The present study on the genomic and transcriptomic analysis of 16 marker-null LCC showed that (i) TP53 was the most frequently inactivated gene (15/16; 93.7%) followed by RB1 (5/16; 31.3%) and KEAP1 (4/16; 25%), while CRKL and MYB genes were amplified in 4/16 (25%) cases and MYC in 3/16 (18.8%) cases and (ii) transcriptomic analysis identified two molecular subtypes including a Pure-LCC and an adenocarcinoma like-LCC (ADLike-LCC) characterized by different activated pathways and cell of origin. Here, TP53 is linked to leukoencephalopathy with calcifications and cysts.