Tumour heterogeneity and clonality – an old theme revisited

Fey, Martin F.; Tobler, Andreas

doi:10.1093/oxfordjournals.annonc.a010537

Cited by 24 publications

(10 citation statements)

References 67 publications

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“…By contrast, loci with AI in tumor but not in plasma DNA were the most frequent in ADC, which is known to be a heterogeneous histologic subtype of lung cancer 56. Altogether, these observations may reflect the presence of several heterogeneous clones in the lung tumor, as reported elsewhere, which could have different access to the bloodstream 19, 20, 21, 22, 23, 29, 57, 58. Specific physiologic characteristics in the progression of each tumor or secretion of DNA in plasma preferentially by metastasis or angiogenesis capacity or the ability to cause local thrombosis and necrosis could be at the origin of our data 59, 60.…”

Section: Discussionsupporting

confidence: 65%

Plasma DNA microsatellite panel as sensitive and tumor‐specific marker in lung cancer patients

Beau‐Faller

Gaub

Schneider

et al. 2003

Intl Journal of Cancer

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The majority of lung cancer patients have tumor-derived genetic alterations in circulating plasma DNA that could be exploited as a diagnostic tool. We used fluorescent microsatellite analysis to detect alterations in plasma and tumor DNA in 34 patients who underwent bronchoscopy for lung cancer, including 11 small cell lung cancer (SCLC) and 23 nonsmall cell lung cancer (NSCLC) (12 adenocarcinomas, 11 squamous cell carcinomas) and 20 controls. Allelotyping was performed with a selected panel of 12 microsatellites from 9 chromosomal regions 3p21, 3p24, 5q, 9p, 9q, 13q, 17p, 17q and 20q. Plasma DNA allelic imbalance (AI) was found in 88% (30 of 34 Key words: plasma DNA alterations; lung cancer; microsatellite analysis; histologic type; prognosisLung cancer is one of the most common tumors in the world. The World Health Organization's (WHO) pathologic description of malignant tumors classifies lung cancer into 4 main groups: 1 small cell lung cancer (SCLC), squamous cell carcinoma (SQC), adenocarcinoma (ADC) and large cell carcinoma (LCC). For prognostic and therapeutic purposes, SQC, ADC and LCC are pooled together in the nonsmall cell lung cancer (NSCLC) group. NSCLC and SCLC represent about 80% and 20% of all primary lung cancers, respectively. 2 Surgery offers the best probability of cure for patients with NSCLC, but surgery cannot be proposed for locally advanced or metastatic stages. In spite of aggressive therapy, however, prognosis of lung cancer patients is generally very poor. Survival at 5 years is 35% for NSCLC operated patients and Ͻ 5% for inoperable NSCLC. Survival is Ͻ 20% at 2 years for limited SCLC and Ͻ 2% for extensive disease. 3-5 Thus, the development of novel diagnostic techniques to identify lung cancer may facilitate earlier diagnosis of primary or recurring cancers and lead to more effective treatments and improved prognosis.As in other cancers, accumulation of genetic alterations is common in lung cancer and can include gene mutations, allelic losses, allelic instabilities and aberrant gene methylation that target oncogenes or tumor suppressor genes (TSG). 6,7 Among microsatellite (MS) alterations, primary lung cancers seldom show microsatellite instability (MSI) but are more often characterized by frequent loss of heterozygosity (LOH). 8 Remarkably, the frequency of MS alterations reported in lung cancers varies substantially and obviously depends on the markers analyzed. For lung cancer, frequent LOH has been reported in regions of chromosomes 3, 5, 9, 13 and 17, with the highest frequency occurring at 3p. 9 -14 Nevertheless, comparison of allelotypes have identified some consistent differences in LOH frequencies such as 50 -80% and 80 -100% at 17p13, 20 -30% and 80 -90% at 13q, 60% and 0 -10% at 9p21, 50% and 90% at 3p in NSCLC and in SCLC, respectively. 14 -17 It has long been known that the concentration of free-circulating DNA in plasma is higher in tumor patients than in healthy people. 18 Microsatellite analysis, mutation analysis in genomic or mitochondrial DNA and gene promot...

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Section: Discussionsupporting

confidence: 65%

Plasma DNA microsatellite panel as sensitive and tumor‐specific marker in lung cancer patients

Beau‐Faller

Gaub

Schneider

et al. 2003

Intl Journal of Cancer

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“…Poor sampling may give a false impression of monoclonality in a polyclonal tumour. [73][74][75] In this respect, Enomoto et al, 76 using the HUMARA method, reported that the bands generated by mixing monoclonal tumour tissue with peripheral blood leukocytes can be distinguished in the proportion 8:2; thus, clonality can be assessed when clonally derived cells comprise 20 per cent or more of the population. Krohn et al 77 quoted 40 per cent, and Noguchi et al 78 50 per cent.…”

Section: Methods For Investigating the Clonal Composition Of Tumoursmentioning

confidence: 99%

Field cancerization, clonality, and epithelial stem cells: the spread of mutated clones in epithelial sheets

et al. 1999

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“…The prevailing model of molecular genetics underlying CRC suggests that this disease arises via clonal expansion of crypt cells bearing genetic mutations, microsatellite alterations (e.g., microsatellite instability [MSI]), or chromosomal abnormalities. Such genetic and epigenetic alterations may result in proliferative advantages in areas of tumor invasion, affecting various tumor‐related factors such as invasive ability and tumor aggressiveness . Chromosomal changes can occur as chromosomal gains or losses, the latter of which involves loss of heterozygosity (LOH), an important classical genetic alteration occurring in tumor cells (e.g., chromosomal instability [CIN]) .…”

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confidence: 99%

“…Chromosomal changes can occur as chromosomal gains or losses, the latter of which involves loss of heterozygosity (LOH), an important classical genetic alteration occurring in tumor cells (e.g., chromosomal instability [CIN]) . Moreover, MSI plays a major role in specific types of CRC (in particular, the MSI‐high phenotype) and is closely associated with tumor development . Subsequent chromosomal changes, including LOH and MSI, act as drivers for tumor progression or invasion .…”

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confidence: 99%

Molecular subtypes of colorectal cancers determined by PCR‐based analysis

et al. 2017

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Tumor tissue consists of a heterogeneous cell population. The allelic imbalance (AI) ratio, determined in isolated tumor glands, is a good index of tumor heterogeneity. However, associations of the patterns of AI and microsatellite instability (MSI) development, observed in most cases of colorectal cancer (CRC), with tumor progression have not been reported previously. In this study, we examined whether CRC genetic profiles stratified by a combination of the AI ratio and MSI facilitate categorization of CRC, and whether these genetic profiles are associated with specific molecular alterations in CRC. A crypt isolation method was used to isolate DNA from tumors and normal glands obtained from 147 sporadic CRCs. AI and MSI statuses were determined using PCR‐based microsatellite analysis and stratified based on AI ratio and MSI status. DNA methylation status (high methylation, intermediate methylation and low methylation status and mutations in KRAS,BRAF, and TP53 were examined. In addition, mucin markers were immunostained. Based on this analysis, four subgroups were categorized. Subgroup 1 was characterized by a high MSI status and BRAF mutation; subgroup 2 was closely associated with a high AI ratio, which accumulated during the early phases of colorectal carcinogenesis, and TP53 mutation; subgroup 3 was associated with a low AI ratio, seen during the later phases of colorectal carcinogenesis, and KRAS mutation; and subgroup 4 was defined as a minor subgroup. These results confirmed that classification of distinct molecular profiles provides important insights into colorectal carcinogenesis.

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Tumour heterogeneity and clonality – an old theme revisited

Cited by 24 publications

References 67 publications

Plasma DNA microsatellite panel as sensitive and tumor‐specific marker in lung cancer patients

Plasma DNA microsatellite panel as sensitive and tumor‐specific marker in lung cancer patients

Field cancerization, clonality, and epithelial stem cells: the spread of mutated clones in epithelial sheets

Molecular subtypes of colorectal cancers determined by PCR‐based analysis

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