Abstract
Families of tumor-suppressor genes, such as those involved in homologous recombination or mismatch repair, contain individual genes implicated in hereditary cancer syndromes. Collectively, such groupings establish that inactivating germline changes in genes within pathways related to genomic repair can promote carcinogenesis. The hypoxia pathway, whose activation is associated with aggressive and resistant sporadic tumors, is another pathway in which tumor-suppressor genes have been identified. von Hippel–Lindau disease, some of the hereditary paraganglioma–pheochromocytoma (PGL/PCC) syndromes, and the syndrome of hereditary leiomyomatosis and renal cell carcinoma are heritable conditions associated with genes involved or associated with the hypoxia pathway. This review links these heritable cancer syndromes to the hypoxia pathway while also comparing the relative aggression and treatment resistance of syndrome-associated tumors to similar, sporadic tumors. The reader will become aware of shared phenotypes (e.g., PGL/PCC, renal cell carcinoma) among these three hypoxia-pathway-associated heritable cancer syndromes as well as the known associations of tumor aggressiveness and treatment resistance within these pathways.
Highlights
Heritable cancer syndromes provide important clinical and research avenues
Insights related to these pathways led to the Abbreviations: FH, fumarate hydratase; HIF1, hypoxia-inducible factor 1; Hereditary leiomyomatosis and renal cell cancer (HLRCC), hereditary leiomyomatosis and renal cell cancer, PGL/PCC, paraganglioma–pheochromocytoma; RCC, renal cell carcinoma; SDH, succinate dehydrogenase; VEGF, vascular endothelial growth factor; VHL, von Hippel–Lindau
Like germline mutations in genes in the homologous recombination pathway and their association with hereditary breast and ovarian cancer; or germline mutations in mismatch repair genes and their association with colorectal cancer; germline mutations in genes associated with the hypoxia pathway (e.g., VHL, the SDHx genes, FH) appear to be associated with RCC and PGL/PCC
Summary
Heritable cancer syndromes provide important clinical and research avenues. Clinically, diagnosing a heritable cancer syndrome allows a patient and his/her family to receive appropriate, targeted cancer screenings or preventive interventions. Families of tumor-suppressor genes consist of individual genes implicated in hereditary cancer syndromes that share common molecular pathways, such as the homologous recombination (e.g., BRCA1, BRCA2, PALB2) or mismatch repair (e.g., MLH1, MSH2, MSH6) pathways. Such groupings establish that inactivating germline changes in genes within pathways related to genomic repair can promote carcinogenesis. Insights related to these pathways led to the Abbreviations: FH, fumarate hydratase; HIF1, hypoxia-inducible factor 1; HLRCC, hereditary leiomyomatosis and renal cell cancer, PGL/PCC, paraganglioma–pheochromocytoma; RCC, renal cell carcinoma; SDH, succinate dehydrogenase; VEGF, vascular endothelial growth factor; VHL, von Hippel–Lindau
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