NRAS A59

Conclusion  This constitutes one of the few reports on comprehensive analysis of molecular alterations underlying melanomas in Indian patients. A larger sample size, with more extensive molecular markers, would yield additional information on the disease manifestation.

RRVs are detected in CRC samples at frequencies even higher than some classical RAS variants, suggesting a role in CRC biology. Application of new ClinGen/CGC/VICC guidelines classify several of them as LO, while some classical variants would be considered as VUS. Despite its classification as LO, some rare variants have been described as germinal mutations, and samples carrying them frequently have co-occurring variants in PIK3CA , RAS and BRAF genes, questioning its role as independent cancer drivers.

Our study demonstrated the clinical relevance of minor mutant subclones in EGFR signaling pathway genes in plasma for predicting response to anti-EGFR treatment. Although sample size of this study was small, preferable threshold for distinguishing responders from non-responders may be 0.5% as VAF of these gene mutations. Clinical trial information: 000034923.

KRAS mutated CRC patients in North Africa have been identified with incidence closer to the European figures. Beside established anti-CRC treatment, better understanding of the causality of CRC can be established by combining epidemiology and genetic/epigenetic on CRC etiology. This approach may be able to significantly reduce the burden of CRC in North Africa.

We conclude that cellular morphology in KLA, a previously undescribed feature, does not appear to be associated with clinical features, site of disease, mutation type, response to sirolimus, or outcome. Although cellular KLA may mimic KHE, there are sufficient clinical, morphologic, and genetic differences such that these are likely unrelated diseases.

Our results demonstrate the potential of small multigene panels that can be used in diagnostics for the detection of rare therapeutically relevant variants. Moreover, the division of patients into groups based on the presence of APC and TP53 mutations enables this panel to be used in retrospective studies on the effectiveness of treatment with anti-EGFR inhibitors.

We establish single-agent cetuximab efficacy in optimally selected patients and show that subclonal RAS/BRAF alterations are uncommon and remain of indeterminate significance.

Structure and biochemistry are consistent with an intermediate level of KRas G13D bound to GTP, relative to wild-type and KRas G12D, observed in genetically engineered mouse models. The results explain in part the elevated frequency of the G13D mutant in KRas over the other isoforms of Ras.

In addition, they suggest that driver mutations in particular genes (e.g. N/KRAS) may specifically predispose to the development of an additional clonally related haematological malignancy or secondary histiocytic neoplasm. Finally, the putative existence of derailed multipotent HSPCs in these patients emphasises the importance of adequate (bone marrow) staging, molecular analysis and long-term follow-up of all histiocytosis patients.

Elucidation of differential effector engagement responsible for the variable phenotypic readouts of the mutants is warranted. If validated by mouse studies and clinical correlates, these can have wider implications in choosing treatment options.

In this study we present a custom RNA sequencing assay that detects fusion genes and SNVs in tandem and has the ability to identify novel fusion partners. These features highlight the advantages associated with utilizing AMP technology for the rapid and highly sensitive detection of somatic variants.

The clonal and subclonal mutational landscapes of RAS WT pts were analyzed using a mCRC-focused custom ctDNA sequencing panel. Randomized pts (1:1) received mFOLFOX6 plus either panitumumab or bevacizumab. The validated ultra-deep plasma sequencing panel was concordant with tissue sequencing and detected tumor heterogeneity. The PARADIGM study will report the efficacy of anti-EGFR/VEGF therapies; post-treatment collection of ctDNA is ongoing. The relationship between therapeutic effects and clonal and subclonal mutational landscapes will be examined in the future.