients

Cited by 154 publications

References 53 publications

KRAS amplification in metastatic colon cancer is associated with a history of inflammatory bowel disease and may confer resistance to anti-EGFR therapy

KRAS amplification in metastatic colon cancer is associated with a history of inflammatory bowel disease and may confer resistance to anti-EGFR therapy

Comprehensive Genomic Landscapes in Early and Later Onset Colorectal Cancer

The Frequency of Ras Mutations in Cancer

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