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PubMed2026

Origin and evolution of colorectal mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN).

Colorectal neuroendocrine carcinoma (NEC) is a rare and aggressive cancer and in a subset of patients associated with an adenocarcinoma (AC) component. When both components exceed 30% of the tumour, it is classified as mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN), although there is an ongoing debate about whether any presence of two distinct components should be sufficient for a MiNEN diagnosis. This study aimed to investigate the origin and subsequent genetic changes of these two components. Ten colorectal cases suitable for sampling of an AC and a poorly differentiated NEC component were identified from the NORDIC NEC 2 study and sequenced across a 360-cancer gene panel. Mock phylogenetic trees were constructed from the molecular profiles of each sample within a patient. All ten cases revealed a common trunk of shared somatic mutations, including well-known colorectal cancer driver mutations such as BRAF, KRAS, APC, and TP53. In all cases, a single branching point separated the AC and NEC components. Private AC and NEC mutations generally had low variant allele frequencies, indicating that most AC and NEC cells were genetically similar. NEC, when compared with AC samples, demonstrated a higher frequency of private mutations (P = 0.009), indicating a higher mutation rate and greater ploidy (P = 0.012), suggesting an association between genomic duplication and AC-to-NEC transition. Shared mutations indicate a common clonal origin, underscoring the role of established colorectal driver mutations in the early development of these tumours, while the mechanisms underlying NEC differentiation remain poorly understood and may involve non-genetic factors.

Humans↗
PubMed2006

Mutational analysis of PDGFR-RAS/MAPK pathway activation in childhood medulloblastoma.

Aberrant signalling via platelet derived growth factor receptors (PDGFRs) and the RAS/MAPK pathway has been implicated in the development of medulloblastoma, the most common malignant brain tumour in childhood. To determine whether genetic mechanisms play a role in the activation of PDGFR-RAS/MAPK signalling in medulloblastoma, we performed a direct sequence analysis of the established mutational "hotspots" of known targets of activating mutations within the pathway (PDGFRA, NRAS, KRAS, HRAS and BRAF) and PDFRFB, in a cohort of 28 primary tumours. A synonymous sequence variation in PDGFRA (CCG to CCA; PRO 567 PRO) was detected in two cases (approximately 7%), but not in 150 normal chromosomes assessed, suggesting that the PDGFRA locus may be associated with medulloblastoma development in certain cases. No evidence for oncogenic mutations affecting NRAS, KRAS, HRAS, BRAF or PDFRFB was found in any case. These data demonstrate that activating mutations in established mutational hotspots within the PDGFR-RAS/MAPK pathway are rare events in medulloblastoma development, and suggest that alternative mechanisms are responsible for RAS/MAPK pathway activation in this disease.

Adolescent↗
PubMed2025

Population-Specific Immunogenomic Alterations in Gallbladder Cancer and Prognostic Significance.

Gallbladder carcinoma is a deadly disease with a poor prognosis, and recent clinical data suggest only a modest benefit of PD1/PDL1 inhibitors in this disease. Optimizing immunotherapeutic approaches will require a detailed understanding of the immunogenomic landscape of this disease worldwide. We combined targeted next-generation sequencing and immunohistochemistry to create detailed immunogenomic landscapes from 2 cohorts of gallbladder cancer cases from the United States (n = 60) and Chile (n = 62). Mutations in TP53, SMAD4, KRAS, PIK3CA, ARID2, ARID1A, ATM, FBXW7, ERBB2, and NF1 were found in both the US and Chilean primary cohorts, as well as amplifications in ERBB2, CCNE1, MDM2/CDK4, and CCND1. Despite similar mutation profiles, the immune profiles were distinct, with the Latin American cohort having higher densities of biomarkers associated with CD4+ T cells and PD-1 but lower densities of CD68+ macrophages compared with the North American cohort. Clustering and correlation analyses suggest novel immune subgroups and clinical associations independently of any specific mutations. Additionally, supported by multiplexed single-cell imaging technology, we identified low CD4 and high V-domain Ig suppressor of T cell activation as a candidate biomarker pair of poor outcomes. In summary, our findings highlight the importance of sensitivity to geographic location when considering therapeutic developments and pave a path for further immune investigations of this understudied disease.

Humans↗
PubMed1998

Molecular and biological features of two new human squamous and adenocarcinoma of the lung cell lines.

Two human cancer cell lines were established from metastatic lesions of an adenocarcinoma (RAL) and a squamous cell (CAEP) carcinoma of the lung. The clinical histories of the patients from whom the cell lines were derived are reported. The lines were maintained in continuous culture with doubling times of 65 (RAL) and 50 (CAEP) hours. The RAL and CAEP cell lines, whose morphology and ultrastructural features are presented, showed extensively rearranged karyotypes with modal number of 85 (RAL) and 98 (CAEP). In particular, chromosome 2 pentasomy and several clonal markers were evident in the RAL cells, whereas a telomeric deletion of chromosome 1, del (1)(q32), was observed in the CAEP cells. The morphologic data were confirmed by high expression of specific antigens for each histotype. A marked positivity of the neuron-specific enolase (NSE) levels was evident by immunoenzymatic assays in the cell lines cytosol with respect to those present in the respective patient's sera. No amplification or rearrangements were evident in the CMYC, LMYC, NMYC, INT-2, ERBB2, HRAS, KRAS, MOS, HST-1 genes by Southern blotting analysis in each cell line. Point mutations in exon 1 of KRAS and in exon 7 of TP53 were evident by polymerase chain reaction (PCR)-DNA sequencing in the RAL cell line, whereas no alterations were present in the HRAS and RB genes. The four genes studied did not show point mutations in the CAEP cell line. The RAL cell line was resistant to all the drugs tested, whereas the CAEP cells were sensitive to vinblastine. These cell lines may represent useful experimental models to investigate lung cancer biology and anticancer drug response.

Adenocarcinoma↗
PubMed1990

Detection of preferential NRAS mutations in human male germ cell tumors by the polymerase chain reaction.

We have studied 31 male germ cell tumors (GCTs) for probable mutations in codons 12, 13, and 61 of HRAS, KRAS, and NRAS oncogenes using the polymerase chain reaction. Twenty of the thirty-one tumors exhibited NRAS gene mutations, 14 in codon 61, and six in codon 12, whereas no mutations were detected in HRAS and KRAS genes. The NRAS mutations were equally prevalent in seminomatous and nonseminomatous GCTs. Thus 13 of 22 seminomas, six of seven embryonal carcinomas, and one of two mixed tumors exhibited mutations. Two non-seminomatous tumors (an embryonal carcinoma and a yolk sac/teratoma) had mutations in both codons 12 and 61. The high frequency of NRAS mutations observed in the present study suggests that NRAS gene products may play an important role in growth regulatory functions of premalignant and malignant germ cells.

DNA Mutational Analysis↗
PubMed2006

Human colorectal mucosal O6-alkylguanine DNA-alkyltransferase activity and DNA-N7-methylguanine levels in colorectal adenoma cases and matched referents.

BACKGROUND AND AIMS: O(6)-alkylguanine DNA-alkyltransferase (MGMT) provides protection against alkylating agent-induced GC-->AT transition mutations. Such mutations are frequently seen in the KRAS oncogene of large colorectal adenomas, but whether adenoma or mutational risk in humans is influenced by MGMT activity and alkylating agent exposure is unclear. Hence, MGMT activity and, as an indicator of alkylating agent exposure, DNA-N7-methylguanine (N7-MeG) levels were determined in the normal tissue of patients with and without adenomas. METHODS: Biopsy specimens of normal colorectal mucosa were collected during colonoscopy from 85 patients with histologically proved colorectal adenomas (cases) and from 85 patients free of gastrointestinal neoplasia (referents) matched by age, sex and biopsy location. MGMT activity and N7-MeG levels were measured in colorectal tissue extracts and DNA, respectively. RESULTS: MGMT activity was higher in the normal mucosa of cases than in referents (6.65+/-3.03 vs 5.61+/-2.74 fmol/micro g DNA, p = 0.01). On stratification of cases, MGMT activity was found to be considerably greater in the normal mucosa of cases with large adenomas (p = 0.003) and slightly higher in cases with a GC-->AT transition mutation in the K-ras gene (p = 0.03). Elevated MGMT levels were associated with an increased risk of adenoma (OR 1.17, 95% CI 1.03 to 1.33 per unit increase in activity). Detectable levels of N7-MeG were found in DNA from 89% of cases and 93% of referents, with levels ranging from <0.1 to 7.7 micro mol/mol dG. Cases and referents had similar DNA-N7-MeG levels. CONCLUSIONS: Human exposure to methylating agents is widespread. MGMT activity is increased in the normal mucosa of patients with adenomas.

Adenoma↗
PubMed1997

Molecular advances in pancreatic cancer.

Our understanding of the molecular genetics of pancreatic cancer has advanced spectacularly over the last 5 years so that this tumour type is now one of the best characterised of all malignancies. A small proportion of cases results from inherited predisposition due to germline transmission of a mutated CDKN2 or BRCA2 gene, while patients with familial pancreatitis due to a mutated cationic trypsinogen gene have a greatly increased risk of developing pancreatic cancer. The majority of cases are sporadic and are characterised at the molecular level by several key genetic abnormalities. The most frequent of these is point mutation of the dominant oncogene KRAS, a lesion which occurs as an early and possibly initiating event in tumourigenesis. Inactivating mutations of the tumour suppressor genes TP53, CDKN2 and SMAD4 are also frequently observed and this constellation of genetic defects sets pancreatic cancer apart from other types of cancer, a feature which could have important implications for molecular diagnosis. Genetic intervention for cancer prevention and therapy is becoming a clinical reality and several approaches are being pursued for pancreatic cancer. As well as tumour suppressor gene replacement and oncogene blockade, strategies with a potential bystander effect are showing promise. These include genetic prodrug activation therapy using selective expression of suicide genes and genetic immunomodulation with cytokines and tumour-associated antigens.

Genes, Tumor Suppressor↗
PubMed1999

Enrichment of mutant alleles by chromatographic removal of wild type alleles: a new principle for the detection of alleles with unknown point mutations at excess of wild type alleles.

In human carcinomas, mutations that alter tumour genes such as the KRAS, P53, or APC genes, are mostly point mutations. The detection of mutant alleles of tumour genes in specimens such as urine, pancreatic juice, sputum, and stool holds great promise for an early diagnosis of cancer. In addition, the detection of mutant tumour genes in tissue samples, such as lymph nodes or resection margins, may allow a sensitive diagnosis of residual malignant disease. However, the reliable detection of mutant alleles in excess of wild type alleles remains an unresolved analytical problem when the mutations are not known a priori. In the present communication, a new approach is described which makes possible the detection of unknown point mutations in tumour genes at excess of wild type alleles. The method is based on the removal of wild type alleles by hybridisation to immobilised complementary oligonucleotides. Using this approach, an enrichment of mutant KRAS, P53 and APC alleles of one mutant in up to 10(3) normal alleles has been achieved. Parallel miniaturised separation units with oligonucleotides complementary to defined sequences of a wild type allele should allow the detection of unknown point mutations as well as small insertions or deletions which occur in the sequence range covered by the oligonucleotides.

Alleles↗
PubMed2026

KRAS Expression Complements Genomic Profiling in Identifying Therapeutic Vulnerability in Gastric Cancer.

BACKGROUND: Gastric cancer (GC) remains a major therapeutic challenge. Although alterations in the RAS pathway occur in over 50% of tumors, only a limited proportion are clinically actionable. We investigated whether KRAS expression complements genomic profiling for patient stratification and therapeutic vulnerability in GC. METHODS: Comprehensive genomic profiling was performed in 19 Taiwanese GC patients and compared with TCGA-STAD data (n = 434). KRAS mRNA expression and overall survival were evaluated by meta-analysis of 13 independent cohorts (n = 2,521). Protein-level validation was performed by immunohistochemistry in an independent cohort (n = 121). Functional KRAS dependency and response to combined MEK/SHP2 inhibition were assessed in eight GC cell lines. RESULTS: KRAS amplification was entirely contained within the KRAS-high population, whereas most KRAS-high tumors lacked detectable amplification. High KRAS expression was associated with poorer overall survival (HR 1.23, p = 0.001) and remained an independent prognostic factor after multivariable adjustment (adjusted HR 1.24, p = 0.003). Protein-level analysis showed a concordant trend. KRAS expression correlated strongly with functional dependency (R2 = 0.88, p = 0.005), was enriched in MSI and CIN subtypes, and identified cell lines with enhanced sensitivity to combined MEK/SHP2 inhibition. CONCLUSIONS: KRAS expression complements genomic profiling by identifying biologically relevant KRAS-dependent GCs beyond mutation or amplification alone. Integrating expression-based stratification with genomic profiling may improve patient selection for RAS pathway-directed combination therapies.

Biomarker↗
PubMed2005

Roles of RAS and BRAF mutations in thyroid carcinogenesis.

Papillary carcinoma and follicular carcinoma are types of differentiated thyroid carcinomas, develop from the same thyroid follicular epithelial cells and show distinct biological behavior. Although several studies have demonstrated differences in the biological characteristics of these carcinomas, little is known about the genetic backgrounds that underlie these differences. The clarification of the genetic background can lead to the understanding of thyroid carcinogenesis, proper therapeutic strategies, and development of the molecular targeting drugs. Recently, aberrant activation of RAS-RAF-MEK-MAP kinase signaling pathway is frequently found in thyroid carcinoma. The pathway transmits a mitogenic signal to the nucleus, and constitutive activation of the pathway is thought to promote uncontrolled cell division. In our series, BRAF mutation was detected exclusively in papillary carcinoma (54%), and was exclusively V599E (a single nucleotide change of A-T at nucleotide 1796). NRAS mutation was observed in follicular carcinoma (50%) and in anaplastic carcinoma (28%), and was exclusively Q61R (a single nucleotide change of A-G at nucleotide 182). No mutations were found in KRAS or HRAS. In this chapter, we explain the role of RAS-RAF-MEK-MAP kinase pathway in carcinogenesis of the thyroid and its clinical implication based on our study. In addition, we review the current knowledge in this field.

Adenocarcinoma, Follicular↗
PubMed2007

Phase II clinical trial of chemotherapy-naive patients > or = 70 years of age treated with erlotinib for advanced non-small-cell lung cancer.

PURPOSE: This is a phase II, multicenter, open-label study of chemotherapy-naïve patients with non-small-cell lung cancer (NSCLC) and age > or = 70 years who were treated with erlotinib and evaluated to determine the median, 1-year, and 2-year survival. The secondary end points include radiographic response rate, time to progression (TTP), toxicity, and symptom improvement. PATIENTS AND METHODS: Eligible patients with NSCLC were treated with erlotinib 150 mg/d until disease progression or significant toxicity. Tumor response was assessed every 8 weeks by computed tomography scan using Response Evaluation Criteria in Solid Tumors. Tumor samples were analyzed for the presence of somatic mutations in EGFR and KRAS. RESULTS: Eighty eligible patients initiated erlotinib therapy between March 2003 and May 2005. There were eight partial responses (10%), and an additional 33 patients (41%) had stable disease for 2 months or longer. The median TTP was 3.5 months (95% CI, 2.0 to 5.5 months). The median survival time was 10.9 months (95% CI, 7.8 to 14.6 months). The 1- and 2- year survival rates were 46% and 19%, respectively. The most common toxicities were acneiform rash (79%) and diarrhea (69%). Four patients developed interstitial lung disease of grade 3 or higher, with one treatment-related death. EGFR mutations were detected in nine of 43 patients studied. The presence of an EGFR mutation was strongly correlated with disease control, prolonged TTP, and survival. CONCLUSION: Erlotinib monotherapy is active and relatively well tolerated in chemotherapy-naïve elderly patients with advanced NSCLC. Erlotinib merits consideration for further investigation as a first-line therapeutic option in elderly patients.

Age Factors↗
PubMed2003

Mutation analysis of the BRAF, ARAF and RAF-1 genes in human colorectal adenocarcinomas.

Colorectal cancer is a multi-step process characterized by a sequence of genetic alterations in cell growth regulatory genes, such as the adenomatous polyposis coli, KRAS, p53 and DCC genes. In the present study mutation analysis was performed with SSCA/direct sequencing of the hot-spot regions in exons 11 and 15 for the BRAF gene and exons 1-2 for the KRAS gene in 130 primary colorectal cancer tumors and correlated with clinico-pathological and mutational data. We also performed mutation analysis of the corresponding conserved regions in the ARAF and RAF-1 genes. Mutations in the BRAF and KRAS genes were found in 11.5 and 40% of the tumors, respectively. One germline exonic and nine germline intronic genetic variants were found in the ARAF and RAF-1 genes. All of the BRAF mutations were located in the kinase domain of the conserved region 3 in exon 15 of the BRAF gene. One novel somatic mutation was also identified in the BRAF gene. The majority of the BRAF mutations were found in colon compared with rectal tumors (P = 0.014). In agreement with others, a statistically significant correlation between BRAF mutations and microsatellite instability could be found. A negative correlation was also evident between mutations in the BRAF and KRAS genes, which supports earlier studies where somatic mutations in these genes are mutually exclusive. Collectively, our results provide support for the idea that activation of the MAP kinase pathway, especially via BRAF and KRAS mutations, is of critical importance for the development of colorectal cancer.

Adenocarcinoma↗
PubMed2005

Cyclooxygenase-2 is a target of KRASD12, which facilitates the outgrowth of murine C26 colorectal liver metastases.

PURPOSE: Mutational activation of the KRAS oncogene and overexpression of cyclooxygenase-2 (COX-2) contribute to colorectal carcinoma (CRC) development, but the relationship between these two events is unclear. This study was designed to clarify that relationship and to assess the contribution of KRAS-dependent COX-2 to the seeding of CRC cells in the liver and to their outgrowth as liver metastases in an experimental mouse model. EXPERIMENTAL DESIGN: The effect of RNA interference-mediated KRAS knockdown on COX-2 expression and activity was tested in murine C26 CRC cells. The contribution of KRAS-dependent COX-2 to early metastatic tumor cell seeding (by intravital microscopy) and outgrowth of metastases in the liver (by bioluminescence imaging) was studied by using parecoxib, a novel and highly selective liver-activated COX-2 inhibitor. Intratumoral cell proliferation, apoptosis, and tumor-associated angiogenesis were assessed by immunohistochemistry on liver tissue sections. RESULTS: Stable knockdown of mutant KRAS(D12) in murine C26 CRC cells by RNA interference lead to a dramatic reduction of COX-2 synthesis and prostaglandin E2 production. Inhibition of host or tumor cell COX-2 activity had no effect on early metastatic cell seeding in the liver but greatly reduced intrahepatic tumor cell proliferation and the rate of liver metastasis outgrowth. COX-2 inhibition had no effect on early tumor vascularization or on tumor cell apoptosis. CONCLUSIONS: The high levels of COX-2 enzyme and prostaglandin production in C26 CRC cells are primarily caused by the presence of endogenous mutant KRAS(D12). Furthermore, COX-2 inhibition affects the tumoral rather than the vascular compartment during the early stages of C26 liver metastasis outgrowth.

Animals↗
PubMed2006

CpG island methylator phenotype (CIMP) of colorectal cancer is best characterised by quantitative DNA methylation analysis and prospective cohort studies.

BACKGROUND: The concept of CpG island methylator phenotype (CIMP) is not universally accepted. Even if specific clinicopathological features have been associated with CIMP, investigators often failed to demonstrate a bimodal distribution of the number of methylated markers, which would suggest CIMP as a distinct subtype of colorectal cancer. Previous studies primarily used methylation specific polymerase chain reaction which might detect biologically insignificant low levels of methylation. AIM: To demonstrate a distinct genetic profile of CIMP colorectal cancer using quantitative DNA methylation analysis that can distinguish high from low levels of DNA methylation. MATERIALS AND METHODS: We developed quantitative real time polymerase chain reaction (MethyLight) assays and measured DNA methylation (percentage of methylated reference) of five carefully selected loci (promoters of CACNA1G, CDKN2A (p16), CRABP1, MLH1, and NEUROG1) in 460 colorectal cancers from large prospective cohorts. RESULTS: There was a clear bimodal distribution of 80 microsatellite instability-high (MSI-H) tumours according to the number of methylated promoters, with no tumours showing 3/5 methylated loci. Thus we defined CIMP as having >or=4/5 methylated loci, and 17% (78) of the 460 tumours were classified as CIMP. CIMP was significantly associated with female sex, MSI, BRAF mutations, and wild-type KRAS. Both CIMP MSI-H tumours and CIMP microsatellite stable (MSS) tumours showed much higher frequencies of BRAF mutations (63% and 54%) than non-CIMP counterparts (non-CIMP MSI-H (0%, p<10(-5)) and non-CIMP MSS tumours (6.6%, p<10(-4)), respectively). CONCLUSION: CIMP is best characterised by quantitative DNA methylation analysis. CIMP is a distinct epigenotype of colorectal cancer and may be less frequent than previously reported.

Colorectal Neoplasms↗
PubMed2001

Comparative analysis of the NF2, TP53, PTEN, KRAS, NRAS and HRAS genes in sporadic and radiation-induced human meningiomas.

Irradiation to the head is associated with a significantly increased incidence of meningiomas. Radiation-induced meningiomas morphologically resemble their sporadically arising counterparts; however, they frequently exhibit a more malignant phenotype. Several genes have been shown to carry mutations in meningiomas, with the NF2 gene being most frequently affected. To examine whether the NF2 gene also plays a role in the development of radiation-induced meningiomas, we compiled a series of meningiomas from 25 patients with a history of previous cranial radiation. This series was compared with 21 atypical WHO grade II meningiomas and 15 anaplastic WHO grade III meningiomas, all from patients without a history of prior irradiation. NF2 mutations occurred significantly more often in sporadic atypical and anaplastic than in radiation-induced meningiomas (p < 0.02). In addition, all meningiomas were examined for mutations in the PTEN, TP53, HRAS, KRAS and NRAS genes. Two mutations in the TP53 gene in a sporadic and a radiation-induced tumor were detected. PTEN mutations were observed in 1 anaplastic and 1 radiation-induced meningioma. No structural alterations were seen in the RAS genes. Our data suggest that, while there is a certain overlap in the mutational spectrum, NF2 mutations may not play such a prominent role in the pathogenesis of radiation-induced compared to sporadic meningiomas.

Adult↗
PubMed2005

Activated Ras enhances insulin-like growth factor I induction of vascular endothelial growth factor in prostate epithelial cells.

Mutations in the three closely related RAS genes, HRAS, KRAS, and NRAS are among the most common mutations found in human cancer; reaching 50% in some types of cancer, such as colorectal carcinoma, and 10% in prostate cancers. The activated Ras proteins produced by these mutations can, among other cellular changes, increase vascular endothelial growth factor (VEGF) production. Moreover, tumors bearing RAS gene mutations are more vascular than tumors without RAS mutations. We find that, in prostate epithelial cells, the introduction of an activated HRAS causes cells to produce VEGF in response to insulin-like growth factor I (IGF-I). In comparison, cells lacking an activated Ras are unable to produce VEGF in response to IGF-I. This effect of Ras may occur through stabilization of a second messenger protein, insulin receptor substrate 1, that mediates PI 3-kinase-dependent signaling. Because IGF-I is a paracrine/endocrine hormone that has been associated with increased risk for several types of cancer, these results suggest a novel interrelationship between oncogenic conversion of a cellular gene such as HRAS, and IGF-I produced locally for normal tissue homeostasis.

Cell Line, Tumor↗
PubMed1988

Analysis of RAS gene mutations in acute myeloid leukemia by polymerase chain reaction and oligonucleotide probes.

In vitro DNA amplification followed by oligonucleotide dot blot analysis were used to study RAS gene mutations in acute myeloid leukemia (AML). Fifty-two presentation AML DNAs were screened for mutations in codons 12, 13, and 61 of NRAS and in codons 12 and 61 of KRAS and HRAS. Fourteen (27%) contained mutations--all in NRAS and predominantly in codon 12. The most common amino acid substitution identified was of glycine by aspartic acid at codon 12 (7/18), with a G----A transition being the most common base change (11/18). No particular correlation was observed between disease subtype and the incidence or type of NRAS mutation. In DNA samples from four patients, 2 NRAS mutations were found to coexist. NIH 3T3 focus-formation assays revealed that in each case the mutations were present in different NRAS alleles. We also report the absence of a mutated RAS gene in relapse DNAs of four patients in which a RAS oncogene had been detected at presentation. These observations suggest that RAS mutations arise as part of the evolution of neoplastic transformation.

DNA, Neoplasm↗
PubMed2005

RAS mutation is associated with hyperdiploidy and parental characteristics in pediatric acute lymphoblastic leukemia.

We explored the relationship of RAS gene mutations with epidemiologic and cytogenetic factors in a case series of children with leukemia. Diagnostic bone marrow samples from 191 incident leukemia cases from the Northern California Childhood Leukemia Study were typed for NRAS and KRAS codon 12 and 13 mutations. A total of 38 cases (20%) harbored RAS mutations. Among the 142 B-cell acute lymphoblastic leukemia (ALL) cases, RAS mutations were more common among Hispanic children (P=0.11) or children born to mothers <30 years (P=0.007). Those with hyperdiploidy at diagnosis (>50 chromosomes) had the highest rates of RAS mutation (P=0.02). A multivariable model confirmed the significant associations between RAS mutation and both maternal age and hyperdiploidy. Interestingly, smoking of the father in the 3 months prior to pregnancy was reported less frequently among hyperdiploid leukemia patients than among those without hyperdiploidy (P=0.02). The data suggest that RAS and high hyperdiploidy may be cooperative genetic events to produce the leukemia subtype; and furthermore, that maternal age and paternal preconception smoking or other factors associated with these parameters are critical in the etiology of subtypes of childhood leukemia.

Adolescent↗