Thesis

Assessing cancer risk in germline genetic conditions

With advances in cancer research, many genes have been identified in sporadic tumorigenesis. Some of the same genes mutated somatically in tumors are mutated in germline genetic conditions. Interestingly, these germline conditions often involve cancer susceptibility (e.g. TP53 and Li-Fraumeni syndrome), but sometimes a cancer association has not been identified (e.g. GATA3 and Hypoparathyroidism, sensorineural deafness, and renal dysplasia syndrome). We hypothesize that there is an unrecognized risk for cancer in some of the germline genetic conditions that share genes with sporadic tumors. To test this hypothesis, we analyzed 127 significantly mutated genes in cancer for their associations with germline genetic syndromes and cancer susceptibility. After excluding 34 known cancer-predisposition conditions and 55 genes with no syndromic associations, we performed a systematic PubMed search on the remaining 38 genes. Case reports of cancer were identified in 13 germline conditions, including Apert syndrome. To perform validation, we searched 13,945,229 pediatric hospital stays from the KID database to look for evidence of cancer among individuals affected with Apert syndrome. We estimated a cancer rate of ~0.37% - 1.1% among affected children, compared to a pediatric population risk of ~0.015%, p < 0.00001. To explore a potential approach to cancer screening, we compared mutational profiles of 54 sporadic tumors that share the same mutations implicated in Apert syndrome. We identified several genes that were frequently mutated across the tumor samples. Over the years of a patient’s life, such acquired gene mutations may be important in tumor predisposition. In conclusion, we developed a new means for assessing cancer risk in germline genetic conditions. Further efforts examining more tumors in both the unselected population and in individuals with syndromes will aid future counseling, tumor prediction or screening methods.

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