Undisclosed GPR161 modulator therapeutic

All germline variants of the ten susceptibility genes of interest (APC, BRCA2, PTCH1, PTCH2, ELP1, SUFU, CTNNB1, SMARCA4, GPR161, and TP53) were annotated and validated...This study provides valuable insights into the genetic landscape of MB in an Asian cohort, emphasizing the importance of population-specific research. The subtype-specific germline variant landscape identified in this study contributes to the understanding of MB and its genetic underpinnings in Asian populations, potentially guiding future research and therapeutic strategies.

Most cases are sporadic, but well characterized germline alterations in APC, ELP1, GPR161, PTCH1, SUFU, and TP53 predispose to medulloblastoma...Approximately one in eight pediatric medulloblastoma survivors had an autosomal dominant P/LP CSG variant. We confirm several known associated genes and identify novel genes that may be important in medulloblastoma.

For six genes [ELP1, GPR161, VHL and SDHA/B/C], a clear lack of mutational constraint calls the pediatric penetrance and/or severity of associated cancers into question. Conversely, out of 23 known pCPS genes associated with biallelic risk, two [9%, DIS3L2 and MSH2] show significant constraint, indicating that they may monoallelically increase childhood cancer risk. In summary, we show that population genetic data provide empirical evidence that heritable childhood cancer leads to natural selection powerful enough to have significantly impacted the present-day gene pool.

We also screened 27 PTCH1/SUFU pathogenic variant-negative patients with Gorlin syndrome for GPR161 and found no suspicious variants. Given the population frequencies of 0.0962% for GPR161 and 0.0687% for ELP1, neither of these genes can be a cause of Gorlin syndrome with an unexplained population frequency far lower at 0.0021%.

Most cases are sporadic, but well characterized germline alterations in APC, ELP1, GPR161, PTCH1, PTCH2, SUFU, and TP53 predispose to medulloblastoma... One-fifth of pediatric medulloblastoma survivors had a P/LP CSG variant, some in genes which had not previously been associated with medulloblastoma, and therefore need to be replicated. These findings suggest that routine germline testing for children with medulloblastoma at diagnosis should be considered.