Malignant transformation and genetic alterations are uncoupled in early colorectal cancer progression
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RESEARCH ARTICLE
Open Access
Malignant transformation and genetic alterations are uncoupled in early colorectal cancer progression Soulafa Mamlouk1,2* , Tincy Simon1,3, Laura Tomás4,5,6, David C. Wedge7,8,9, Alexander Arnold1, Andrea Menne1,2, David Horst1, David Capper1,10, Markus Morkel1, David Posada4,5,6, Christine Sers1,2† and Hendrik Bläker11†
Abstract Background: Colorectal cancer (CRC) development is generally accepted as a sequential process, with genetic mutations determining phenotypic tumor progression. However, matching genetic profiles with histological transition requires the analyses of temporal samples from the same patient at key stages of progression. Results: Here, we compared the genetic profiles of 34 early carcinomas with their respective adenomatous precursors to assess timing and heterogeneity of driver alterations accompanying the switch from benign adenoma to malignant carcinoma. In almost half of the cases, driver mutations specific to the carcinoma stage were not observed. In samples where carcinoma-specific alterations were present, TP53 mutations and chromosome 20 copy gains commonly accompanied the switch from adenomatous tissue to carcinoma. Remarkably, 40% and 50% of high-grade adenomas shared TP53 mutations and chromosome 20 gains, respectively, with their matched carcinomas. In addition, multi-regional analyses revealed greater heterogeneity of driver mutations in adenomas compared to their matched carcinomas. Conclusion: Genetic alterations in TP53 and chromosome 20 occur at the earliest histological stage in colorectal carcinomas (pTis and pT1). However, high-grade adenomas can share these alterations despite their histological distinction. Based on the well-defined sequence of CRC development, we suggest that the timing of genetic changes during neoplastic progression is frequently uncoupled from histological progression. Keywords: Adenoma, Carcinoma, Cancer progression, Cancer driver mutations, TP53 mutations, Copy number alterations, Polyp
Background It is estimated that the global burden of colorectal cancer (CRC) will reach 2.2 million new cases by 2030, leading to more than one million cancer-related deaths [1]. Most CRCs follow a well-defined adenoma-to-carcinoma sequence, beginning as a polyp and progressing to invasive metastatic disease. Adenomas are classified as low* Correspondence: [email protected] † Christine Sers and Hendrik Bläker are shared co-last authors. 1 Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany 2 German Cancer Consortium (DKTK), Heidelberg, Germany Full list of author information is available at the end of the article
or high-grade intraepithelial neoplasia depending on the extent and severity of their histological changes. Some adenomas undergo spontaneous regression, while others progress to carcinoma [2]. The earliest and potentially life-threatening stage of carcinoma is pT1, characterized by the presence of cancer glands that have invaded the submucosal layer of the bowel wall. These cancers are preced
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