Colorectal cancer (CRC) is the third most common cancer and the second main cause of cancer mortality worldwide. The colorectum and the small bowel are part of a continuous passageway called the gastrointestinal (GI) tract, however, the cancer incidence varies greatly between these two organs. Although the small bowel constitutes three quarters of the length of the GI tract, only 3% of GI cancers are located in the small bowel. These cancers develop due to both somatic and inherited germline mutations. Thus, characterizing the genetic events that drive tumorigenesis is crucial to provide ways to improve prevention and clinical management of the disease. The general aim of this thesis was to gain new insights into the molecular genetic backgrounds of CRC and small bowel adenocarcinoma (SBA). The first aim of the thesis was to characterize the somatic mutation patterns of the AT-Rich Interaction Domain (ARID) family genes in CRCs with microsatellite instability (MSI). Approximately 15% of CRCs display MSI which arises due to a defective DNA mismatch repair system. These tumors accumulate a high number of mutations, especially small insertions and deletions in repetitive genomic areas called microsatellites. The ARID gene family comprises 15 members, including a known tumor suppressor gene ARID1A. We utilized exome sequencing data of 25 MSI CRCs and their corresponding normal tissues and identified 12 of the ARID genes to display mutations with a frequency of 4-52%. Four genes were selected for further analysis in 21 additional MSI CRCs. We found that, in addition to ARID1A, also ARID1B, ARID2, and ARID4A were frequently mutated and might play a role in MSI CRC. However, additional studies are warranted to further scrutinize the function of these mutations in MSI CRC genesis. The second aim of the thesis was to identify novel oncogenes in MSI CRC. These tumors represent a sensitive system for studying the generation and selection of oncogenic mutations. In contrast to many reported MSI target genes, few oncogenes are known in MSI CRC and they often display specific mutation hotspots. Thus, we used the exome sequencing data of 25 MSI CRCs and their corresponding normal tissues to search for genes with recurrent somatic missense mutations. We identified 33 novel candidate oncogenes of which the following fourteen genes displayed hotspot mutations also in the validation set of 254 MSI CRCs: ANTXR1, CEP135, CRYBB1, MORC2, SLC36A1, GALNT9, PI15, KRT82, CNTF, GLDC, MBTPS1, OR9Q2, R3HDM1, and TTPAL. This work revealed a variety of novel recurrent candidate oncogene mutations that might potentially be used to develop personalized therapies. Further research is still needed to confirm their pathogenic role and detailed function in tumorigenesis. The third aim of the thesis was to study the genetic overlap within synchronous CRCs (SCRCs). Approximately 4% of CRC patients display multiple simultaneous primary cancers in the colorectum. Understanding whether SCRCs within a patient are genetically similar or distinct is essential when designing personalized treatments. Exome sequencing data of 23 SCRC pairs and their corresponding healthy tissues revealed that the paired tumors shared a maximum of only a few somatic mutations. This indicated that the tumors have independent origins. Furthermore, paired tumors favored different somatic mutations in known CRC genes and signaling pathways. Variation was observed among clinically relevant genes, such as the discordant KRAS mutation status in a quarter of patients. Tumors within pairs also displayed variation in their mutational signature content suggesting that, regardless of the shared environment, some pairs might have undergone different mutational processes. Finally, by analyzing immune cell counts, we observed that the intratumor immune response varied within most tumor pairs. This was not explained by mutation burden or clinicopathological variables. Overall, this work revealed major diversity within SCRCs and highlights the need to evaluate all synchronous lesions within an individual for optimized therapeutic approach. Additional studies are still required to further elucidate the reasons underlying tumor multiplicity. The fourth aim of the thesis was to characterize the somatic mutation content in SBA. Due to its rarity, knowledge on the genetic background of SBA has remained somewhat elusive. We conducted the first large exome sequencing effort of 106 population-based SBAs representing all three small bowel segments. This work revealed significantly mutated genes previously associated with SBA (TP53, KRAS, APC, SMAD4, and BRAF), as well as novel candidate drivers, such as ACVR2A, ACVR1B, BRCA2, and SMARCA4. We identified clear mutation hotspot patterns in ERBB2 and BRAF. Interestingly, we observed no V600E mutations, the most common BRAF mutation hotspot in CRC. Other clinically relevant aspects included mutations in ERBB family genes in over a quarter of SBAs as well as mutations in multiple genes that could predict anti-EGFR treatment resistance. We performed the first comprehensive mutation signature analysis on SBA that highlighted four signatures: 1A, 6, 17, and U2. Comparison of the three small bowel segments unveiled some variation in tumor characteristics. Further studies are needed to robustly clarify these differences and their clinical relevance. This comprehensive characterization provided further evidence that SBA is a distinct tumor type and singled out many potential therapeutic targets that could be utilized in SBA treatment development.
  • Aaltonen, Lauri, Valvoja
  • Mäkinen, Netta, Valvoja
  • Tuupanen, Sari , Valvoja
Painoksen ISBN978-951-51-6487-2
Sähköinen ISBN978-951-51-6488-9
TilaJulkaistu - 2020
OKM-julkaisutyyppiG5 Tohtorinväitöskirja (artikkeli)


M1 - 89 s. + liitteet


  • 3111 Biolääketieteet
  • 1184 Genetiikka, kehitysbiologia, fysiologia

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