Table 2.
Somatic Variants Identified in Sporadic Pituitary NFAsa
| Gene Symbol | Gene Name | Transcript | Nucleotide Change | Protein Change | Mutation Type | Predicted Zygosity (Variant Allele %)b | Variant Type | Tumor Number |
|---|---|---|---|---|---|---|---|---|
| ABCA10 | ATP-binding cassette, subfamily A (ABC1), member 10 | NM_080282 | c.A841G | p.T281A | Missense | het (33%) | SNV | 6 |
| ASS1 | Argininosuccinate synthase 1 | NM_054012 | c.A1223G | p.K408R | Missense | het (40%) | SNV | 3 |
| CRTAC1 | Cartilage acidic protein 1 | NM_001206528 | c.G89A | p.R30Q | Missense | het (32%) | SNV | 4 |
| DOCK9 | Dedicator of cytokinesis 9 | NM_001130048 | c.A4006G | p.I1336V | Missense | het (12%) | SNV | 5 |
| GRM7 | Glutamate receptor, metabotropic 7 | NM_000844 | c.G1140A | p.G380G | Synonomous | het (33%) | SNV | 2 |
| KEL | Kell blood group, metallo-endopeptidase | NM_000420 | c.G937A | p.A313T | Missense | het (42%) | SNV | 3 |
| KLHL4 | Kelch-like 4 | NM_019117 | c.G1441A | p.V481M | Missense | het (25%) | SNV | 2 |
| MYBPH | Myosin binding protein H | NM_004997 | c.A1G | p.M1V | Missense | het (41%) | SNV | 3 |
| NDRG4 | N-myc down-regulated gene family member 4 | NM_001130487 | c.167_168del | p.T56RfsX6 | Frameshift | het (30%) | indel | 4 |
| NFXL1 | Nuclear transcription factor, X-box binding-like 1 | NM_152995 | c.C1300T | p.H434Y | Missense | het (39%) | SNV | 6 |
| PDGFD | Platelet derived growth factor D | NM_025208 | c.A791G | p.N264S | Missense | het (30%) | SNV | 2 |
| POMT2 | Protein-O-mannosyltransferase 2 | NM_013382 | c.C1317T | p.V439V | Synonomous | het (40%) | SNV | 2 |
| PPP3R2 | Protein phosphatase 3, regulatory subunit B, β | NM_147180 | c.C167T | p.P56L | Missense | het (42%) | SNV | 4 |
| RNF135 | Ring finger protein 135 | NM_032322 | c.854_855delinsCA | p.H285P | Missense | het (30%) | indel | 7 |
| ROPN1L | Rhophilin associated tail protein 1-like | NM_031916 | c.T116A | p.L39Q | Missense | het (39%) | SNV | 2 |
| SETBP1 | SET binding protein 1 | NM_015559 | c.C3718A | p.Q1240K | Missense | het (41%) | SNV | 4 |
| SLC35E3 | Solute carrier family 35, member E3 | NM_018656 | c.A95T | p.N32I | Missense | het (43%) | SNV | 1 |
| SLC5A10 | Solute carrier family 5 (sodium/glucose cotransporter), member 10 | NM_001042450 | c.T404A | p.M135K | Missense | het (29%) | SNV | 4 |
| SORCS1 | Sortilin-related VPS10 domain containing receptor 1 | NM_001013031 | c.G940T | p.V314L | Missense | het (34%) | SNV | 1 |
| SPHKAP | SPHK1 interactor, AKAP domain containing | NM_001142644 | c.A3773G | p.N1258S | Missense | het (33%) | SNV | 2 |
| SPTBN5 | Spectrin, β, non-erythrocytic 5 | NM_016642 | c.G913A | p.A305T | Missense | het (60%) | SNV | 2 |
| TCF7L2 | Transcription factor 7-like 2 | NM_001198530 | c.A407G: | p.H136R | Missense | het (23%) | SNV | 3 |
| TOMM70A | Translocase of outer mitochondrial membrane 70 homolog A | NM_014820 | c.613delG | p.E205NfsX3 | Frameshift | het (40%) | indel | 7 |
| ZAK | Zipper sterile-α-motif kinase | NM_016653 | c.G592C | p.E198Q | Missense | het (39%) | SNV | 3 |
Abbreviations: het, heterozygous; homo, homozygous; indel, insertion or deletion. Genes in boldface were identified as putative candidate driver mutations and sequenced in an additional 24 pituitary NFAs.
Only somatic variants that were confirmed by a second method of capillary sequencing are shown. The concordance between the variant calling algorithm and confirmatory capillary sequencing for somatic variants was 86%, which is lower than that observed for germline variants. This lower concordance, which has been reported by other studies (9, 10, 17), may be due to the occurrence of variants with low-allele frequencies in tumor samples, which may be genetically heterogeneous, and the limitations of capillary sequencing that may not be able to detect variants with an allele percentage of less than 15% (10). The Platypus variant calling algorithm was used to identify the somatic variants because it has been successfully validated by other studies including the 1000 Genomes Project (1000 Genomes Project Consortium, Abecasis GR, Auton A, Brooks LD, DePristo MA, Durbin RM, et al. Nature. 2012;491:56–65; Nesbit MA, Hannan FM, Howles SA, Reed AA, Cranston T, Thakker CE, et al. Nat Genet. 2013;45:93–97). However, it remains possible that the use of alternate variant calling algorithms may identify some different somatic variants and reduce the false-positive rate.
The variant allele percentage was calculated by dividing the total number of variant allele calls by the total number of calls for that nucleotide. Deviation from predicted heterozygote (50%) and homozygote (100%) allele frequencies may reflect contamination with normal tissue, genetic heterogeneity of tumor tissue, and/or a preference for the wild-type allele in the sequencing and alignment process.