In spite of all we have learned about the genetic basis of colorectal cancer (CRC) over the past 25 years, a large proportion of patients with some form of familial CRC (FCC) cannot be characterized in a way that the family can be rationally counseled. This proposal is a dual-principal investigator renewal application for a highly productive program that has been ongoing for 18 years. Over the past 5 years, we have made progress in our understanding of how methylation-based silencing of the DNA mismatch repair (MMR) genes play a role in the genesis of CRC; our work has characterized early-onset CRCs that occur in the absence of FCC, and we found that genetic and epigenetic alterations in the tumor tissues of these patients are similar to that of non- Lynch syndrome FCC (or, FCC-type X). We characterized how alterations in expression of the MSH3 gene are involved in the genesis of sporadic CRCs. We have provided insights into the role of epigenetics in the genesis and clinical behavior of CRCs. The overarching goal of this program is to move toward a more complete personalization of the concepts used in the classification of familiality in CRC. We have four specific aims. Based upon our work on the somatic inactivation of MSH3 in CRCs, we propose to test the hypothesis that germline mutations in the MSH3 gene cause a previously unidentified disease - Lynch syndrome-MSH3 type, which would have a phenotype that would be systematically overlooked because of how we currently screen for Lynch syndrome. Second, we plan to develop an approach for finding balanced inversions in the Lynch syndrome-associated MMR genes to resolve the uncertainty in families where the anticipated germline mutations cannot be identified. Third, we propose that FCC-type X is associated with a unique tumor phenotype that will lead us to the germline basis of that disease. Finally, we propose to use whole genome sequencing techniques to test the hypothesis that the serrated polyposis syndrome (SPS) is a rare recessive disease caused by biallelic mutations in a gene involved in the methylator pathway of colorectal tumorigenesis. If successful, this work will fill several remaining gaps in the FCC problem, and is likely to have a substantial impact on patient care.

Public Health Relevance

Colorectal cancer (CRC) is a common problem, and is often associated with a positive family history of CRC or polyposis syndrome. Although progress has been made in understanding the highly penetrant genetic forms of familial CRC, there are substantial gaps that prevent clinicians from being able to assess risk and develop management plans for most patients. This application proposes to address four important unresolved issues in familial CRC.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Thurin, Magdalena
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Baylor Research Institute
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Wang, Wei; Kandimalla, Raju; Huang, Hao et al. (2018) Molecular subtyping of colorectal cancer: Recent progress, new challenges and emerging opportunities. Semin Cancer Biol :
Ravindranathan, Preethi; Pasham, Divya; Balaji, Uthra et al. (2018) A combination of curcumin and oligomeric proanthocyanidins offer superior anti-tumorigenic properties in colorectal cancer. Sci Rep 8:13869
Ozawa, Tsuyoshi; Kandimalla, Raju; Gao, Feng et al. (2018) A MicroRNA Signature Associated With Metastasis of T1 Colorectal Cancers to Lymph Nodes. Gastroenterology 154:844-848.e7
Boland, Patrick M; Yurgelun, Matthew B; Boland, C Richard (2018) Recent progress in Lynch syndrome and other familial colorectal cancer syndromes. CA Cancer J Clin 68:217-231
Kandimalla, Raju; Gao, Feng; Matsuyama, Takatoshi et al. (2018) Genome-wide Discovery and Identification of a Novel miRNA Signature for Recurrence Prediction in Stage II and III Colorectal Cancer. Clin Cancer Res 24:3867-3877
Ruiz-Bañobre, Juan; Goel, Ajay (2018) DNA Mismatch Repair Deficiency and Immune Checkpoint Inhibitors in Gastrointestinal Cancers. Gastroenterology :
Perea, José; García, Juan L; Corchete, Luis et al. (2018) Redefining synchronous colorectal cancers based on tumor clonality. Int J Cancer :
Toden, Shusuke; Ravindranathan, Preethi; Gu, Jinghua et al. (2018) Oligomeric proanthocyanidins (OPCs) target cancer stem-like cells and suppress tumor organoid formation in colorectal cancer. Sci Rep 8:3335
Weng, Wenhao; Liu, Na; Toiyama, Yuji et al. (2018) Novel evidence for a PIWI-interacting RNA (piRNA) as an oncogenic mediator of disease progression, and a potential prognostic biomarker in colorectal cancer. Mol Cancer 17:16
Takehara, Yuko; Nagasaka, Takeshi; Nyuya, Akihiro et al. (2018) Accuracy of four mononucleotide-repeat markers for the identification of DNA mismatch-repair deficiency in solid tumors. J Transl Med 16:5

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