An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers

Roberts, Steven A.; Lawrence, Michael S.; Klimczak, Leszek J.; Grimm, Sara A.; Fargo, David C.; Stojanov, Petar; Kiežun, Adam; Kryukov, Gregory V.; Carter, Scott L.; Saksena, Gordon; Harris, Shawn; Shah, Ruchir; Resnick, Michael A.; Getz, Gad; Gordenin, Dmitry A.

doi:10.1038/ng.2702

Cited by 1,075 publications

(1,405 citation statements)

References 49 publications

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“…The preponderance of A3 mutations in HPV driven cervical cancer, together with the observation that A3 mutations are enriched in the HPVassociated subset of head and neck squamous cell carcinoma (HNSC), suggest a possible off-target response to the virus [37,38,43,44]. Consistent with this, HPV16 infection has recently been shown to upregulate A3A and A3B mRNA expression in a keratinocyte cell line, and both are upregulated in pre-invasive cervical lesions [19,45].…”

Section: A3 Expression and Stimulationmentioning

confidence: 80%

“…A role for A3B in generating kataegis in tumors is also supported by studies showing that it can induce similar mutation showers when overexpressed in yeast, as can A3A [24]. Subsequent pan-cancer screens by all three groups suggest a mutagenic role for one or more of the TC-specific A3s in numerous tumor types [36][37][38].…”

Section: Apobecs As Mutators Of Genomic Dna: the Cancer Connectionmentioning

confidence: 86%

“…Although there is a bias in publicly available datasets, it does appear that A3 mutagenesis is particularly prevalent in carcinomas [36][37][38]. This may be because epithelia are a front-line barrier to viruses, and hence the innate immune response, including A3 viral restriction, is more primed or active in these cells.…”

Section: A3 Expression and Stimulationmentioning

confidence: 99%

“…This may be because epithelia are a front-line barrier to viruses, and hence the innate immune response, including A3 viral restriction, is more primed or active in these cells. A3B is highly expressed in tumor types with enrichment of A3 mutation signatures [37,38], and its expression correlates with prevalence of A3 signatures in breast and ovarian cancers [22,35]. Much attention therefore, has focused on A3B as an agent for genomic mutations.…”

Section: A3 Expression and Stimulationmentioning

confidence: 99%

“…Among breast cancers, the HER2-amplified subset displays the greatest enrichment for A3 signature mutations [38] and also displays elevated markers of genomic instability, harboring twice the number of CNVs seen in other breast tumors [57,58].…”

Section: Availability Of Ssdna Substratementioning

confidence: 99%

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APOBEC3 genes: retroviral restriction factors to cancer drivers

Henderson

Fenton

2015

Trends in Molecular Medicine

106

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Abstract:The APOBEC3 cytosine deaminases play key roles in innate immunity through their ability to mutagenize viral DNA and restrict viral replication. Now recent advances in cancer genomics together with biochemical characterization of the APOBEC3 enzymes have implicated at least two family members in somatic mutagenesis during tumor development. Here we review the evidence linking these enzymes to carcinogenesis and highlight key questions, including the potential mechanisms that misdirect APOBEC3 activity to the host genome, the links to viral infection, and the association between a common APOBEC3 polymorphism and cancer risk. Powered by Editorial Manager® and ProduXion Manager® from Aries Systems CorporationHenderson and Fenton: highlights AbstractThe APOBEC3 cytosine deaminases play key roles in innate immunity through their

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Section: A3 Expression and Stimulationmentioning

confidence: 80%

Section: Apobecs As Mutators Of Genomic Dna: the Cancer Connectionmentioning

confidence: 86%

Section: A3 Expression and Stimulationmentioning

confidence: 99%

Section: A3 Expression and Stimulationmentioning

confidence: 99%

Section: Availability Of Ssdna Substratementioning

confidence: 99%

See 3 more Smart Citations

APOBEC3 genes: retroviral restriction factors to cancer drivers

Henderson

Fenton

2015

Trends in Molecular Medicine

106

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The Molecular Landscape of Recurrent and Metastatic Head and Neck Cancers

et al. 2017

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IMPORTANCE Recurrent and/or metastatic head and neck cancer is usually incurable. Implementation of precision oncology for these patients has been limited by incomplete understanding of the molecular alterations underlying advanced disease. At the same time, the molecular profiles of many rare head and neck cancer types are unknown. These significant gaps in knowledge need to be addressed to rationally devise new therapies. OBJECTIVE To illuminate the distinct biology of recurrent and metastatic head and neck cancers and review implementation of precision oncology for patients with advanced disease. DESIGN, SETTING, AND PARTICIPANTS After exclusions, 151 patients with advanced, treatment-resistant head and neck tumors, including squamous cell carcinoma (HNSCC), adenoid cystic carcinoma (ACC), and other salivary and cutaneous cancers, whose tumors were sequenced between January 2014 and July 2015 at Memorial Sloan Kettering were recruited. Next-generation sequencing of tumors as part of clinical care included high-depth (median 600×) exonic coverage of 410 cancer genes and whole-genome copy number analysis. INTERVENTIONS Next-generation sequencing of tumors and matched normal DNA. MAIN OUTCOMES AND MEASURES Feasibility, the frequency of actionable molecular alterations, the effect on decision making, and identification of alterations associated with recurrent and metastatic disease. RESULTS Overall, 151 patients (95 men and 56 women; mean [range] age, 61.8 [17-100] years) were included in the study. Next-generation sequencing ultimately guided therapy in 21 of 151 patients (14%) (13 of 53 [25%] of patients with HNSCC) by refining diagnoses and matching patients to specific therapies, in some cases with dramatic responses on basket studies. Molecular alterations were potentially actionable in 28 of 135 patients (21%). The genetic profiles of recurrent and metastatic tumors were often distinct from primary tumors. Compared to primary human papillomavirus (HPV)-positive tumors, many recurrent and metastatic HPV-positive tumors exhibited a molecular profile more similar to HPV-negative tumors, including enriched frequencies of TP53 mutation (3 of 20 tumors [15%]), whole genome duplication (5 of 20 tumors [25%]), and 3p deletion (11 of 20 tumors [55%]). There were high rates of TERT promoter mutation in recurrent and metastatic HPV-negative HNSCC (13 of 30 tumors [43%]), cutaneous SCC (11 of 21 tumors [52%]), basal cell carcinoma (3 of 4 tumors [75%]), and ACC (5 of 36 tumors [14%]). Activating NOTCH1 mutations were enriched in metastatic ACCs (8 of 36 tumors [22%]). CONCLUSIONS AND RELEVANCE These findings reveal the molecular landscape of advanced disease and rare cancer subtypes, both predominant challenges in head and neck oncology. To understand the repertoire of targetable alterations in advanced cancers, it is necessary to sequence recurrent and metastatic tumors. These data are important first steps toward implementation of precision head and neck oncology.

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Comparison of Prevalence and Types of Mutations in Lung Cancers Among Black and White Populations

et al. 2017

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IMPORTANCE Lung cancer is the leading cause of cancer death in the United States in all ethnic and racial groups. The overall death rate from lung cancer is higher in black patients than in white patients. OBJECTIVE To compare the prevalence and types of somatic alterations between lung cancers from black patients and white patients. Differences in mutational frequencies could illuminate differences in prognosis and lead to the reduction of outcome disparities by more precisely targeting patients’ treatment. DESIGN, SETTING, AND PARTICIPANTS Tumor specimens were collected from Baptist Cancer Center (Memphis, Tennessee) over the course of 9 years (January 2004-December 2012). Genomic analysis by massively parallel sequencing of 504 cancer genes was performed at Dana-Farber Cancer Institute (Boston, Massachusetts). Overall, 509 lung cancer tumors specimens (319 adenocarcinomas; 142 squamous cell carcinomas) were profiled from 245 black patients and 264 white patients. MAIN OUTCOMES AND MEASURES The frequencies of genomic alterations were compared between tumors from black and white populations. RESULTS Overall, 509 lung cancers were collected and analyzed (273 women [129 black patients; 144 white patients] and 236 men [116 black patients; 120 white patients]). Using 313 adenocarcinomas and 138 squamous cell carcinomas with genetically supported ancestry, overall mutational frequencies and copy number changes were not significantly different between black and white populations in either tumor type after correcting for multiple hypothesis testing. Furthermore, specific activating alterations in members of the receptor tyrosine kinase/Ras/Raf pathway including EGFR and KRAS were not significantly different between populations in lung adenocarcinoma. CONCLUSIONS AND RELEVANCE These results demonstrate that lung cancers from black patients are similar to cancers from white patients with respect to clinically actionable genomic alterations and suggest that clinical trials of targeted therapies could significantly benefit patients in both groups.

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An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers

Cited by 1,075 publications

References 49 publications

APOBEC3 genes: retroviral restriction factors to cancer drivers

APOBEC3 genes: retroviral restriction factors to cancer drivers

The Molecular Landscape of Recurrent and Metastatic Head and Neck Cancers

Comparison of Prevalence and Types of Mutations in Lung Cancers Among Black and White Populations

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