Final Report Summary - NGG (Next Generation Genetics of Cancer Predisposition)
Unraveling genetic components of human tumor predisposition has contributed significantly to our understanding on molecular basis of cancer. Such understanding can be translated into improved markers for diagnosis and prognosis, and identification of drug targets. Cancer prevention in the context of hereditary tumor susceptibility is one of the early examples of benefits from genetic disease information. Research into cancer susceptibility is of great importance, and Finland provides unique interdisciplinary possibilities to take the field forward.
Most or all genes for common high-penetrance Mendelian cancer syndromes have been identified in previous studies by us and others. These conditions explain perhaps 5% of the common cancers. At the start of the NGG project the genome wide association study (GWAS) data explained a small proportion of familial cancer, e.g. about 6% in colorectal cancer (CRC). Much remained to be discovered and genetics of cancer predisposition in different contexts remains to be a key field of medical translational research. The project thrived on the powerful synergistic combination of advancing technologies, unique national materials and infrastructure, and sophisticated data analyses.
Work on rare high-penetrance Mendelian cancer predisposition conditions, and the respective susceptibility genes resulted e.g. in the following findings: We identified to our knowledge the first published case of familial primary mediastinal large B-cell lymphoma, as well as provides data to suggest that MLL may be the predisposition gene. High familial Risk in nodular lymphocyte predominant hodgkin lymphoma was demonstrated in a national Finnish registry based study. A defect in the SUFU gene was identified as the culprit in a family segregating multiple meningiomas. Whole genome sequencing identified STAT4 as a putative susceptibility gene in classic Kaposi sarcoma.
Efforts to identify moderate penetrance cancer susceptibility genes were also successful. Such phenotypes have been difficult to approach with traditional gene identification methods because large pedigrees with multiple affected individuals and few or no phenocopies are not easily identified. Also, the current GWAS approaches are not ideal to detect these loci due to relative rarity of the responsible variants. Several genes were identified during the project, for further validation in a systematic search for rare variants in Finnish early-onset colorectal cancer patients.
Characterization of common variants associated with cancer susceptibility is important for population-level cancer prevention. In particular, little is known about the biology underlying these variants – starting from identification of the truly causative variants from the associated genomic regions. Here a particular focus was on colorectal cancer, where NGG, often in collaboration with others, contributed to detection and functional validation of multiple loci predisposing to low penetrance CRC. These include MYC, CDKN1A, POLD3, SHROOM2, GREM1, BMP4, and BMP2. Also variation at 2q35 (at PNKD and TMBIM1 genes) was found to influence colorectal cancer risk. NGG has also contributed to translation of this knowledge, to identify biomarkers for cancer predisposition to facilitate adequate and early detection of predisposed individuals. These efforts will facilitate cancer prevention in individuals with increased cancer risk.
Most or all genes for common high-penetrance Mendelian cancer syndromes have been identified in previous studies by us and others. These conditions explain perhaps 5% of the common cancers. At the start of the NGG project the genome wide association study (GWAS) data explained a small proportion of familial cancer, e.g. about 6% in colorectal cancer (CRC). Much remained to be discovered and genetics of cancer predisposition in different contexts remains to be a key field of medical translational research. The project thrived on the powerful synergistic combination of advancing technologies, unique national materials and infrastructure, and sophisticated data analyses.
Work on rare high-penetrance Mendelian cancer predisposition conditions, and the respective susceptibility genes resulted e.g. in the following findings: We identified to our knowledge the first published case of familial primary mediastinal large B-cell lymphoma, as well as provides data to suggest that MLL may be the predisposition gene. High familial Risk in nodular lymphocyte predominant hodgkin lymphoma was demonstrated in a national Finnish registry based study. A defect in the SUFU gene was identified as the culprit in a family segregating multiple meningiomas. Whole genome sequencing identified STAT4 as a putative susceptibility gene in classic Kaposi sarcoma.
Efforts to identify moderate penetrance cancer susceptibility genes were also successful. Such phenotypes have been difficult to approach with traditional gene identification methods because large pedigrees with multiple affected individuals and few or no phenocopies are not easily identified. Also, the current GWAS approaches are not ideal to detect these loci due to relative rarity of the responsible variants. Several genes were identified during the project, for further validation in a systematic search for rare variants in Finnish early-onset colorectal cancer patients.
Characterization of common variants associated with cancer susceptibility is important for population-level cancer prevention. In particular, little is known about the biology underlying these variants – starting from identification of the truly causative variants from the associated genomic regions. Here a particular focus was on colorectal cancer, where NGG, often in collaboration with others, contributed to detection and functional validation of multiple loci predisposing to low penetrance CRC. These include MYC, CDKN1A, POLD3, SHROOM2, GREM1, BMP4, and BMP2. Also variation at 2q35 (at PNKD and TMBIM1 genes) was found to influence colorectal cancer risk. NGG has also contributed to translation of this knowledge, to identify biomarkers for cancer predisposition to facilitate adequate and early detection of predisposed individuals. These efforts will facilitate cancer prevention in individuals with increased cancer risk.