BRAF gene: From human cancers to developmental syndromes

Muhammad Ramzan Manwar Hussain, Mukhtiar Baig, Hussein Sheik Ali Mohamoud, Zaheer Ulhaq, Daniel C Hoessli, Ghaidaa Siraj Khogeer, Ranem Radwan Al-Sayed, Jumana Yousuf Al-Aama, Muhammad Ramzan Manwar Hussain, Mukhtiar Baig, Hussein Sheik Ali Mohamoud, Zaheer Ulhaq, Daniel C Hoessli, Ghaidaa Siraj Khogeer, Ranem Radwan Al-Sayed, Jumana Yousuf Al-Aama

Abstract

The BRAF gene encodes for a serine/threonine protein kinase that participates in the MAPK/ERK signalling pathway and plays a vital role in cancers and developmental syndromes (RASopathies). The current review discusses the clinical significance of the BRAF gene and other members of RAS/RAF cascade in human cancers and RAS/MAPK syndromes, and focuses the molecular basis and clinical genetics of BRAF to better understand its parallel involvement in both tumourigenesis and RAS/MAPK syndromes-Noonan syndrome, cardio-facio-cutaneous syndrome and LEOPARD syndrome.

Keywords: BRAF gene; Cancers; Developmental syndromes; RAS–RAF overactivation.

Figures

Figure 1
Figure 1
Protein domains connecting the cancers and RASopathies, and 3D structure of the BRAF protein. (A) BRAF mutations common to kinase domain (457–717 amino acids) are characterised mostly in melanoma, colorectal cancer, lung cancer, thyroid cancer and ovarian cancer, and CFC. (B) 3D structure of the BRAF protein with highlighted residues at the 241, 257, 469, 499 and 600 positions—the most common sites for amino acid substitutions, screened in NS, CFC and cancer diseases.
Figure 2
Figure 2
Venn diagram to show BRAF mutations (amino acid variations), characterised in different cancer types. The highest number of mutations is seen in melanomas, indicated in blue colour circle. The smaller number of mutations is observed in thyroid cancer, shown in red colour circle. However, mutations observed in more than one type of cancer are shown in the overlapping regions. For example, the G469R and V600E mutations are characterised in all 4 types of cancers, shown by the overlapping region.
Figure 3
Figure 3
Schematic diagram showing the RAS–RAF signalling pathway with different cancers (A) and RASopathies (B). In melanoma, in red colour, RAS and BRAF mutations activate both effector pathways: Raf–MEK–ERK (BRAF gene) and PI3K–Akt signalling. In thyroid cancer (papillary carcinoma), in grey colour, both RAS and RAF (BRAF) play a combined critical role in proliferation. Molecular cascade underlying prostate cancer (turquoise) underlies both MAPK and p53 pathways. The glioma involves PDGF, PDGFR, Sch, Grb2, SOS, Ras, Raf and MAPK. In colorectal cancer, indicated in blue colour, both TGF-β and MAPK signalling pathways play a critical role. RAS/RAF signalling transduction for developmental syndromes (NS, CFC and LEOPARD) is indicated in B.
Figure 3
Figure 3
Schematic diagram showing the RAS–RAF signalling pathway with different cancers (A) and RASopathies (B). In melanoma, in red colour, RAS and BRAF mutations activate both effector pathways: Raf–MEK–ERK (BRAF gene) and PI3K–Akt signalling. In thyroid cancer (papillary carcinoma), in grey colour, both RAS and RAF (BRAF) play a combined critical role in proliferation. Molecular cascade underlying prostate cancer (turquoise) underlies both MAPK and p53 pathways. The glioma involves PDGF, PDGFR, Sch, Grb2, SOS, Ras, Raf and MAPK. In colorectal cancer, indicated in blue colour, both TGF-β and MAPK signalling pathways play a critical role. RAS/RAF signalling transduction for developmental syndromes (NS, CFC and LEOPARD) is indicated in B.
Figure 4
Figure 4
Genes—KRAS, BRAF, PTPN11 and SOS1—characterised in both human cancers and RAS/MAPK syndromes (CFC & Noonan).

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