We developed a quantitative measure of intratumor genetic heterogeneity. Ngh is, therefore, a surrogate of tumor resilience but its quantification is confounded by genetic heterogeneity. Watch the guest editors talk about taming the cancer cell here. The csc model is a hierarchical model in which only cscs can generate a tumour, based on their selfrenewal properties and high proliferative potential figure 1 a. The interdifferentiation between cell states promotes cancer cell survival under stress and fosters nongenetic heterogeneity ngh. In this article, we aim to address the question of the impact of tumour heterogeneity on malignancy. Pdf populations of tumour cells display remarkable variability in almost every discernable phenotypic trait, including clinically important phenotypes. Summary breast cancer heterogeneity intertumour genetic heterogeneity intratumour genetic heterogeneity. Breast cancer intratumor genetic heterogeneity medscape. These advances are, to a large extent, attributable to the addition of proteasome inhibitors and immunomodulatory drugs to the armamentarium of treatment options. Jan 17, 2017 colorectal cancer crc is a highly heterogeneous disease, with pathologically similar cancers having completely different responses to treatment and patient survival.
At memorial sloan kettering and at other research centers around the world, the push is on to characterize the molecular variations between tumors known as intertumor heterogeneity and offer individualized treatments to more patients. Nonsynonymous mutations and insertionsdeletions of 16 genes containing actionable mutations, and intron 2 deletion polymorphism of bcl2like11 were analyzed in 41 primary tumor and. Intratumoral heterogeneity of her2neu expression and its consequences for the management of advanced breast cancer. Experimental evidence suggests that noninvasive or poorly invasive tumour cells can be driven to invade by invasioncompetent cancer cells 17,18,2224 or stromal fibroblasts 15,16,25 through a leaderfollower invasion mechanism,26.
Intra tumour heterogeneity defined as distinct morphological and phenotypic differences has recently been demonstrated to be an important factor in the development and behaviour of cancer cells and can be used to determine. Subpopulations of cancer cells with distinct phenotypic and molecular features. Translational implications of tumor heterogeneity clinical cancer. Differences in mutational processes and intratumour heterogeneity. Different levels of mutations and intra tumour heterogeneity have been observed between cancer types and organs. However, lack of standardized algorithm definitions and image processing severely hampers. Tumor genotype variations among tumors within different patients are known as interpatient heterogeneity, and variability among multiple tumors of the same type arising in the same patient is referred to as intrapatient heterogeneity. This includes cellular morphology, gene expression, proliferation, metabolism, motility and metastatic potential.
Stochastic phenotype switching leads to intratumor. Clonal evolution in multiple myeloma clinical lymphoma. Intratumour heterogeneity was initially explained by means of the cancer stemlike cell csc or clonalevolution models shown in figure 1. Breast cancer inter and intra tumor genetic heterogeneity jorge s reisfilho, md phd frcpath department of pathology human oncology and pathogenesis program. Genetic and epigenetic intratumour heterogeneity in. Tp53 and pic3ca and microsatellite instability may have provided further insight into the cause of intra tumour heterogeneity. Tumor heterogeneity and cancer stem cell paradigm wiley online. The researchers also discovered that the greater risk of death for patients with high intratumour heterogeneity also applied to patients with luminal a breast cancer, a subtype of oestrogen. Genomic studies have demonstrated the complex and heterogeneous clonal landscape of tumors of different origins and the potential impact of intratumor heterogeneity on treatment response and resistance, cancer progression, and the risk of disease relapse. Apr 15, 2020 these passenger mutations, albeit not conferring direct advantage to cancer cells under a given repertoire of selective pressures, may contribute to intratumor phenotypic and genetic heterogeneity. Anticancer defences are unequal between our organs. Translational implications of tumor heterogeneity clinical. High intratumour heterogeneity doubles risk of death from.
Intratumor molecular subtype heterogeneity based on rnasequencing data. Burgeoning genetic, epigenetic and phenomenological data support the existence of intra tumor genetic heterogeneity in breast cancers. Phenotypic and functional heterogeneity arise among cancer cells within the same tumour as a consequence of genetic change, environmental differences and reversible changes in cell properties. Early diseasedefinitive driver events, such as erbb2 amplification in breast cancer are crucial for the classification and treatment of neoplasms. Radiomics aims to quantify phenotypic characteristics on medical imaging through the use of automated algorithms. Nov 29, 2017 transcriptomic profiling of breast tumors provides opportunity for subtyping and molecularbased patient stratification. Two of the most widely evoked concepts to explain the. Genomic studies have demonstrated the complex and heterogeneous clonal landscape of tumors of different origins and the potential impact of intratumor heterogeneity on treatment response and resistance, cancer progression, and the risk of disease. A cnp is a vector where each component is a nonnegative integer representing the number of copies of a specific gene or segment of interest. The challenges of tumor genetic diversity mroz 2017.
The intratumor heterogeneity is associated with cancer progression and therapeutic resistance, such as in breast cancer. Cancers of all types are now recognised to consist of highly diverse populations of cells 3, where ith is detectable at the genetic, epigenetic, and phenotypic levels see table 1 for a pan cancer summary. High intratumor genetic heterogeneity is related to worse. Tumor cell subpopulations reflect the phenotypic heterogeneity of cancer that may stem from both genetic and non. Intratumoral heterogeneity presents challenges in the management of cancer. However, evidence is emerging that multiple driver mutations can coexist. Mar 05, 20 glioblastoma gb is the most common and aggressive primary brain malignancy, with poor prognosis and a lack of effective therapeutic options. Differences among cancer cells within a tumor are important in tumorigenesis and treatment resistance, yet no measure of intratumor heterogeneity is suitable for routine application. Unsupervised deconvolution of dynamic imaging reveals. Breast cancer inter and intratumor genetic heterogeneity.
Burgeoning genetic, epigenetic and phenomenological data support the existence of intratumor genetic heterogeneity in breast cancers. Andriy marusyk 1, vanessa almendro 1,2 and kornelia polyak 1 abstract populations of tumour cells display remarkable variability in almost. Multiple myeloma mm is the second most common hematologic malignancy encountered among patients in the united states. Intratumour heterogeneity is defined as the distinct morphological and phenotypic differences within a tumour. A minimal level of intratumour heterogeneity is a simple consequence of the imperfection of dna replication.
Whereas phenotypic heterogeneity of cells within tumours has been noted since the earliest days of can cer biology, the experimental. The cancer stem cell model asserts that within a population of tumour cells, there is only a small subset of cells that are tumourigenic able to form tumours. Intra tumour heterogeneity ith has been documented for many decades, initially from a morphological perspective 1,2. It has been known since the earliest days of cancer cell biology that phenotypic heterogeneity of cancer cells within a tumour exists. Pdf genomic problems involving copy number profiles. Cancer evolution, intratumour heterogeneity, evolutionary. Phenotypic heterogeneity has been widely described by pathologists. Advances in nextgeneration sequencing and bioinformatics have led to an unprecedented view of the cancer genome and its evolution. Intratumor heterogeneity is increasingly recognized as a major factor impacting diagnosis and personalized treatment of cancer. Advances in our understanding of molecular mechanisms of tumorigenesis have translated into knowledgebased therapies directed against specific oncoge.
Breast cancer intratumor heterogeneity breast cancer. Indeed, extensive intratumour heterogeneity has been demonstrated across different tumour types, which corroborates the tumour evolution paradigm. These passenger mutations, albeit not conferring direct advantage to cancer cells under a given repertoire of selective pressures, may contribute to. Tumour heterogeneity promotes collective invasion and. Differences in mutational processes and intratumour. Every persons cancer develops and grows in its own way and is unique in terms of what therapies its sensitive to. Although tumor heterogeneity is widely accepted, the existence of cancer stem cells cscs and their proposed role in tumor. Apr 19, 2012 indeed, the degree of intra tumour genetic heterogeneity has been associated with poor prognosis in oesophageal cancer 65 and breast cancer 87. We discuss the implications of intratumour heterogeneity in diagnostics and the development of therapeutic resistance. The latter includes phenotypic diversity such as cell surface markers, epigenetic abnormality, growth rate, apoptosis and other hallmarks of cancer that. These cells are termed cancer stem cells cscs, and are marked by the ability to both selfrenew and differentiate into nontumourigenic progeny. The challenge of intratumour heterogeneity in precision medicine.
Revealing tumor heterogeneity of breast cancer by utilizing. Intrapatient tumor heterogeneity refers to heterogeneity among the tumor cells of an. Indeed, the degree of intratumour genetic heterogeneity has been associated with poor prognosis in oesophageal cancer 65 and breast cancer 87. May 20, 2014 in recent years it has become clear that cancer cells within a single tumor can display striking morphological, genetic and behavioral variability. However, intratumor vascular heterogeneity cannot be resolved directly by most in vivo dynamic imaging.
Intra tumour heterogeneity ith has been documented for many decades, initially from a morphological perspective 1, 2. The routine clinicopathological data on nhg, er, pr, her2 and ki67 statuses for these 12 breast tumors are illustrated in fig. Breast cancer inter and intratumor genetic heterogeneity jorge s reisfilho, md phd frcpath. I will not discuss off label use and or investigational use in my presentation. We discuss the implications of intra tumour heterogeneity in diagnostics and the development of therapeutic resistance. Tumour heterogeneity wikimili, the best wikipedia reader. Tumor heterogeneity represents an ongoing challenge in the field of cancer therapy. Recently, due to the genomic sequence analysis in several types of cancer, the genomic data based on \em copy number profiles \em cnp for short are getting more and more popular. Tumor heterogeneity and texture analysis metrics quantify the perceived feature of an image. However, lack of standardized algorithm definitions and image processing severely. Two of the most widely evoked concepts to explain the origin of. The heterogeneity of cancer cells introduces significant challenges in designing effective treatment.
Intratumor heterogeneity from a cancer stem cell perspective. Functionally, heterogeneity provides tumors with significant adaptability. The csc model posits that the heterogeneity observed between tumour cells is the result. Heterogeneity is evident between cancers from different patients intertumor heterogeneity and within a single tumor intra tumor heterogeneity. This technique could be utilised in humans to aid in the difficult task of measuring epigenetic heterogeneity in cancer. The intra tumor heterogeneity is associated with cancer progression and therapeutic resistance, such as in breast cancer. Intratumor heterogeneity in human glioblastoma reflects.
With the existence of biologically distinctive malignant cells originated within the same tumor, intratumor functional heterogeneity is present in many cancers and is often manifested by the intermingled vascular compartments with distinct pharmacokinetics. When too much of a good thing is bad anne trinh1,2 and kornelia polyak1,2, 1department of medical oncology, danafarber cancer institute boston, ma 02215, usa. Intratumoral heterogeneity arises through complex genetic, epigenetic, and protein modifications that drive phenotypic selection in response to environmental pressures. Unlike other measures of genetic heterogeneity, math does not depend on preidentifying subclonal markers or on single. The repertoire of serous ovarian cancer nongenetic. Intratumour heterogeneity ith has been documented for many decades, initially from a morphological perspective 1, 2. Aug 23, 2017 experimental evidence suggests that noninvasive or poorly invasive tumour cells can be driven to invade by invasioncompetent cancer cells 17,18,2224 or stromal fibroblasts 15,16,25 through a leaderfollower invasion mechanism,26.
Different levels of mutations and intratumour heterogeneity have been observed between cancer types and organs. Radiomic artificial intelligence ai technology, either based on engineered hardcoded algorithms or deep learning methods, can be used to develop noninvasive imagingbased biomarkers. Intratumour heterogeneity ith has been documented for many decades, initially from a morphological perspective 1,2. In diagnostic applications the specimen profiled should be representative of the expression profile of the whole tumor and ideally capture properties of the most aggressive part of the tumor. Intra tumour heterogeneity was initially explained by means of the cancer stemlike cell csc or clonalevolution models shown in figure 1. In past few years, scientists have established tumor heterogeneity as a phenomenon of critical importance in the natural history of individual neoplasms and drug resistance 3. The last decade has seen incremental improvements in the survival of patients with mm. Analysis of intratumoral heterogeneity and amplification status in. In past few years, scientists have established tumor heterogeneity as a phenomenon of critical importance in the natural history of individual neoplasms and drug resistance 35. Feb 29, 2016 the origins of intra tumour heterogeneity. However, breast cancers commonly exhibit intra tumor heterogeneity at molecular. Tumour heterogeneity describes the observation that different tumour cells can show distinct.
Heterogeneity is evident between cancers from different patients intertumor heterogeneity and within a single tumor intratumor heterogeneity. The origin of intratumor heterogeneity and initial csc gen. Notch expression in small cell lung cancer for the heterogeneity in sclc and should be regulated by various techniques. Intratumor heterogeneity in breast cancer has limited. However, the extent of intratumor heterogeneity as a result of tumor evolution is still poorly understood. Can recent advances in biology and molecular biology be translated into improved outcomes. The researchers also discovered that the greater risk of death for patients with high intra tumour heterogeneity also applied to patients with luminal a breast cancer, a subtype of oestrogen. Tumor genotype variations among tumors within different patients are known as interpatient heterogeneity, and variability among multiple tumors of the same type arising in the same patient is referred to as intra patient heterogeneity. However, our understanding of genetic intra tumor heterogeneity has been limited until recently due to our incomplete structural knowledge of the cancer genome, and to the lack of technology sensitive enough to easily detect tumor subclones. Tumour heterogeneity and cancer cell plasticity nature. Anti cancer defences are unequal between our organs.
In recent years it has become clear that cancer cells within a single tumor can display striking morphological, genetic and behavioral variability. Phenotypic and functional heterogeneity is one of the hallmarks of human cancers. Biopsy for lung cancer diagnosis is usually done at a single site. Tumour heterogeneity promotes collective invasion and cancer. Glioblastoma gb is the most common and aggressive primary brain malignancy, with poor prognosis and a lack of effective therapeutic options. Sep 18, 20 phenotypic and functional heterogeneity arise among cancer cells within the same tumour as a consequence of genetic change, environmental differences and reversible changes in cell properties. The potential effect of intra tumor heterogeneity on molecular diagnostics was assessed in a set of 43 tumor pieces from 12 breast tumors cohort 1 fig. Cancer is a leading cause of death in men worldwide and the major cause of cancer related death is drug resistance 1,2. We characterized stochastic phenotype switching as a mechanism contributing to intratumor heterogeneity and malignant potential of liver cancer. In conclusion, the significance of notch signaling in. Math, a novel measure of intratumor genetic heterogeneity.
However, our understanding of genetic intratumor heterogeneity has been limited until recently due to our incomplete structural knowledge of the cancer genome, and to the lack of technology sensitive enough to. A minimal level of intratumour heterogeneity is a simple consequence of the imperfection of dna. In cancer, the concept of clone has been used to describe the different subpopulations of cells present in the same malignancy. These are the cancer stem cell model and the clonal evolution model. To gain deeper insight in intratumoral heterogeneity at different levels and tumor sites for common biomarkers in breast cancers, this report examines seven cases of invasive breast cancer with multiple axillary nodal metastases andor recurrences for immunohistochemical expression of estrogen receptors, progesterone. Furthermore, current gdc specifications do not require reporting the maf values needed to assess heterogeneity. While the existing methods for studying tumor heterogeneity only analyze variant allele frequency vaf, the genotype of variant is also informative for inferring subclones, which can be detected by long reads or pairedend reads. Heterogeneity of molecular profile represents one of the most challenging issues in cancer, particularly in lung cancer, in the light of the resulting therapeutic implications. Intratumor genomic heterogeneity has been recently documented in many tumor types including hcc. In lung cancer, different levels of molecular heterogeneity have been recognized including interpatients, intra and inter tumour variability.
In situ singlecell analysis identifies heterogeneity for. Genetic heterogeneity of actionable genes between primary. Cancers of all types are now recognised to consist of highly diverse populations of cells 3, where ith is detectable at the genetic, epigenetic, and phenotypic levels see table 1 for a pancancer summary. Intratumor heterogeneity in breast cancer has limited impact. Accumulating evidence suggests that intratumor heterogeneity likely is the key to understanding treatment failure. But it is unclear that genetic information at one biopsy site represents that of other lesions and is sufficient for therapeutic decision making. Epigenetic heterogeneity in cancer biomarker research.