Signs of an immune response within colorectal cancers are associated with the absence of pathological evidence of early metastatic invasion and with prolonged survival.
Summary
We report a comprehensive molecular characterization of pheochromocytomas
and paragangliomas (PCC/PGLs), a rare tumor type. Multi-platform integration
revealed that PCC/PGLs are driven by diverse alterations affecting multiple
genes and pathways. Pathogenic germline mutations occurred in eight PCC/PGL
susceptibility genes. We identified CSDE1 as a
somatically-mutated driver gene, complementing four known drivers
(HRAS, RET, EPAS1,
NF1). We also discovered fusion genes in PCC/PGL, involving
MAML3, BRAF, NGFR and
NF1. Integrated analysis classified PCC/PGLs into four
molecularly-defined groups: a kinase signaling subtype, a pseudohypoxia subtype,
a Wnt-altered subtype, driven by MAML3 and
CSDE1, and a cortical admixture subtype. Correlates of
metastatic PCC/PGL included the MAML3 fusion gene. This
integrated molecular characterization provides a comprehensive foundation for
developing PCC/PGL precision medicine.
Assessment of CD8(+) cytotoxic T lymphocytes in combined tumor regions provides an indicator of tumor recurrence beyond that predicted by AJCC/UICC-TNM staging.
Summary
Background
Phaeochromocytomas and paragangliomas are neuro-endocrine tumours that occur sporadically and in several hereditary tumour syndromes, including the phaeochromocytoma–paraganglioma syndrome. This syndrome is caused by germline mutations in succinate dehydrogenase B (SDHB), C (SDHC), or D (SDHD) genes. Clinically, the phaeochromocytoma–paraganglioma syndrome is often unrecognised, although 10–30% of apparently sporadic phaeochromocytomas and paragangliomas harbour germline SDH-gene mutations. Despite these figures, the screening of phaeochromocytomas and paragangliomas for mutations in the SDH genes to detect phaeochromocytoma–paraganglioma syndrome is rarely done because of time and financial constraints. We investigated whether SDHB immunohistochemistry could effectively discriminate between SDH-related and non-SDH-related phaeochromocytomas and paragangliomas in large retrospective and prospective tumour series.
Methods
Immunohistochemistry for SDHB was done on 220 tumours. Two retrospective series of 175 phaeochromocytomas and paragangliomas with known germline mutation status for phaeochromocytoma-susceptibility or paraganglioma-susceptibility genes were investigated. Additionally, a prospective series of 45 phaeochromocytomas and paragangliomas was investigated for SDHB immunostaining followed by SDHB, SDHC, and SDHD mutation testing.
Findings
SDHB protein expression was absent in all 102 phaeochromocytomas and paragangliomas with an SDHB, SDHC, or SDHD mutation, but was present in all 65 paraganglionic tumours related to multiple endocrine neoplasia type 2, von Hippel–Lindau disease, and neurofibromatosis type 1. 47 (89%) of the 53 phaeochromocytomas and paragangliomas with no syndromic germline mutation showed SDHB expression. The sensitivity and specificity of the SDHB immunohistochemistry to detect the presence of an SDH mutation in the prospective series were 100% (95% CI 87–100) and 84% (60–97), respectively.
Interpretation
Phaeochromocytoma–paraganglioma syndrome can be diagnosed reliably by an immunohistochemical procedure. SDHB, SDHC, and SDHD germline mutation testing is indicated only in patients with SDHB-negative tumours. SDHB immunohistochemistry on phaeochromocytomas and paragangliomas could improve the diagnosis of phaeochromocytoma–paraganglioma syndrome.
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