Haplotype-resolved germline and somatic alterations in renal medullary carcinomas

Tan KT, Kim H, Carrot-Zhang J, Zhang Y, Kim WJ, Kugener G, Wala JA, Howard TP, Chi YY, Beroukhim R, Li H, Ha G, Alper SL, Perlman EJ, Mullen EA, Hahn WC, Meyerson M, Hong AL. Haplotype-resolved germline and somatic alterations in renal medullary carcinomas. Genome Med. 2021 Jul 14;13(1):114. doi: 10.1186/s13073-021-00929-4. PubMed PMID: 34261517; PubMed Central PMCID: PMC8281718.

Renal medullary carcinomas (RMCs) are rare kidney cancers that occur in adolescents and young adults of African ancestry. Although RMC is associated with the sickle cell trait and somatic loss of the tumor suppressor, SMARCB1, the ancestral origins of RMC remain unknown. Further, characterization of structural variants (SVs) involving SMARCB1 in RMC remains limited. We used linked-read genome sequencing to reconstruct germline and somatic haplotypes in 15 unrelated patients with RMC registered on the Children’s Oncology Group (COG) AREN03B2 study between 2006 and 2017 or from our prior study. We performed fine-mapping of the HBB locus and assessed the germline for cancer predisposition genes. Subsequently, we assessed the tumor samples for mutations outside of SMARCB1 and integrated RNA sequencing to interrogate the structural variants at the SMARCB1 locus.