Dataset Information

A temporal shift of the evolutionary principle shaping intratumor heterogeneity in colorectal cancer.

ABSTRACT: Advanced colorectal cancer harbors extensive intratumor heterogeneity shaped by neutral evolution; however, intratumor heterogeneity in colorectal precancerous lesions has been poorly studied. We perform multiregion whole-exome sequencing on ten early colorectal tumors, which contained adenoma and carcinoma in situ. By comparing with sequencing data from advanced colorectal tumors, we show that the early tumors accumulate a higher proportion of subclonal driver mutations than the advanced tumors, which is highlighted by subclonal mutations in KRAS and APC. We also demonstrate that variant allele frequencies of subclonal mutations tend to be higher in early tumors, suggesting that the subclonal mutations are subject to selective sweep in early tumorigenesis while neutral evolution is dominant in advanced ones. This study establishes that the evolutionary principle underlying intratumor heterogeneity shifts from Darwinian to neutral evolution during colorectal tumor progression.

SUBMITTER: Saito T

PROVIDER: S-EPMC6056524 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A temporal shift of the evolutionary principle shaping intratumor heterogeneity in colorectal cancer.

Saito Tomoko T Niida Atsushi A Uchi Ryutaro R Hirata Hidenari H Komatsu Hisateru H Sakimura Shotaro S Hayashi Shuto S Nambara Sho S Kuroda Yosuke Y Ito Shuhei S Eguchi Hidetoshi H Masuda Takaaki T Sugimachi Keishi K Tobo Taro T Nishida Haruto H Daa Tsutomu T Chiba Kenichi K Shiraishi Yuichi Y Yoshizato Tetsuichi T Kodama Masaaki M Okimoto Tadayoshi T Mizukami Kazuhiro K Ogawa Ryo R Okamoto Kazuhisa K Shuto Mitsutaka M Fukuda Kensuke K Matsui Yusuke Y Shimamura Teppei T Hasegawa Takanori T Doki Yuichiro Y Nagayama Satoshi S Yamada Kazutaka K Kato Mamoru M Shibata Tatsuhiro T Mori Masaki M Aburatani Hiroyuki H Murakami Kazunari K Suzuki Yutaka Y Ogawa Seishi S Miyano Satoru S Mimori Koshi K

Nature communications 20180723 1

Advanced colorectal cancer harbors extensive intratumor heterogeneity shaped by neutral evolution; however, intratumor heterogeneity in colorectal precancerous lesions has been poorly studied. We perform multiregion whole-exome sequencing on ten early colorectal tumors, which contained adenoma and carcinoma in situ. By comparing with sequencing data from advanced colorectal tumors, we show that the early tumors accumulate a higher proportion of subclonal driver mutations than the advanced tumors ...[more]

PMID: 30038269

Similar Datasets

Project description:Patient-derived in vitro cultures of colorectal cancer (CRC) may help guide treatment strategies prior to patient treatment. However, most previous studies have been performed on a single biopsy per tumor. The purpose of this study was to analyze multiple spatially distinct biopsies from CRCs and see how well intratumor heterogeneity (ITH) was recapitulated in matching patient-derived spheroids. Three to five biopsies were collected from six CRC tumors. Each biopsy was split in two; one half was used for spheroid culturing, while the other half was used for DNA and RNA purification. For two patients, lymph node metastases were analyzed. Somatic mutations were called from whole exome sequencing data. Each tumor contained mutations shared across all biopsies and spheroids, including major CRC drivers such as APC, KRAS, and TP53. At the same time, all tumors exhibited ITH on both mutation and copy number level. The concordance between biopsies and spheroids ranged between 40 and 70% for coding mutations. For three patients, the biopsy and spheroid from matching areas clustered together, meaning that the spheroid resembled the area of origin more than the other areas. However, all biopsies and spheroids contained private mutations. Therefore, multiple cultures from spatially distinct sites of the tumor increase the insight into the genetic profile of the entire tumor. Molecular subtypes were called from RNA sequencing data. When based on transcripts from both cancer and noncancerous cells, the subtypes were largely independent of sampling site. In contrast, subtyping based on cancer cell transcripts alone was dependent on sample site and genetic ITH. In conclusion, all examined CRC tumors showed genetic ITH. Spheroid cultures partly reflected this ITH, and having multiple cultures from distinct tumor sites improved the representation of the genetic tumor subclones. This should be taken into account when establishing patient-derived models for drug screening.

Project description:PurposeIntratumor metabolic heterogeneity parameters on 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography-computed tomography (PET-CT) have been proven to be predictors of the clinical prognosis of cancer patients. The study aimed to examine the correlation between 18F-FDG PET-CT-defined heterogeneity parameters and the prognostic significance in patients with colorectal cancer.MethodsThe study included 188 patients with colorectal cancer who received surgery and 18F-FDG PET/CT examinations. Preoperative 18F-FDG PET/CT conventional and metabolic heterogeneity parameters were collected, including maximum, peak, and mean standardized uptake value (SUVmax, SUVpeak, and SUVmean), metabolic tumor volume (MTV), total lesion glycolysis (TLG), heterogeneity index-1 (HI-1) and heterogeneity index-2 (HI-2), and clinicopathological information. Correlations between these parameters and patient survival outcomes were inferred.ResultsThe associations between 18F-FDG PET/CT parameters and clinical outcomes were analyzed. Tumor thrombus (P < 0.001), tumor stage (P=0.001), MTV (P=0.003), HI-1 (P=0.032), and HI-2 (P=0.001) differed between the two groups with and without recurrence. Multivariate analysis showed that, in the radical surgery group, HI-2 (HR = 1.10, 95% CI: 1.04-1.17, P=0.001), tumor stage (HR = 20.65, 95% CI: 4.81-88.62, P < 0.001), and regional lymph nodes status (HR = 0.16, 95% CI: 0.04-0.57, P=0.005) were independent variables significantly correlated with progression-free survival (PFS) and HI-2 (HR = 1.16, 95% CI: 1.07-1.26, P < 0.001) was an independent variable affecting overall survival (OS). In the palliative surgery group, HI-2 (HR = 1.03, 95% CI: 1.01-1.06, P=0.020) was an independent variable affecting PFS, and all the parameters were not statistically significant for OS.ConclusionHI-2, tumor stage, and regional lymph nodes status might predict the outcomes of colorectal cancer more effectively than other 18F-FDG PET/CT defined parameters.

Dataset Information

A temporal shift of the evolutionary principle shaping intratumor heterogeneity in colorectal cancer.

Publications

A temporal shift of the evolutionary principle shaping intratumor heterogeneity in colorectal cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets