A good biomarker should assist clinical decision-making – either by stratifying prognosis or identifying therapeutic opportunities. These issues will be highlighted in considering two such immunohistochemistry biomarkers now used routinely in our institution: detection of oncogenic BRAFin thyroid cancer; and detection of SDH deficiency in phaeochromocytomas and paragangliomas.
A majority of thyroid cancers contain somatic gene alterations causing activation of the MAP kinase signaling pathway, of which the commonest is BRAFV600E that occurs in about 60% of papillary thyroid cancer (PTC) cases in Australia. A recent multicenter study found that BRAFV600E was significantly associated with increased cancer-related mortality among patients with PTC. The conundrum in using BRAF as an adverse biomarker is that occurs so commonly in a disease that usually has a good outcome: it has been recently recognized that mortality is better predicted when BRAFV600E is accompanied by mutation in the TERT promoter.
Germline mutations in one of the four genes encoding subunits of succinate dehydrogenase (SDH) are collectively the commonest cause of heritable phaeochromocytoma/paraganglioma syndromes. Loss of SDHB immunostaining has proved to be an important tool for recognising tumours associated with mutations in any of the SDHx genes; loss of SDHA immunostaining is more specific for germline mutation in SDHA. The utility of these biomarkers was emphasized in characterizing SDH-deficient renal cell cancers, gastrointestinal stromal tumours and pituitary adenomas that are also associated with germline SDHx mutations. Moreover, negative SDHB immunohistochemistry provides functional validation of pathogenicity when variants of otherwise uncertain significance are identified in SDHx genes.