Clinical and molecular characteristics of GI malignancies exhibiting MTAP alterations, presented as gene loss, mutations and amplification in the TCGA PanCancer Atlas Studies and the Niguarda Cancer Center cohort
| TCGA cohort (N=135) | Niguarda cohort (N=27) | ||||
| MTAP loss | MTAP mutant | MTAP amplified | MTAP loss | MTAP mutant | |
| No of patients | 128 | 7 | 4 | 22 | 5 |
| Median age (IQR) | 63 (56–72) | 71 (62–72) | 62 (53.72) | 62 (48–72) | 55 (47–68) |
| Gender (%) | |||||
| Male | 89 (69.5) | 1 (14.3) | 3 (75.0) | 13 (59.1) | 3 (60.0) |
| Female | 39 (30.5) | 6 (85.7) | 1 (25.0) | 9 (40.9) | 2 (40.0) |
| Cancer type (%) | |||||
| Pancreas | 40 (31.3) | 0 (0.0) | 1 (25.0) | 12 (54.5) | 0 (0.0) |
| Gastro-oesophageal | 78 (60.9) | 3 (42.9) | 1 (25.0) | 4 (18.2) | 0 (0.0) |
| Colorectal | 6 (4.7) | 4 (57.1) | 2 (50.0) | 2 (9.1)* | 5 (100.0) |
| Biliary tract | 4 (3.1) | 0 (0.0) | 0 (0.0) | 2 (9.1) | 0 (0.0) |
| Others | 0 (0.0) | 0 (0.0) | 0 (0.0) | 2 (9.1) | 0 (0.0) |
| Tumour histology (%) | |||||
| Adenocarcinoma | 95 (74.2) | 5 (71.4) | 4 (100.0) | 19 (86.4) | 5 (100.0)† |
| Mucinous adenocarcinoma | 2 (1.6) | 0 (0.0) | 0 (0.0) | 1 (4.5) | 0 (0.0) |
| Signet ring carcinoma | 4 (3.1) | 1 (14.3) | 0 (0.0) | 1 (4.5) | 0 (0.0) |
| Squamous carcinoma | 27 (21.1) | 1 (14.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Undifferentiated carcinoma | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (4.5) | 0 (0.0) |
| Stage at diagnosis (%) | |||||
| Non metastatic | 82 (64.1) | 5 (71.4) | 2 (50.0) | 9 (40.9) | 4 (80.0) |
| Metastatic | 12 (9.4) | 1 (14.3) | 1 (25.0) | 13 (59.1) | 1 (20.0) |
| NA | 34 (36.2) | 1 (14.3) | 1 (25.0) | 0 (0.0) | 0 (0.0) |
| Tumour mutational burden-high‡ (%) | 4§ (3.1) | 4§ (57.1) | 0§ (0.0) | 1 (4.5)¶ | 1 (20.0) |
| Microsatellite instability (%) | 1** (0.8) | 4** (57.1) | 0** (0.0) | 0 (0.0) | 1 (20.0) |
| Concomitant CDKN2A-CDKN2B deletion (%) | 125†† (97.7) | 1 (14.3) | 1 (25.0) | 22 (100.0) | 0 (0.0) |
| Concomitant MTAP loss-RAS mutations (%) | |||||
| Pancreatic | 34 (85.0) | NA | 1 (100.0) | 12 (100.0) | NA |
| Colorectal | 2 (40.0) | 3 (75.0) | 1 (50.0) | 1 (14.3) | 1 (20.0) |
*Both colorectal cancers were RAS and BRAF wild type, MSS, with low TMB.
†One adenocarcinoma had squamous foci.
‡≥10 mutations/megabase.
§Non-synonymous TMB.
¶POLE mutatation found.
**According to the MANTIS score with a threshold of 0.4.
††CDKN2A in 97.7% of cases, while CDKN2B in 92.2%. CDKN2A loss always reported for all CDKN2B loss cases, co-occurrence 118/128 cases. Log2 OR >3, p<0.001 (derived from two-sided Fisher’s exact test).
GI, gastrointestinal; MANTIS, Microsatellite Analysis for Normal-Tumor InStability; MSS, Microsatellite stable; MTAP, methylthioadenosine phosphorylase; NA, not applicable; OR, Odds ratio; TCGA, The Cancer Genome Atlas; TMB, Tumour mutational burden.