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PubMed2005

The Cables gene on chromosome 18Q regulates colon cancer progression in vivo.

Early events involved in the pathogenesis of colorectal cancer include mutations in the Adenomatous Polyposis Coli tumor-suppressor gene and oncogenic KRAS mutations. Later events include deletions on chromosome 18q, which are observed in a high proportion of colorectal cancers. However, the important tumor suppressor genes targeted by these deletions have not been fully defined. A previous study found Cables is located on human chromosome 18q11-12. Loss of Cables expression as determined by immunohistochemical staining (IHC) occurred in 60-70% of sporadic colorectal cancers that were usually correlated to loss of heterozygosity at 18q. To determine if Cables is an important target for the chromosome 18q deletions, the susceptibility of Cables-/- mice to develop colon tumors was studied. A well characterized colonic carcinogen, 1,2-dimethylhydrazine (DMH) was used as a tumor initiator. Cables-/- mice (n = 25) and the Cables+/+ littermates (n = 25) were treated with subcutaneous DMH injections over 20 weeks to initiate tumorigenesis. The median survival after DMH injections was significantly shorter for the Cables-/- mice compared to Cables+/+ littermates. The total number of colorectal tumors that developed in the Cables-/- mice was 46 tumors versus 21 tumors. The increased numbers of colorectal tumors, as well as shorter survival of the Cables-/- mice provides compelling evidence that Cables could play an important role in the pathogenesis and progression of colon cancer in mice. These data coupled with previous observations support the hypothesis that Cables is a relevant target of the chromosome 18q deletions frequently seen in human colorectal cancer.

1,2-Dimethylhydrazine↗
PubMed2006

Mist1-KrasG12D knock-in mice develop mixed differentiation metastatic exocrine pancreatic carcinoma and hepatocellular carcinoma.

Despite the prevalence of oncogenic Kras mutations in the earliest stages of pancreatic ductal adenocarcinoma, the cellular compartment in which oncogenic Kras initiates tumorigenesis remains unknown. To address this, we have gene targeted KrasG12D into the open reading frame of Mist1, a basic helix-loop-helix transcription factor that is expressed during pancreatic development and required for proper pancreatic acinar organization. Although the pancreata of Mist1(KrasG12D/+) mutant mice predictably exhibited acinar metaplasia and dysplasia, the frequent death of these mice from invasive and metastatic pancreatic cancer with mixed histologic characteristics, including acinar, cystic, and ductal features, was unexpected and in contrast to previously described mutant mice that ectopically expressed the Kras oncogene in either acinar or ductal compartments. Interestingly, many of the mutant mice developed hepatocellular carcinoma, implicating Mist1(KrasG12D/+) cells in both pancreatic and hepatic neoplasia. Concomitant Trp53+/- mutation cooperated with Mist1(KrasG12D/+) to accelerate lethality and was associated with advanced histopathologic findings, including parenchymal liver metastasis. These findings suggest that Mist1-expressing cells represent a permissive compartment for transformation by oncogenic Kras in pancreatic tumorigenesis.

Animals↗
PubMed2005

Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain.

BACKGROUND: Lung adenocarcinomas from patients who respond to the tyrosine kinase inhibitors gefitinib (Iressa) or erlotinib (Tarceva) usually harbor somatic gain-of-function mutations in exons encoding the kinase domain of the epidermal growth factor receptor (EGFR). Despite initial responses, patients eventually progress by unknown mechanisms of "acquired" resistance. METHODS AND FINDINGS: We show that in two of five patients with acquired resistance to gefitinib or erlotinib, progressing tumors contain, in addition to a primary drug-sensitive mutation in EGFR, a secondary mutation in exon 20, which leads to substitution of methionine for threonine at position 790 (T790M) in the kinase domain. Tumor cells from a sixth patient with a drug-sensitive EGFR mutation whose tumor progressed on adjuvant gefitinib after complete resection also contained the T790M mutation. This mutation was not detected in untreated tumor samples. Moreover, no tumors with acquired resistance had KRAS mutations, which have been associated with primary resistance to these drugs. Biochemical analyses of transfected cells and growth inhibition studies with lung cancer cell lines demonstrate that the T790M mutation confers resistance to EGFR mutants usually sensitive to either gefitinib or erlotinib. Interestingly, a mutation analogous to T790M has been observed in other kinases with acquired resistance to another kinase inhibitor, imatinib (Gleevec). CONCLUSION: In patients with tumors bearing gefitinib- or erlotinib-sensitive EGFR mutations, resistant subclones containing an additional EGFR mutation emerge in the presence of drug. This observation should help guide the search for more effective therapy against a specific subset of lung cancers.

Adenocarcinoma↗
PubMed2006

KRAS and BRAF mutations in ovarian tumors: a comprehensive study of invasive carcinomas, borderline tumors and extraovarian implants.

OBJECTIVE: Mutations of BRAF, a downstream mediator of K-RAS, have been described in serous borderline tumors of the ovary. Data concerning other types of ovarian tumors are scarce. Therefore, we assessed KRAS and BRAF mutation in a series of more than 100 different ovarian tumors. METHODS: Paraffin-embedded material, including invasive carcinomas, borderline tumors, benign lesions and implants, was used. BRAF codon 600 in exon 15 and K-RAS codon 12 in exon 2 were analysed. RESULTS: 92 cases (92%), including all serous carcinomas (100%), did not show a mutation of BRAF. Eight cases (8.0%), including five serous borderline tumors (31.25%), contained a mutation. In all serous borderline tumors, codon 600 was affected. The remaining three cases were invasive carcinomas of endometrioid (mutation on codon 600), mucinous (mutation on codon 600) and clear cell (mutation on codon 615) subtype. There was no BRAF mutation in mucinous borderline tumors. Regarding K-RAS, 89 cases (87.25%) did not show an aberration. The 11 positive borderline tumors (10.7%) were of serous (22.2%) and of mucinous type (46.6%). There was a KRAS mutation in a serous and a mucinous invasive carcinoma each. BRAF and K-RAS mutations were mutually exclusive and not seen in implants. CONCLUSION: Mutation of either K-RAS or BRAF is frequent in borderline tumors but is not found in invasive serous carcinomas and is very rare in other invasive subtypes. This supports the notion of different pathological pathways. For the development of extraovarian implants, further studies are observed.

Adenocarcinoma, Clear Cell↗
PubMed2025

Comprehensive assessment of genomic heterogeneity, coalterations, and outcomes of patients with colorectal cancer: An AACR GENIE project analysis.

INTRODUCTION: Colorectal cancer remains a leading cause of cancer mortality in the United States and can be characterized by racial and sex-based disparities. The objective of the current study was to characterize the genomic heterogeneity of colorectal cancer among diverse demographic groups, assess coalteration patterns and their impact on long-term outcomes among patients with colorectal cancer. METHODS: Data from the American Association for Cancer Research GENIE registry were analyzed to assess genomic alterations in colorectal cancer. The cohort included 20,542 samples from 19,542 patients, stratified by race or ethnicity, sex, and age of onset (<50 years for early-onset colorectal cancer). Genomic alterations and coalterations among the 48 most prevalent loci were evaluated for any association with overall survival in an external Memorial Sloan Kettering Cancer Center cohort. RESULTS: Among 19,542 patients, KRAS mutations were more prevalent among Black patients (57.1%) compared with White (41.8%) and Asian (43.4%) patients (P < .001), whereas TP53 alterations were more frequent among Asian (75.6%) than White (69.9%) or Black (71.9%) patients (P < .001). Coalterations with KRAS were associated with improved survival over KRAS alteration alone, a pattern less-frequently observed among Black patients. Sex-based differences were also observed, with BRAF mutations more prevalent among females (14.6% vs 9.7%; P < .001) and TP53 mutations more common among males (73% vs 70.5%;P = .009). Although KRAS alterations tended to co-occur with alterations in ATM, ARID1A, CREBBP, FAT1, KMT2B, and KMT2D genes among patients with "early onset" colorectal cancer (all p & q < 0.05), alterations of these gene pairs were mutually exclusive among individuals with late onset colorectal cancer. CONCLUSION: Genomic alterations and coalteration patterns varied relative to race/ethnicity, sex, and age at disease onset. Differences in genomic alteration patterns of colorectal cancer somatic tumor cells are an important consideration to help address disparities among different demographic groups.

Humans↗
PubMed2005

Clinicopathologic significance of the mutations of the epidermal growth factor receptor gene in patients with non-small cell lung cancer.

PURPOSE: It has been reported that the mutations of epidermal growth factor receptor (EGFR) are detected in lung cancers. Studies of EGFR mutations in large numbers of patients' tumors with clinical data including response to EGFR tyrosine kinase directed therapy are needed to develop a robust database for clinical use. The purpose of the present study is to gain further insights into the significance of EGFR mutation in non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: We investigated the clinicopathologic significance of tyrosine kinase domain (exons 18-21) EGFR mutations in 120 patients with primary NSCLC and the correlation between EGFR mutation and sensitivity to gefitinib in an additional 20 NSCLC patients treated with gefitinib. In addition, onocogenic KRAS mutations and RASSF1A promoter methylation were determined in the same samples. RESULTS: EGFR mutation was detected in 29 of 120 (24%) tumors. All of the 29 (40%) mutations occurred in 72 adenocarcinomas. EGFR mutation was significantly more frequent in females (47%) than males (12%, P < 0.0001), in younger patients (38%) than older patients (10%, P = 0.0005), in nonsmokers (47%) than smokers (13%, P < 0.0001), and in well-differentiated tumors (39%) than moderately and poorly differentiated tumors (7%, P < 0.0001). Mutation of the EGFR gene was preferentially observed in advanced disease. Furthermore, EGFR mutations were detected in 11 of 14 (79%) responders, whereas none of six (0%) nonresponders had the mutation (P = 0.0022). CONCLUSIONS: These results in Japanese (East Asian) patients indicated that EGFR mutation plays an important role in pathogenesis of lung adenocarcinoma.

Adenocarcinoma↗
PubMed2006

Both p16(Ink4a) and the p19(Arf)-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse.

Activating KRAS mutations and p16(Ink4a) inactivation are near universal events in human pancreatic ductal adenocarcinoma (PDAC). In mouse models, Kras(G12D) initiates formation of premalignant pancreatic ductal lesions, and loss of either Ink4a/Arf (p16(Ink4a)/p19(Arf)) or p53 enables their malignant progression. As recent mouse modeling studies have suggested a less prominent role for p16(Ink4a) in constraining malignant progression, we sought to assess the pathological and genomic impact of inactivation of p16(Ink4a), p19(Arf), and/or p53 in the Kras(G12D) model. Rapidly progressive PDAC was observed in the setting of homozygous deletion of either p53 or p16(Ink4a), the latter with intact germ-line p53 and p19(Arf) sequences. Additionally, Kras(G12D) in the context of heterozygosity either for p53 plus p16(Ink4a) or for p16(Ink4a)/p19(Arf) produced PDAC with longer latency and greater propensity for distant metastases relative to mice with homozygous deletion of p53 or p16(Ink4a)/p19(Arf). Tumors from the double-heterozygous cohorts showed frequent p16(Ink4a) inactivation and loss of either p53 or p19(Arf). Different genotypes were associated with specific histopathologic characteristics, most notably a trend toward less differentiated features in the homozygous p16(Ink4a)/p19(Arf) mutant model. High-resolution genomic analysis revealed that the tumor suppressor genotype influenced the specific genomic patterns of these tumors and showed overlap in regional chromosomal alterations between murine and human PDAC. Collectively, our results establish that disruptions of p16(Ink4a) and the p19(ARF)-p53 circuit play critical and cooperative roles in PDAC progression, with specific tumor suppressor genotypes provocatively influencing the tumor biological phenotypes and genomic profiles of the resultant tumors.

Adenocarcinoma↗
PubMed2025

AI-HOPE: an AI-driven conversational agent for enhanced clinical and genomic data integration in precision medicine research.

MOTIVATION: The growing complexity of clinical cancer research has fueled a surge in demand for automated bioinformatics tools capable of integrating clinical and genomic data to accelerate discovery efforts. RESULTS: We present the Artificial Intelligence Agent for High-Optimization and Precision Medicine (AI-HOPE), an AI-driven system that enables domain experts to conduct integrative data analyses through natural language interactions. Powered by Large Language Models, AI-HOPE interprets user instructions, converts them into executable code, and autonomously analyzes locally stored data. It supports flexible association studies, subset comparisons, clinical prevalence assessments and survival analyses. In addition, AI-HOPE enables global variable scans to identify features significantly associated with a user-defined outcome, making a powerful and intuitive tool for advancing precision medicine research. Importantly, its closed-system design prevents clinical data leakage. To demonstrate its utility, AI-HOPE was applied to The Cancer Genome Atlas data to address two clinical questions. First, it identified significant enrichment of TP53 mutations in late-stage colorectal cancer compared to early-stage cases. Second, it uncovered a strong association between KRAS mutations and poorer progression-free survival in FOLFOX-treated patients. These findings align with established literature and demonstrate AI-HOPE's ability to generate meaningful insights independently, without prior assumptions. By removing programming barriers and simplifying complex analyses, AI-HOPE bridges the gap between data complexity and research needs. With its scalable and adaptable framework, AI-HOPE has the potential to support diverse biomedical research fields, driving innovation and efficiency in translational studies. AVAILABILITY AND IMPLEMENTATION: The AI-HOPE software and demonstration data is available at https://github.com/Velazquez-Villarreal-Lab/AI-HOPE.

Precision Medicine↗
PubMed2026

Changes in the transcriptome and synthetic lethal dependencies following KRAS mutant expression reveal profound tissue specificity.

Oncogenic KRAS mutations exhibit a striking tissue-restricted tropism, occurring with high frequency in pancreatic, colorectal, and lung adenocarcinomas while remaining rare in other lineages. The molecular basis for why these specific tissues are uniquely permissive to KRAS transformation, and how this context shapes therapeutic vulnerabilities, remains poorly defined. Here, we utilized CRISPR-mediated genome engineering to generate endogenous, conditional KRAS-mutant isogenic cell line models across three primary permissive lineages (lung, colon, and pancreas) and the nonpermissive breast lineage. Integrated genome-wide CRISPR fitness screens and comparative transcriptome analyses revealed that KRAS-driven synthetic lethal (SL) dependencies are profoundly shaped by their tissue of origin. Strikingly, we observed minimal overlap in SL hits across lineages, with only three genes shared among the permissive lines, suggesting that the KRAS oncogene operates through divergent, context-specific genetic networks. Mechanistically, we show that KRAS activation induces a universal MYC-driven metabolic signature, but the specific machinery required to sustain this state is lineage-restricted. We identified a dependency on the diphthamide synthesis pathway to maintain translational fidelity amid a KRAS-induced hypertranslational state. These findings demonstrate that even when driven by the same oncogene, tumors exhibit distinct regulatory landscapes and unique genetic vulnerabilities. Our results provide a framework for developing lineage-aware therapeutic strategies, moving beyond universal KRAS inhibition toward targeted interventions tailored to a tumor's specific tissue context.

Proto-Oncogene Proteins p21(ras)↗
PubMed2025

A comparative genomic analysis of left- and right-sided colon cancer using real-world data from the AACR project GENIE BPC dataset.

Left- and Right-sided colon cancers (LCC and RCC) are increasingly recognized as distinct clinicopathological and molecular subtypes with divergent prognoses and therapeutic responses. Leveraging a large, multi-institutional cohort from the AACR Project Genomics Evidence Neoplasia Information Exchange (GENIE) Biopharma Collaborative (BPC) (n = 750; LCC: 363 vs. RCC: 387), we conducted a comprehensive analysis of mutational profiles, tumor mutation burden (TMB), and survival outcomes. Our findings revealed a markedly higher TMB in RCC compared to LCC (6.65 &#xb1; 11.3 vs. 3.17 &#xb1; 4.35; adjusted P = 3.12&#xd7;10-32), suggesting greater genomic instability in RCC. After applying functional annotation filters (PolyPhen > 0.85, SIFT < 0.05), RCC tumors were significantly enriched for mutations in BRAF (23.1% vs. 6.7%), KMT2D (8.6% vs. 3.2%), and SMAD4 (13.1% vs. 7.3%), while TP53 mutations predominated in LCC (40.6% vs. 31.8%). Multivariate Cox regression analysis identified RCC as an independent predictor of poorer overall survival (OS) relative to LCC (HR: 1.30, 95% CI: 1.02-1.66, P = 0.033). Notably, KRAS mutations were associated with significantly worse OS in LCC (HR: 1.68, 95% CI: 1.06-2.70, P = 0.027), while BRAF mutations predicted adverse outcomes in RCC (HR: 1.58, 95% CI: 1.05-2.37, P = 0.028). These results underscore the prognostic value of tumor sidedness and specific genetic alterations in colon adenocarcinoma. Our study highlights the need for sidedness-specific molecular profiling to inform precision oncology strategies in colon cancer management.

BRAF↗
PubMed2005

Mutations of PIK3CA in gastric adenocarcinoma.

BACKGROUND: Activation of the phosphatidylinositol 3-kinase (PI3K) through mutational inactivation of PTEN tumour suppressor gene is common in diverse cancer types, but rarely reported in gastric cancer. Recently, mutations in PIK3CA, which encodes the p110alpha catalytic subunit of PI3K, have been identified in various human cancers, including 3 of 12 gastric cancers. Eighty percent of these reported mutations clustered within 2 regions involving the helical and kinase domains. In vitro study on one of the "hot-spot" mutants has demonstrated it as an activating mutation. METHODS: Based on these data, we initiated PIK3CA mutation screening in 94 human gastric cancers by direct sequencing of the gene regions in which 80% of all the known PIK3CA mutations were found. We also examined PIK3CA expression level by extracting data from the previous large-scale gene expression profiling study. Using Significance Analysis of Microarrays (SAM), we further searched for genes that show correlating expression with PIK3CA. RESULTS: We have identified PIK3CA mutations in 4 cases (4.3%), all involving the previously reported hotspots. Among these 4 cases, 3 tumours demonstrated microsatellite instability and 2 tumours harboured concurrent KRAS mutation. Data extracted from microarray studies showed an increased expression of PIK3CA in gastric cancers when compared with the non-neoplastic gastric mucosae (p < 0.001). SAM further identified 2910 genes whose expression levels were positively associated with that of PIK3CA. CONCLUSION: Our data suggested that activation of the PI3K signalling pathway in gastric cancer may be achieved through up-regulation or mutation of PIK3CA, in which the latter may be a consequence of mismatch repair deficiency.

Adenocarcinoma↗
PubMedDate not supplied

Anticorresponding mutations of the KRAS and PTEN genes in human endometrial cancer.

PTEN is a newly isolated candidate tumor suppressor gene and its mutation is the most frequently found in endometrial cancer (EC), a very common female pelvic malignant disease. Mutations of the KRAS gene are also reported in this disease. Recent analysis of the PTEN protein suggested the possibility that this protein acts in the same pathway as does the RAS protein. To elucidate this possibility further, we performed a mutation analysis of these two genes in 44 endometrial cancer specimens (38 primary tumors and 6 cell lines). Altogether 23 (52%) of 44 tumors had mutations in either PTEN or KRAS, but none of them had mutations in both of these genes. These results support the idea that the protein products of these two genes act in the same growth regulatory pathway in the endometrium.

Adenocarcinoma↗
PubMed2003

Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma.

Activating mutations in KRAS and in one of its downstream mediators, BRAF, have been identified in a variety of human cancers. To determine the role of mutations in BRAF and KRAS in ovarian carcinoma, we analyzed both genes for three common mutations (at codon 599 of BRAF and codons 12 and 13 of KRAS). Mutations in either codon 599 of BRAF or codons 12 and 13 of KRAS occurred in 15 of 22 (68%) invasive micropapillary serous carcinomas (MPSCs; low-grade tumors) and in 31 of 51 (61%) serous borderline tumors (precursor lesions to invasive MPSCs). None of the tumors contained a mutation in both BRAF and KRAS. In contrast, none of the 72 conventional aggressive high-grade serous carcinomas analyzed contained the BRAF codon 599 mutation or either of the two KRAS mutations. The apparent restriction of these BRAF and KRAS mutations to low-grade serous ovarian carcinoma and its precursors suggests that low-grade and high-grade ovarian serous carcinomas develop through independent pathways.

Codon↗
PubMed2004

Transcriptional basis of KRAS oncogene-mediated cellular transformation in ovarian epithelial cells.

To understand the relationship between oncogenic signaling and the reprogramming of gene expression, we performed transcriptional profiling in rat ovarian surface epithelial cells (ROSE), in which neoplastic transformation is driven by a mutated KRAS oncogene. We identified >200 genes whose expression was elevated or reduced following permanent KRAS expression. Deregulated KRAS-responsive genes encode transcriptional regulators, signaling effectors, proteases, extracellular matrix and adhesion proteins, transformation-suppressing proteins and negative growth regulators. Many of them have not been previously identified in cells expressing oncogenic RAS genes or in other well-studied models of oncogenic signaling. The number of critical genes related to the execution of anchorage-independent proliferation and epithelial-mesenchymal transition was narrowed down to 79 by selectively inhibiting the mitogen-activated protein kinase (MAPK/ERK) and phosphatidylinositol 3-kinase (PI3K) pathways. Blocking MAPK/ERK-signaling caused reversion to the normal epithelial phenotype in conjunction with the reversal of deregulated target transcription to pretransformation levels. In addition, silencing of the overexpressed transcriptional regulator Fra-1 by RNA interference resulted in growth reduction, suggesting that this factor partially contributes to, but is not sufficient for the proliferative capacity of KRAS-transformed epithelial cells.

Animals↗
PubMed2006

Epigenetic profiling of synchronous colorectal neoplasias by quantitative DNA methylation analysis.

Transcriptional inactivation of tumor-suppressor genes by promoter CpG island methylation is thought to be an important mechanism in human carcinogenesis. The CpG island methylator phenotype (CIMP) with extensive promoter methylation appears to be a distinct epigenetic subtype of colorectal carcinoma. Most previous studies on CpG island methylation in colorectal carcinoma used methylation-specific PCR, which may detect low levels of DNA methylation with little or no biological significance. In contrast, quantitative DNA methylation assays have been shown to provide useful information beyond that which can be achieved with methylation-specific PCR. Synchronous neoplasias provide a unique model for investigators to examine molecular alterations in multistep tumorigenesis within one individual. However, no study to date has quantified DNA methylation of CIMP-specific promoters in synchronous colorectal neoplasias. Utilizing real-time PCR (MethyLight), we quantified DNA methylation in five CIMP-specific gene promoters [CACNA1G (calcium channel, voltage-dependent, T type alpha-1G subunit), CDKN2A (p16/INK4A), CRABP1 (cellular retinoic acid binding protein-1), MLH1 and NEUROG1 (neurogenin 1)] and MGMT in six synchronous carcinoma pairs (12 carcinomas) and eight synchronous carcinoma and adenoma pairs (16 tumors). We found that while some synchronous tumor pairs showed discordant promoter methylation patterns, other tumor pairs showed similar, but not exactly identical, patterns of promoter methylation. All but two pairs showed concordant patterns of CIMP status (CIMP positive vs CIMP negative) (P = 0.05 in cancer pairs). BRAF mutations were present in only CIMP-positive tumors. A high degree of microsatellite instability (MSI-H) was observed in both CIMP-positive and CIMP-negative tumors. KRAS mutations were not concordant in any synchronous neoplasia pair. In conclusion, epigenetic alterations at CIMP-specific promoter CpG islands in synchronous colorectal neoplasias likely have both random and nonrandom components.

Adenocarcinoma↗
PubMed2006

Germline mutations in components of the Ras signaling pathway in Noonan syndrome and related disorders.

Ras proteins control a variety of critical cellular processes, and somatic mutations in RAS genes (and other members of signaling networks regulated by Ras) are common in human malignancies. Ras proteins are guanosine triphosphate (GTP)-binding proteins that cycle between active GTP-bound and inactive guanosine diphosphate (GDP) bound conformations. Cancer-associated Ras mutations typically alter amino acids G12, G13 or Q61. These mutant Ras proteins display impaired GTPase activity and are resistant to GTPase activating proteins (GAPs). We and others recently discovered novel germline KRAS mutations in individuals diagnosed with Noonan or cardio-facio-cutanous (CFC) syndrome, two clinically overlapping disorders characterized by short stature, distinct facial anomalies, heart defects, and other developmental abnormalities. We found that the mutant K-Ras proteins encoded by NS-associated alleles have less pronounced biochemical defects than known Ras oncoproteins, which likely explains why these mutations are tolerated in the germline. Together with the recent findings of mutations in other members of the Ras signaling cascade in CFC syndrome and in Costello syndrome, another clinically related disorder, it is now clear that Noonan-like features are common phenotypic consequences of systemic deregulation of the Ras pathway. The discovery of germline mutations in this group of related genetic disorders underscores the pivotal role of the degree and duration of Ras activation in cell fate decisions during embryonic development and morphogenesis.

Animals↗
PubMed2026

Impact of Tumor Genomic Profile on Adjuvant Chemotherapy Efficacy in Resected Pancreatic Adenocarcinoma: Results From the PRODIGE-24/CCTG PA6 Study.

PURPOSE: Modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX/mFFX) is the standard adjuvant chemotherapy for resected pancreatic ductal adenocarcinoma (PDAC), offering survival benefits over gemcitabine (GEM). However, the contribution of molecular biomarkers to treatment selection remains unclear. Here, we characterize the molecular landscape of tumors from the PRODIGE-24/CCTG PA6 trial and assess the clinical impact of genomic alterations and molecular subtypes. PATIENTS AND METHODS: Tumor DNA sequencing was successfully performed in 317/350 tumors (168 mFFX; 149 GEM), complemented by transcriptomic subtyping using the PurIST classifier. Mutational status of four key PDAC driver genes and 24 homologous recombination repair (HRR)-associated genes was analyzed, alongside single-base substitution (SBS) mutational signatures. Primary and secondary end points were disease-free survival (DFS) and cancer-specific survival (CSS), respectively. RESULTS: In the mFFX group, the PurIST subtype was prognostic, with classical tumors showing superior DFS compared with basal-like tumors (stratified hazard ratio [sHR], 0.48 [95% CI, 0.31 to 0.77]). Among KRAS-mutated patients, mFFX significantly improved DFS compared with GEM (sHR, 0.60 [95% CI, 0.45 to 0.79]; P < .001), while no benefit was observed in KRAS wild-type tumors (interaction test, Pint. = 0.010). HRR and BRCA status were not predictive (Pint. = .568 and Pint. = .785, respectively). The benefit of mFFX was consistent across SBS-positive and SBS-negative subgroups. CONCLUSION: Overall, these results do not support a change in current adjuvant treatment strategies. mFFX remains the standard adjuvant regimen in PDAC, and the observed lack of benefit in KRAS wild-type tumors should be considered hypothesis-generating and warrants further investigation.

Humans↗
PubMed2006

Germline gain-of-function mutations in SOS1 cause Noonan syndrome.

Noonan syndrome, the most common single-gene cause of congenital heart disease, is characterized by short stature, characteristic facies, learning problems and leukemia predisposition. Gain-of-function mutations in PTPN11, encoding the tyrosine phosphatase SHP2, cause approximately 50% of Noonan syndrome cases. SHP2 is required for RAS-ERK MAP kinase (MAPK) cascade activation, and Noonan syndrome mutants enhance ERK activation ex vivo and in mice. KRAS mutations account for <5% of cases of Noonan syndrome, but the gene(s) responsible for the remainder are unknown. We identified missense mutations in SOS1, which encodes an essential RAS guanine nucleotide-exchange factor (RAS-GEF), in approximately 20% of cases of Noonan syndrome without PTPN11 mutation. The prevalence of specific cardiac defects differs in SOS1 mutation-associated Noonan syndrome. Noonan syndrome-associated SOS1 mutations are hypermorphs encoding products that enhance RAS and ERK activation. Our results identify SOS1 mutants as a major cause of Noonan syndrome, representing the first example of activating GEF mutations associated with human disease and providing new insights into RAS-GEF regulation.

Adolescent↗