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Beyond Structural Bioinformatics for Genomics with Dynamics Characterization of an Expanded KRAS Mutational Landscape.

ABSTRACT: Current capabilities in genomic sequencing outpace functional interpretations. Our previous work showed that 3D protein structure calculations enhance mechanistic understanding of genetic variation in sequenced tumors and patients with rare diseases. The KRAS GTPase is among the critical genetic factors driving cancer and germline conditions. Because KRAS-altered tumors frequently harbor one of three classic hotspot mutations, nearly all studies have focused on these mutations, leaving significant functional ambiguity across the broader KRAS genomic landscape observed in cancer and non-cancer diseases. Herein, we extend structural bioinformatics with molecular simulations to study an expanded landscape of 86 KRAS mutations. We identify multiple coordinated changes strongly associated with experimentally established KRAS biophysical and biochemical properties. The patterns we observe span hotspot and non-hotspot alterations, which can all dysregulate Switch regions, producing mutation-restricted conformations with different effector binding propensities. We experimentally measured mutation thermostability and identified shared and distinct patterns with simulations. Our results indicate mutation-specific conformations which show potential for future research into how these alterations reverberate into different molecular and cellular functions. The data we present is not predictable using current genomic tools, demonstrating the added functional information derived from molecular simulations for interpreting human genetic variation.

SUBMITTER: Ratnasinghe BD

PROVIDER: S-EPMC10189839 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Beyond Structural Bioinformatics for Genomics with Dynamics Characterization of an Expanded KRAS Mutational Landscape.

Ratnasinghe Brian D BD Haque Neshatul N Wagenknecht Jessica B JB Jensen Davin R DR Esparza Guadalupe V GV Leverence Elise N EN De Assuncao Thiago Milech TM Mathison Angela J AJ Lomberk Gwen G Smith Brian C BC Volkman Brian F BF Urrutia Raul R Zimmermann Michael T MT

bioRxiv : the preprint server for biology 20230428

Current capabilities in genomic sequencing outpace functional interpretations. Our previous work showed that 3D protein structure calculations enhance mechanistic understanding of genetic variation in sequenced tumors and patients with rare diseases. The KRAS GTPase is among the critical genetic factors driving cancer and germline conditions. Because KRAS-altered tumors frequently harbor one of three classic hotspot mutations, nearly all studies have focused on these mutations, leaving significa ...[more]

PMID: 37207265

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Project description:BackgroundWe previously reported rare regressive genetic trajectories of KRAS pathogenic mutations as a specific hallmark of the genuine oligometastatic status in colorectal cancer (CRC).MethodsSurvival and prognostic impact of disease extent in 140 metastatic CRC patients were evaluated through the Kaplan-Meyer curves and the Log-Rank test. KRAS mutations were assessed through the Illumina NovaSeq 6000 platform and TruSight™ Oncology 500 kit. HLA typing was carried out by PCR with sequence-specific oligonucleotides. Lymphocyte densities in tumors were expressed as cells per square millimeter. NKs isolated and CD8+ from NK-depleted PBMCs were characterized through flow cytometry. CD107a externalization was evaluated as NKs/CD8 cytotoxicity toward human colon cancer cells HT29, SW620, HCT116, and LS174T carrying different KRAS mutations.ResultsThe oligometastatic status was a strong and independent variable for survival (HR: 0.08 vs. polymetastatic disease; 95% CI: 0.02-0.26; p < 0.001). Eighteen oligometastatic patients were selected. Twelve were alive at the last follow-up, and 9 were characterized. Genetic regression of KRAS was observed in 3 patients: patient (PAT)2, PAT5, and PAT8. PAT2 and PAT5 presented the highest levels of GrzB+ lymphocytes in the tumor cores of the metastases (120 ± 11.2 and 132 ± 12.2 cells/mm2, respectively). Six out of 9 patients (67%), including PAT2 and PAT5, expressed HLA-C7. Twopatients (PAT2 and PAT5) presented high CD3+/CD8+-dependent cytotoxicity against HLA-C7+ SW620 cells (p.G12V-mutated cells), which was consistent with their observed mutational regression (p.G12V/p.G13D in primary→p.G13D in metastatic tumor).ConclusionsWe provide evidence that CD3+/CD8+ lymphocytes from oligometastatic CRC patients display differential cytotoxicity against human colon cancer cells carrying KRAS mutations. This could provide an interesting basis for monitoring oligometastatic disease and developing future adoptive immunotherapies.

Dataset Information

Beyond Structural Bioinformatics for Genomics with Dynamics Characterization of an Expanded KRAS Mutational Landscape.

Publications

Beyond Structural Bioinformatics for Genomics with Dynamics Characterization of an Expanded KRAS Mutational Landscape.

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