Frequency and distinctive spectrum of <i>KRAS</i> mutations in never smokers with lung adenocarcinoma

Riely, Gregory J.; Kris, Mark G.; Marks, Jenifer L.; Li, A.; Chitale, Dhananjay; Riedel, Elyn; Hsu, Myriam Y.; Pao, William; Miller, V. A.; Ladanyi, M.

doi:10.1200/jco.2008.26.15_suppl.8006

Cited by 68 publications

(96 citation statements)

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“…38 Kras is mutated in about 25% 39 of lung tumors from smokers but only in 15% of non-smokers. 40 Interestingly, Kras mutations in smokers were predominantly transversions while those in never smokers were more likely to be transitions. 40 In both cases, activating mutations were predominantly in codon 12 with few in codons 13 and 61.…”

Section: Cancer Geneticsmentioning

confidence: 98%

“…40 Interestingly, Kras mutations in smokers were predominantly transversions while those in never smokers were more likely to be transitions. 40 In both cases, activating mutations were predominantly in codon 12 with few in codons 13 and 61. Seventy-one percent of Kras mutations in human lung tumors were G!T transversions, while G!A transitions and G!C transversions were found in equal numbers.…”

Section: Cancer Geneticsmentioning

confidence: 98%

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Epistatic interactions govern chemically‐induced lung tumor susceptibility and Kras mutation site in murine C57BL/6J‐ChrA/J chromosome substitution strains

Dwyer‐Nield

McQuillan

Hill-Baskin

et al. 2009

Intl Journal of Cancer

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Cancer susceptibility results from interactions between sensitivity and resistance alleles. We employed murine chromosome substitution strains to study how resistance alleles affected sensitive alleles during chemically-induced lung carcinogenesis. The C57BL/6J-Chr# A/J strains, constructed by selectively breeding sensitive A/J and resistant C57BL/6J (B6) mice, each contain one pair of A/J chromosomes within an otherwise B6 genome. Pas1, the major locus responsible for this differential strain response to urethane carcinogenesis, resides on Chr 6, but C57BL/6J-Chr6 A/J mice (hereafter CSS-6) developed few tumors following a single urethane injection, which demonstrates epistatic interactions with other B6 alleles. CSS6 mice developed dozens of lung tumors after chronic urethane exposure, however, indicating that these epistatic interactions could be overcome by repeated carcinogen administration. Unlike A/J, but similar to B6 mice, CSS6 mice were resistant to lung carcinogenesis induced by 3-methylcholanthrene (MCA). Tumor multiplicity increased if BHT administration followed urethane exposure, showing that a Chr 6 gene(s) regulates sensitivity to chemically-induced tumor promotion. Unlike A/J tumors (predominantly codon 61 AfiT transversions), Kras mutations in tumors induced by urethane in CSS-6 mice were similar to B6 tumors (codon 61 AfiG transitions). DNA repair genes not located on Chr 6 may determine the nature of Kras mutations. CSS-6 mice are a valuable resource for testing the ability of candidate genes to modulate lung carcinogenesis.Lung cancer is the leading cause of cancer death in both men and women in the USA, with 200,000 new cases of lung cancer estimated to be diagnosed this year. The dismal 15% survival rate over 5 years indicates that only 30,000 of these patients will be alive in 2014. 1 Smoking contributes to 85-90% of all lung cancers, but non-smoking-related lung cancer, which is more common in women than men, is the 7 th leading cause of cancer death.2 Since only 15% of smokers develop lung cancer, genetic factors presumably contribute to disease susceptibility.Recent lung cancer familial linkage studies delineated regions on human Chromosomes 6 and 12 that contributed to the risk of lung cancer, chronic obstructive pulmonary disease (COPD), and diminished lung function.3,4 Chronic pulmonary inflammation predisposes toward lung cancer, and several chromosomal sites in mice that determine responsiveness to pro-inflammatory pneumotoxicants correspond to loci containing lung cancer susceptibility genes. 5Mice develop pulmonary adenocarcinoma (AC) that is histologically and genetically similar to human AC within a relatively short time span (6-42 wks) in response to chemical carcinogens 6 and within 2-36 wks in response to genetic induction with oncogenessuch as Kras.7-9 A/J mice are particularly sensitive to carcinogen-induced lung tumorigenesis, and develop spontaneous lung tumors during their lifespan.

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Section: Cancer Geneticsmentioning

confidence: 98%

Section: Cancer Geneticsmentioning

confidence: 98%

Epistatic interactions govern chemically‐induced lung tumor susceptibility and Kras mutation site in murine C57BL/6J‐ChrA/J chromosome substitution strains

Dwyer‐Nield

McQuillan

Hill-Baskin

et al. 2009

Intl Journal of Cancer

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“…In human lung cancers, K-ras transversion mutations have been identified as a molecular signature for the carcinogenic effects of cigarette smoke. 39,40 However, it has also been reported that there was no difference in overall survival for patients metastatic lung adenocarcinomas when comparing KRAS transition versus transversion mutations. 41 In the current study, only 3 of 14 (21.4%) K-ras mutations were transversion mutations in the TP53-273H and nontransgenics lung tumors, whereas 6 of 7 (85.7%) K-ras mutations were transversions in the p53-175H tumors.…”

Section: Discussionmentioning

confidence: 99%

Type of TP53 mutation influences oncogenic potential and spectrum of associated K‐ras mutations in lung‐specific transgenic mice

Duan

Kalvala

et al. 2019

Intl Journal of Cancer

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TP53 and K‐ras mutations are two of the major genetic alterations in human nonsmall cell lung cancers. The association between these two genes during lung tumorigenesis is unknown. We evaluated the potential of two common Type I (273H, contact) and Type II (175H, conformational) TP53 mutations to induce lung tumors in transgenic mice, as well as K‐ras status, and other driver mutations in these tumors. Among 516 (138 nontransgenic, 207 SPC‐TP53‐273H, 171 SPC‐TP53‐175H) mice analyzed, 91 tumors, all adenocarcinomas, were observed. Type II mutants developed tumors more frequently (as compared to nontransgenics, p = 0.0003; and Type I, p = 0.010), and had an earlier tumor onset compared to Type I (p = 0.012). K‐ras mutations occurred in 21 of 50 (42%) of murine lung tumors sequenced. For both the nontransgenic and the SPC‐TP53‐273H transgenics, tumor K‐ras codon 12–13 mutations occurred after 13 months with a peak incidence at 16–18 months. However, for the SPC‐TP53‐175H transgenics, K‐ras codon 12–13 mutations were observed as early as 6 months, with a peak incidence between the ages of 10–12 months. Codons 12–13 transversion mutations were the predominant changes in the SPC‐TP53‐175H transgenics, whereas codon 61 transition mutations were more common in the SPC‐TP53‐273H transgenics. The observation of accelerated tumor onset, early appearance and high frequency of K‐ras codon 12–13 mutations in the Type II TP53‐175H mice suggests an enhanced oncogenic function of conformational TP53 mutations, and gains in early genetic instability for tumors containing these mutations compared to contact mutations.

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“…KRAS mutations can occur as transversion mutations (substitution of a purine nucleotide to a pyrimidine or vice versa) or transition mutations (purine to purine or pyrimidine to pyrimidine substitution). Transversion mutations appear more commonly in tumors of current or former smokers, whereas transition mutations are more common in never smokers [27]. G12D is the most common transition seen in never smokers, whereas G12C isthe mostcommon transversion seen in smokers [25].…”

Section: Kras Pathway Biologymentioning

confidence: 99%

“…G12D is the most common transition seen in never smokers, whereas G12C isthe mostcommon transversion seen in smokers [25]. Data regarding differential clinical outcomes for patients with KRAS transition and transversion tumor mutations are conflicting [26][27][28]. More substantial differences in clinical outcomes of patients with KRAS-mutant NSCLC have been described based on mutation location (i.e., in codon 12 or 13) [29,30].…”

Section: Kras Pathway Biologymentioning

confidence: 99%

Targeting the KRAS Pathway in Non-Small Cell Lung Cancer

et al. 2016

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Lung cancer remains the leading cause of cancer‐related deaths worldwide. However, significant progress has been made individualizing therapy based on molecular aberrations (e.g., EGFR, ALK) and pathologic subtype. KRAS is one of the most frequently mutated genes in non‐small cell lung cancer (NSCLC), found in approximately 30% of lung adenocarcinomas, and is thus an appealing target for new therapies. Although no targeted therapy has yet been approved for the treatment of KRAS‐mutant NSCLC, there are multiple potential therapeutic approaches. These may include direct inhibition of KRAS protein, inhibition of KRAS regulators, alteration of KRAS membrane localization, and inhibition of effector molecules downstream of mutant KRAS. This article provides an overview of the KRAS pathway in lung cancer and related therapeutic strategies under investigation. Implications for Practice: The identification of oncogene‐addicted cancers and specific inhibitors has revolutionized non‐small cell lung cancer (NSCLC) treatment and outcomes. One of the most commonly mutated genes in adenocarcinoma is KRAS, found in approximately 30% of lung adenocarcinomas, and thus it is an appealing target for new therapies. This review provides an overview of the KRAS pathway and related targeted therapies under investigation in NSCLC. Some of these agents may play a key role in KRAS‐mutant NSCLC treatment in the future.

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Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma

Cited by 68 publications

References 0 publications

Epistatic interactions govern chemically‐induced lung tumor susceptibility and Kras mutation site in murine C57BL/6J‐ChrA/J chromosome substitution strains

Epistatic interactions govern chemically‐induced lung tumor susceptibility and Kras mutation site in murine C57BL/6J‐ChrA/J chromosome substitution strains

Type of TP53 mutation influences oncogenic potential and spectrum of associated K‐ras mutations in lung‐specific transgenic mice

Targeting the KRAS Pathway in Non-Small Cell Lung Cancer

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