Targeted molecular profiling of rare genetic alterations in colorectal cancer using next-generation sequencing

Jauhri, Mayank; Bhatnagar, Akanksha; Gupta, Satish; Shokeen, Yogender; Minhas, S.; Aggarwal, Shyam

doi:10.1007/s12032-016-0820-2

Cited by 26 publications

(26 citation statements)

References 39 publications

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“…To the best of our knowledge, this study is one of the largest retrospective studies to date characterizing SMAD4 mutations in CRC patients and demonstrates a prognostic role for this mutation in metastatic CRC cases. The prevalence and spectrum of SMAD4 mutations in our patients who underwent full-length sequencing (n = 49) were consistent with those in previous studies and data from TCGA [29, 31, 42]. Most of the mutations were missense mutations, and the hotspot regions affected by mutations were Arg361 and Pro356, which are located in the MH2 domain.…”

Section: Discussionsupporting

confidence: 90%

“…Sporadic mutation of SMAD4 has been reported in 2.1–20.0% of CRC cases [25–30]. The occurrence of SMAD4 mutation in CRC is considered a late event and usually happens in combination with other alterations [27, 31]. In a study performed on primary and metastatic tumor pairs, SMAD4 mutation was one of the frequent novel mutations in metastases; the finding that suggests SMAD4 is involved in clonal divergence [32].…”

Section: Introductionmentioning

confidence: 99%

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Association of SMAD4 mutation with patient demographics, tumor characteristics, and clinical outcomes in colorectal cancer

et al. 2017

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SMAD4 is an essential mediator in the transforming growth factor-β pathway. Sporadic mutations of SMAD4 are present in 2.1–20.0% of colorectal cancers (CRCs) but data are limited. In this study, we aimed to evaluate clinicopathologic characteristics, prognosis, and clinical outcome associated with this mutation in CRC cases. Data for patients with metastatic or unresectable CRC who underwent genotyping for SMAD4 mutation and received treatment at The University of Texas MD Anderson Cancer Center from 2000 to 2014 were reviewed. Their tumors were sequenced using a hotspot panel predicted to cover 80% of the reported SMAD4 mutations, and further targeted resequencing that included full-length SMAD4 was performed on mutated tumors using a HiSeq sequencing system. Using The Cancer Genome Atlas data on CRC, the characteristics of SMAD4 and transforming growth factor-β pathway mutations were evaluated according to different consensus molecular subtypes of CRC. Among 734 patients with CRC, 90 (12%) had SMAD4 mutations according to hotspot testing. SMAD4 mutation was associated with colon cancer more so than with rectal cancer (odds ratio 2.85; p<0.001), female sex (odds ratio 1.71; p = 0.02), and shorter overall survival than in wild-type SMAD4 cases (median, 29 months versus 56 months; hazard ratio 2.08; p<0.001 [log-rank test]). SMAD4 mutation was not associated with age, stage at presentation, colonic location, distant metastasis, or tumor grade. A subset of patients with metastatic CRC (n = 44) wild-type for KRAS, NRAS, and BRAF who received anti-epidermal growth factor receptor therapy with mutated SMAD4 (n = 13) had shorter progression-free survival duration than did patients wild-type for SMAD4 (n = 31) (median, 111 days versus 180 days; p = 0.003 [log-rank test]). Full-length sequencing confirmed that missense mutations at R361 and P356 in the MH2 domain were the most common SMAD4 alterations. In The Cancer Genome Atlas data, SMAD4 mutation frequently occurred with KRAS, NRAS, and BRAF mutations and was more common in patients with the consensus molecular subtype 3 of CRC than in those with the other 3 subtypes. This is one of the largest retrospective studies to date characterizing SMAD4 mutations in CRC patients and demonstrates the prognostic role and lack of response of CRC to anti-epidermal growth factor receptor therapy. Further studies are required to validate these findings and the role of SMAD4 mutation in CRC.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Association of SMAD4 mutation with patient demographics, tumor characteristics, and clinical outcomes in colorectal cancer

et al. 2017

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“…Meanwhile, genotypes of major mature cancer cells would be identical to those of cancer tissues; therefore, it was expected that genotypes of cancer tissue-derived iPSC lines would be identical to those of their starting cancer tissues. It was reported that ERBB2 mutations were persistent in 3.6% of patients with colorectal cancer[18]. Indeed, a mutated genotype in ERBB2 of the colon cancer tissues was also identified in this study.…”

Section: Discussionsupporting

confidence: 73%

Next-generation sequencing traces human induced pluripotent stem cell lines clonally generated from heterogeneous cancer tissue

Ishikawa¹

2017

WJSC

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AIMTo investigate genotype variation among induced pluripotent stem cell (iPSC) lines that were clonally generated from heterogeneous colon cancer tissues using next-generation sequencing.METHODSHuman iPSC lines were clonally established by selecting independent single colonies expanded from heterogeneous primary cells of S-shaped colon cancer tissues by retroviral gene transfer (OCT3/4, SOX2, and KLF4). The ten iPSC lines, their starting cancer tissues, and the matched adjacent non-cancerous tissues were analyzed using next-generation sequencing and bioinformatics analysis using the human reference genome hg19. Non-synonymous single-nucleotide variants (SNVs) (missense, nonsense, and read-through) were identified within the target region of 612 genes related to cancer and the human kinome. All SNVs were annotated using dbSNP135, CCDS, RefSeq, GENCODE, and 1000 Genomes. The SNVs of the iPSC lines were compared with the genotypes of the cancerous and non-cancerous tissues. The putative genotypes were validated using allelic depth and genotype quality. For final confirmation, mutated genotypes were manually curated using the Integrative Genomics Viewer.RESULTSIn eight of the ten iPSC lines, one or two non-synonymous SNVs in EIF2AK2, TTN, ULK4, TSSK1B, FLT4, STK19, STK31, TRRAP, WNK1, PLK1 or PIK3R5 were identified as novel SNVs and were not identical to the genotypes found in the cancer and non-cancerous tissues. This result suggests that the SNVs were de novo or pre-existing mutations that originated from minor populations, such as multifocal pre-cancer (stem) cells or pre-metastatic cancer cells from multiple, different clonal evolutions, present within the heterogeneous cancer tissue. The genotypes of all ten iPSC lines were different from the mutated ERBB2 and MKNK2 genotypes of the cancer tissues and were identical to those of the non-cancerous tissues and that found in the human reference genome hg19. Furthermore, two of the ten iPSC lines did not have any confirmed mutated genotypes, despite being derived from cancerous tissue. These results suggest that the traceability and preference of the starting single cells being derived from pre-cancer (stem) cells, stroma cells such as cancer-associated fibroblasts, and immune cells that co-existed in the tissues along with the mature cancer cells.CONCLUSIONThe genotypes of iPSC lines derived from heterogeneous cancer tissues can provide information on the type of starting cell that the iPSC line was generated from.

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“…Recent studies of ERBB2 amplification and sequence mutations in colorectal cancer (CRC) suggest that HER2 is a therapy target in this disease, in addition to being a mechanism of resistance to epidermal growth factor receptor (EGFR)‐targeted therapies such as cetuximab and panitumumab . Similarly, reports of high‐level ERBB3 amplification being a negative prognostic factor within the context of CRC suggest that HER3 may also be a target in this tumor type .…”

Section: Introductionmentioning

confidence: 99%

“…11,[19][20][21][22][23][24][25] Alterations in the HER2 dimerization partner HER3, encoded by ERBB3, can also activate HER2 signaling and underlie sensitivity to targeted therapies. 11,[26][27][28] Recent studies of ERBB2 amplification and sequence mutations in colorectal cancer (CRC) suggest that HER2 is a therapy target in this disease, [29][30][31][32][33] in addition to being a mechanism of resistance to epidermal growth factor receptor (EGFR)-targeted therapies such as cetuximab and panitumumab. [34][35][36][37][38] Similarly, reports of high-level ERBB3 amplification being a negative prognostic factor within the context of CRC suggest that HER3 may also be a target in this tumor type.…”

Section: Introductionmentioning

confidence: 99%

Targeting HER2 in colorectal cancer: The landscape of amplification and short variant mutations in ERBB2 and ERBB3

Ross¹,

Fakih

Ali³

et al. 2018

Cancer

171

116

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BACKGROUNDIn contrast to lung cancer, few precision treatments are available for colorectal cancer (CRC). One rapidly emerging treatment target in CRC is ERBB2 (human epidermal growth factor receptor 2 [HER2]). Oncogenic alterations in HER2, or its dimerization partner HER3, can underlie sensitivity to HER2‐targeted therapies.METHODSIn this study, 8887 CRC cases were evaluated by comprehensive genomic profiling for genomic alterations in 315 cancer‐related genes, tumor mutational burden, and microsatellite instability. This cohort included both colonic (7599 cases; 85.5%) and rectal (1288 cases; 14.5%) adenocarcinomas.RESULTSA total of 569 mCRCs were positive for ERBB2 (429 cases; 4.8%) and/or ERBB3 (148 cases; 1.7%) and featured ERBB amplification, short variant alterations, or a combination of the 2. High tumor mutational burden (≥20 mutations/Mb) was significantly more common in ERBB‐mutated samples, and ERBB3‐mutated CRCs were significantly more likely to have high microsatellite instability (P<.002). Alterations affecting KRAS (27.3%) were significantly underrepresented in ERBB2‐amplified samples compared with wild‐type CRC samples (51.8%), and ERBB2‐ or ERBB3‐mutated samples (49.0% and 60.8%, respectively) (P<.01). Other significant differences in mutation frequency were observed for genes in the PI3K/MTOR and mismatch repair pathways.CONCLUSIONSAlthough observed less often than in breast or upper gastrointestinal carcinomas, indications for which anti‐HER2 therapies are approved, the percentage of CRC with ERBB genomic alterations is significant. Importantly, 32% of ERBB2‐positive CRCs harbor short variant alterations that are undetectable by routine immunohistochemistry or fluorescence in situ hybridization testing. The success of anti‐HER2 therapies in ongoing clinical trials is a promising development for patients with CRC. Cancer 2018;124:1358‐73. © 2018 Foundation Medicine, Inc. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

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Targeted molecular profiling of rare genetic alterations in colorectal cancer using next-generation sequencing

Cited by 26 publications

References 39 publications

Association of SMAD4 mutation with patient demographics, tumor characteristics, and clinical outcomes in colorectal cancer

Association of SMAD4 mutation with patient demographics, tumor characteristics, and clinical outcomes in colorectal cancer

Next-generation sequencing traces human induced pluripotent stem cell lines clonally generated from heterogeneous cancer tissue

Targeting HER2 in colorectal cancer: The landscape of amplification and short variant mutations in ERBB2 and ERBB3

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