Genetic Heterogeneity in Colorectal Cancer and its Clinical Implications

Abstract

RESUMOApesar dos recentes avanços no desenvolvimento de métodos complementares de diagnóstico e de novas terapêuticas dirigidas, o cancro colo-rectal continua a ser uma importante causa mundial de morbilidade e mortalidade. Neste sentido, têm sido desenvolvidos nos últimos anos inúmeros trabalhos de investigação com o intuito de encontrar possíveis marcadores de mau prognóstico ainda não caracterizados. A existência de uma arquitectura tumoral complexa formada por vários subclones com heterogeneidade genética entre si tem sido consistentemente apontada em linhas de investigação recentes como um elemento de particular importância. Esta característica parece ter implicações em factores tão relevantes como a representatividade da amostragem tumoral de biópsias para diagnóstico genético e a eficácia de terapias dirigidas, existindo um crescente grau de evidência da relação entre a heterogeneidade genética e o prognóstico dos doentes. O uso generalizado de técnicas de sequenciação de nova geração irá permitir uma melhor compreensão do verdadeiro grau de heterogeneidade genética dos tumores colo-rectais, das suas causas e do seu real impacto na evolução da doença. Nesta revisão pretendemos analisar as recentes descobertas relacionadas com a heterogeneidade genética do cancro colo-rectal, bem como as suas principais implicações clínicas. Palavras-chave: Heterogeneidade Genética; Investigação Médica Translacional; Neoplasias Colo-Rectais/genética; Terapia Molecular Dirigida. ABSTRACTDespite the recent advances in the development of complementary diagnostic exams and modern targeted therapies, colorectal cancer remains a major cause of morbidity and mortality worldwide. In this context, a lot of research has been conducted in the last years to find new markers of poor prognosis. The existence of a complex tumour architecture formed by multiple subclones genetically heterogeneous has been increasingly considered in recent studies as an element of particular importance. This feature seems to influence factors as relevant as the representativeness of tumour biopsies for genetic diagnosis and the efficacy of targeted therapies. There is growing evidence suggesting a relation between genetic heterogeneity and the patients' prognosis. The widespread use of next-generation sequencing techniques will allow a better understanding of the true degree of genetic heterogeneity in colorectal tumours, its causes and impact on the course of the disease. In this review we intend to analyse the recent findings related to the genetic heterogeneity of colorectal cancer, as well as its major clinical implications.

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“…It is well established that intra‐tumour heterogeneity results due to the presence of different subpopulations of cancer cells that have unique genotypes within a single tumour [32–34]. In neuroblastoma, it is possible that the clonal subpopulations with different mutational loads exist within a single tumour mass.…”

Extracellular vesicles containing oncogenic mutant β‐catenin activate Wnt signalling pathway in the recipient cells

“…It is well known that tumours are comprised of different subpopulations of cancer cells that exhibit salient genetic and behavioural variations leading to intra‐tumour heterogeneity [19,31,32]. This diversity within a single tumour is known to be attributed to the different subpopulations of cells displaying genetic and epigenetic factors and acquiring random mutations.…”

The oncogenic role of Wnt10a in colorectal cancer through activation of canonical Wnt/β‑catenin signaling

“…The main therapeutic options for CRC include traditional methods, such as surgery, chemotherapy, and possibly radiation if the tumor is well localized (2–6). In addition, genetic heterogeneity of CRC is associated with patient prognosis (7). It is therefore crucial to determine the underlying mechanism of CRC in order to develop novel therapeutic drugs for its treatment.…”