Germline Variation Controls the Architecture of Somatic Alterations in Tumors

Dworkin, Amy M.; Ridd, Katie; Bautista, Dianne; Allain, Dawn C.; Iwenofu, O. Hans; Roy, Ritu; Bastian, Boris C.; Toland, Amanda E.

doi:10.1371/journal.pgen.1001136

Cited by 34 publications

(48 citation statements)

References 33 publications

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“…The relationship between frequency of genomic alterations and genetic background has also been observed in other murine models of cancer (15). Data from analyses of mouse (16) and human (17) squamous cell carcinomas also support the notion of genetic background affecting the pattern of somatic alterations in tumors. The potential interactions between germline variants and somatic alterations could influence not only cancer susceptibility (18), but can also affect tumor progression and disease prognosis.…”

Section: Discussionmentioning

confidence: 61%

Progressive Genomic Instability in the FVB/KrasLA2 Mouse Model of Lung Cancer

Quigley

Mao

et al. 2011

Molecular Cancer Research

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Alterations in DNA copy number contribute to the development and progression of cancers and are common in epithelial tumors. We have used array Comparative Genomic Hybridization (aCGH) to visualize DNA copy number alterations across the genomes of lung tumors in the KrasLA2 model of lung cancer. Copy number gain involving the Kras locus, as focal amplification or whole chromosome gain, is the most common alteration in these tumors, and with a prevalence that increased significantly with increasing tumor size. Furthermore, Kras amplification was the only major genomic event among the smallest lung tumors, suggesting that this alteration occurs early during the development of mutant Kras driven lung cancers. Recurring gains and deletions of other chromosomes occur progressively more frequently among larger tumors. These results are in contrast to a previous aCGH analysis of lung tumors from KrasLA2 mice on a mixed genetic background, in which relatively few DNA copy number alterations were observed regardless of tumor size. Our model features the KrasLA2 allele on the inbred FVB/N mouse strain, and in this genetic background there is a highly statistically significant increase in level of genomic instability with increasing tumor size. These data suggest that recurring DNA copy alterations are important for tumor progression in the KrasLA2 model of lung cancer, and that the requirement for these alterations may be dependent on the genetic background of the mouse strain.

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Section: Discussionmentioning

confidence: 61%

Progressive Genomic Instability in the FVB/KrasLA2 Mouse Model of Lung Cancer

Quigley

Mao

et al. 2011

Molecular Cancer Research

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“…Although C57BL/6 is highly resistant to DMBA/TPA skin carcinogenesis and developed only a modest number of papillomas in WT mice (~16 tumors/mouse), it was found that Hras KO/KO animals developed significantly fewer tumors (~3 tumors/mouse) 17 . Because genetic background can affect tumor development as well as pattern of genetic alterations in tumors 10, 18-20 , we backcrossed the Hras KO allele into the FVB/N background for more than 15 generations. FVB/N mice are highly susceptible to the development of epithelial tumors, and particularly skin tumors 21 .…”

Section: Resultsmentioning

confidence: 99%

Interactions between wild-type and mutant Ras genes in lung and skin carcinogenesis

Rosario

Westcott

et al. 2012

Oncogene

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Ras oncogenes (Hras, Kras, and Nras) are important drivers of carcinogenesis. However, tumors with Ras mutations often show loss of the corresponding wildtype (WT) allele, suggesting that proto-oncogenic forms of Ras can function as a suppressor of carcinogenesis. In vitro studies also suggest that WT Ras proteins can suppress the tumorigenic properties of alternate mutant Ras family members, but in vivo evidence for these heterologous interactions is lacking. We have investigated the genetic interactions between different combinations of mutant and WT Ras alleles in vivo using carcinogen-induced lung and skin carcinogenesis in mice with targeted deletion of different Ras family members. The major suppressor effect of WT Kras is observed only in mutant Kras-driven lung carcinogenesis, where loss of one Kras allele led to increased tumor number and size. Deletion of one Hras allele dramatically reduced the number of skin papillomas with Hras mutations, consistent with Hras as the major target of mutation in these tumors. However, skin carcinoma numbers were very similar, suggesting that WT Hras functions as a suppressor of progression from papillomas to invasive squamous carcinomas. In the skin, the Kras proto-oncogene functions cooperatively with mutant Hras to promote papilloma development, although the effect is relatively small. In contrast, the Hras proto-oncogene attenuated the activity of mutant Kras in lung carcinogenesis. Interestingly, loss of Nras increased the number of mutant Kras-induced lung tumors but decreased the number of mutant Hras-induced skin papillomas. These results show that the strongest suppressor effects of WT Ras are only seen in the context of mutation of the cognate Ras protein, and only relatively weak effects are detected on tumor development induced by mutations in alternative family members. The data also underscore the complex and context-dependent nature of interactions between proto-oncogenic and oncogenic forms of different Ras family members during tumor development.

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“…A different spectrum of somatic mutations might also be caused by the distinct genetic backgrounds of Asian and Western populations, as germline variations have been shown to influence the somatic alterations that occur in tumors. 57 Moreover, exposure to certain etiological agents such as infectious diseases, including oncogenic viruses, or dietary habits could result on the usage of different oncogenic pathways. Indeed, 45% of the Chinese patients screened by exome sequencing presented some types of chronic infection at diagnosis including hepatitis B virus (23%), EpsteinBarr virus (10%), Helicobacter pylori (10%), and tuberculosis (10%), most of which have been shown to be highly prevalent in Chinese populations.…”

Section: Discussionmentioning

confidence: 99%