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Authors
Advisor(s)
Abstract(s)
O cancro colo-rectal (CCR) continua a ser uma das principais causas de morte por cancro nos
países desenvolvidos. No entanto, o CCR pode ser prevenido através da remoção das suas
lesões precursoras - os adenomas. Diversos estudos demonstraram já que esta atitude reduz a
mortalidade por CCR e que as características dos adenomas na primeira colonoscopia
permitem definir estratégias de vigilância.
Sabe-se atualmente que diferentes vias de carcinogénese podem conduzir ao CCR esporádico,
evoluindo ao longo de anos numa mucosa macroscopicamente inalterada. Alguns dados
apontam para que os primeiros eventos nestas sequências de carcinogénese possam remontar
à embriogénese e afetar apenas determinadas áreas do cólon, derivadas de células
precursoras mutadas. A acumulação posterior de outras mutações vai culminar na primeira
manifestação clínica – o adenoma, numa janela temporal limitada.
Numa análise de doentes com adenomas esporádicos, demonstrámos que sob ação da
polipectomia, a incidência de adenomas decai ao longo do tempo, sugerindo um efeito de
eliminação de todos os clones derivados de células precocemente mutadas.
Em doentes com CCR e adenomas síncronos, demonstrámos uma co localização das lesões que
favorece a noção de alguma forma de mosaicismo cólico.
Finalmente, numa amostra de doentes com CCR avaliada prospectivamente, confirmámos a
diversidade de vias de carcinogénese que culminam no mesmo evento final e a importância da
avaliação molecular e genética para a sua distinção, com implicações clínicas.
Apesar de não ter sido possível demonstrar a base genética do mosaicismo cólico, defendemos
que os dados acumulados até ao presente continuam a apontar nesse sentido e que o
conhecimento aprofundado da origem celular e sub-celular do CCR será o caminho para a sua
erradicação.
Colorectal cancer (CRC) remains one of the main causes of death by cancer in developed countries. Yet, it is potentially preventable, by removing the precursor lesions - adenomas. Several studies proved that this intervention reduces CRC mortality and that the adenomas’ characteristics at the first colonoscopy can guide surveillance strategies. It is now known that several carcinogenesis pathways may lead to sporadic CRC, evolving for years in macroscopically unchanged mucosa. Some data points to an embryonic origin for the first events in these pathways, affecting only some colonic areas, derived from mutated precursor cells. The latter accumulation of other mutations then leads to the fist clinical manifestation – the adenoma, in a limited time frame. In a sporadic adenomas patient population, we showed that under polypectomy the adenoma incidence decays along time, suggesting an effect of the elimination of all clones derived from early mutated cells. In CRC patients with synchronous adenomas, a co-localization of lesions was found, favoring the notion of some form of colonic mosaicism. Finally, in a prospectively evaluated CRC patient sample, we confirmed the diverse carcinogenesis pathways leading to the same final event and the importance of molecular and genetic studies to distinguish them, with clinical implications. Although we could not prove the genetic basis of the colonic mosaicism, we state that all accumulated evidence still points to it and that the deeper knowledge of the cellular and subcellular origin of CRC will be the way to its eradication.
Colorectal cancer (CRC) remains one of the main causes of death by cancer in developed countries. Yet, it is potentially preventable, by removing the precursor lesions - adenomas. Several studies proved that this intervention reduces CRC mortality and that the adenomas’ characteristics at the first colonoscopy can guide surveillance strategies. It is now known that several carcinogenesis pathways may lead to sporadic CRC, evolving for years in macroscopically unchanged mucosa. Some data points to an embryonic origin for the first events in these pathways, affecting only some colonic areas, derived from mutated precursor cells. The latter accumulation of other mutations then leads to the fist clinical manifestation – the adenoma, in a limited time frame. In a sporadic adenomas patient population, we showed that under polypectomy the adenoma incidence decays along time, suggesting an effect of the elimination of all clones derived from early mutated cells. In CRC patients with synchronous adenomas, a co-localization of lesions was found, favoring the notion of some form of colonic mosaicism. Finally, in a prospectively evaluated CRC patient sample, we confirmed the diverse carcinogenesis pathways leading to the same final event and the importance of molecular and genetic studies to distinguish them, with clinical implications. Although we could not prove the genetic basis of the colonic mosaicism, we state that all accumulated evidence still points to it and that the deeper knowledge of the cellular and subcellular origin of CRC will be the way to its eradication.
Description
Keywords
Cancro colo-rectal Adenoma Mosaicismo Carcinogénese