Using evolutionary constraint to define novel candidate driver genes in medulloblastoma
Authors: Roy Ananya , Sakthikumar Sharadha , Kozyrev Sergey V. , Nordin Jessika , Pensch Raphaela , Mäkeläinen Suvi , Pettersson Mats ,   Zoonomia Consortium, Karlsson Elinor K. , Lindblad-Toh Kerstin , Forsberg-Nilsson Karin , Andrews Gregory , Armstrong Joel C. , Bianchi Matteo , Birren Bruce W. , Bredemeyer Kevin R. , Breit Ana M. , Christmas Matthew J. , Clawson Hiram , Damas Joana , Di Palma Federica , Diekhans Mark , Dong Michael X. , Eizirik Eduardo , Fan Kaili , Fanter Cornelia , Foley Nicole M. , Forsberg-Nilsson Karin , Garcia Carlos J. , Gatesy John , Gazal Steven , Genereux Diane P. , Goodman Linda , Grimshaw Jenna , Halsey Michaela K. , Harris Andrew J. , Hickey Glenn , Hiller Michael , Hindle Allyson G. , Hubley Robert M. , Hughes Graham M. , Johnson Jeremy , Juan David , Kaplow Irene M. , Karlsson Elinor K. , Keough Kathleen C. , Kirilenko Bogdan , Koepfli Klaus-Peter , Korstian Jennifer M. , Kowalczyk Amanda , Kozyrev Sergey V. , Lawler Alyssa J. , Lawless Colleen , Lehmann Thomas , Levesque Danielle L. , Lewin Harris A. , Li Xue , Lind Abigail , Lindblad-Toh Kerstin , Mackay-Smith Ava , Marinescu Voichita D. , Marques-Bonet Tomas , Mason Victor C. , Meadows Jennifer R. S. , Meyer Wynn K. , Moore Jill E. , Moreira Lucas R. , Moreno-Santillan Diana D. , Morrill Kathleen M. , Muntané Gerard , Murphy William J. , Navarro Arcadi , Nweeia Martin , Ortmann Sylvia , Osmanski Austin , Paten Benedict , Paulat Nicole S. , Pfenning Andreas R. , Phan BaDoi N. , Pollard Katherine S. , Pratt Henry E. , Ray David A. , Reilly Steven K. , Rosen Jeb R. , Ruf Irina , Ryan Louise , Ryder Oliver A. , Sabeti Pardis C. , Schäffer Daniel E. , Serres Aitor , Shapiro Beth , Smit Arian F. A. , Springer Mark , Srinivasan Chaitanya , Steiner Cynthia , Storer Jessica M. , Sullivan Kevin A. M. , Sullivan Patrick F. , Sundström Elisabeth , Supple Megan A. , Swofford Ross , Talbot Joy-El , Teeling Emma , Turner-Maier Jason , Valenzuela Alejandro , Wagner Franziska , Wallerman Ola , Wang Chao , Wang Juehan , Weng Zhiping , Wilder Aryn P. , Wirthlin Morgan E. , Xue James R. , Zhang Xiaomeng 
Published: August 2023

Current knowledge of cancer genomics remains biased against noncoding mutations. To systematically search for regulatory noncoding mutations, we assessed mutations in conserved positions in the genome under the assumption that these are more likely to be functional than mutations in positions with low conservation. To this end, we use whole-genome sequencing data from the International Cancer Genome Consortium and combined it with evolutionary constraint inferred from 240 mammals, to identify genes enriched in noncoding constraint mutations (NCCMs), mutations likely to be regulatory in nature. We compare medulloblastoma (MB), which is malignant, to pilocytic astrocytoma (PA), a primarily benign tumor, and find highly different NCCM frequencies between the two, in agreement with the fact that malignant cancers tend to have more mutations. In PA, a high NCCM frequency only affects the
BRAF
locus, which is the most commonly mutated gene in PA. In contrast, in MB, >500 genes have high levels of NCCMs. Intriguingly, several loci with NCCMs in MB are associated with different ages of onset, such as the
HOXB
cluster in young MB patients. In adult patients, NCCMs occurred in, e.g., the
WASF-2/AHDC1/FGR
locus. One of these NCCMs led to increased expression of the SRC kinase
FGR
and augmented responsiveness of MB cells to dasatinib, a SRC kinase inhibitor. Our analysis thus points to different molecular pathways in different patient groups. These newly identified putative candidate driver mutations may aid in patient stratification in MB and could be valuable for future selection of personalized treatment options.