Molecular biology of anal squamous cell carcinoma: implications for future research and clinical intervention

Bernardi, M.-P.; Ngan, Samuel Y; Michael, Michael; Lynch, A. C.; Heriot, Alexander G.; Ramsay, Robert G.; Phillips, Wayne A.

doi:10.1016/s1470-2045(15)00292-2

Cited by 64 publications

(44 citation statements)

References 97 publications

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“…As VDR ablation sensitizes skin to chemically induced squamous cell carcinoma these data suggest that lack of VDR specifically in the transitional epithelia/epidermis of the anus causes susceptibility to chemical carcinogen induced tumorigenesis [35] (Supplementary Figure S5). The anal cancers had increased expression and nuclear localization of activated β-catenin and cyclin D1 consistent with the earlier observation that targeted expression of active β-catenin in the skin of Vdr −/− mice induces basal cell carcinoma [36] (Figure 3G). As there are few examples of anal cancer animal models our approach may find utility in preclinical studies of squamous cell carcinoma of the anus [36].…”

Section: Resultssupporting

confidence: 90%

“…The anal cancers had increased expression and nuclear localization of activated β-catenin and cyclin D1 consistent with the earlier observation that targeted expression of active β-catenin in the skin of Vdr −/− mice induces basal cell carcinoma [36] (Figure 3G). As there are few examples of anal cancer animal models our approach may find utility in preclinical studies of squamous cell carcinoma of the anus [36]. …”

Section: Resultssupporting

confidence: 90%

“…Our data indicate that altered activity of the vitamin D/VDR pathway associated with polymorphisms in genes that regulate vitamin D transport and/or metabolism may contribute to the occurrence of the extra-colonic manifestations in FAP patients. In addition, regulation of the vitamin D/VDR axis in the context of other co-factors such as mutation or viral infection may also be important in the etiology of anal cancer, a rapidly growing public health problem with no viable preclinical models [36]. …”

Section: Discussionmentioning

confidence: 99%

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A role for the vitamin D pathway in non-intestinal lesions in genetic and carcinogen models of colorectal cancer and in familial adenomatous polyposis

et al. 2016

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Vitamin D is implicated in the etiology of cancers of the gastrointestinal tract, usually characterized by alteration in the APC/β-catenin/TCF tumor suppressor pathway. The vitamin D receptor (VDR) is also implicated in cardiovascular and skin diseases as well as in immunity. Activated VDR can indirectly alter β-catenin nuclear localization and directly suppress β-catenin/TCF mediated transcriptional activity. We treated VDR null mice with the carcinogen azoxymethane (AOM) and generated mice bearing a mutated APC (hypomorph) on a VDR null background (Apc1638N/+Vdr−/−). VDR null mice do not develop GI or extra-colonic tumors but loss of VDR decreased intestinal tumor latency and increased progression to adenocarcinoma in both models. AOM treatment of VDR null mice also caused squamous cell carcinoma of the anus. Although levels and distribution of total or activated β-catenin in the epithelial component of tumors were unaffected by loss of VDR, β-catenin dependent cyclin D1 expression was affected suggesting a direct VDR effect on β-catenin co-activator activity. Extra-colonic mucosa manifestations in Apc1638N/+Vdr−/− animals included increased nuclear β-catenin in submucosal stromal cells, spleno- and cardiomegaly and large epidermoid cysts characteristic of the FAP variant, Gardner's syndrome. Consistent with this, SNPs in the VDR, vitamin D binding protein and CYP24 as well as mutations in APC distal to codon 850 were strongly associated with Gardners syndrome in a cohort of 457 FAP patients, This work suggests that alterations in the vitamin D/VDR axis are important in Gardner's syndrome, as well as in the etiology of anal cancer.

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Section: Resultssupporting

confidence: 90%

Section: Resultssupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

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A role for the vitamin D pathway in non-intestinal lesions in genetic and carcinogen models of colorectal cancer and in familial adenomatous polyposis

et al. 2016

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“…Further supporting this hypothesis, the invasive recurrence arose in the setting of diffuse HPV-associated anal intraepithelial neoplasia (AIN) in a patient with poorly-controlled HIV, underscoring the role of HPV and host immune status in ASCC risk and pathogenesis. [26]…”

Section: Resultsmentioning

confidence: 99%

Genomic Evolution after Chemoradiotherapy in Anal Squamous Cell Carcinoma

Mouw

Cleary

Reardon

et al. 2017

Clinical Cancer Research

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Purpose Squamous cell carcinoma of the anal canal (ASCC) accounts for 2-4% of gastrointestinal (GI) malignancies in the US and is increasing in incidence; however, genomic features of ASCC are incompletely characterized. Primary treatment of ASCC involves concurrent chemotherapy and radiation (CRT), but the mutational landscape of resistance to CRT is unknown. Here, we aim to compare mutational features of ASCC in the pre- and post-CRT setting. Experimental Design We perform whole exome sequencing of primary (n=31) and recurrent (n=30) ASCCs and correlate findings with clinical data. We compare genomic features of matched pre- and post-CRT tumors to identify genomic features of CRT response. Finally, we investigate the mutational underpinnings of an extraordinary ASCC response to immunotherapy. Results We find that both primary and recurrent ASCC tumors harbor mutations in genes such as PIK3CA and FBXW7 that are also mutated in other HPV-associated cancers. Overall mutational burden was not significantly different in pre- versus post-CRT tumors, and several examples of shared clonal driver mutations were identified. In two cases, clonally related pre- and post-CRT tumors harbored distinct oncogenic driver mutations in the same cancer gene (KRAS or FBXW7). A patient with recurrent disease achieved an exceptional response to anti-Programmed Death (PD-1) therapy, and genomic dissection revealed high mutational burden and predicted neoantigen load. Conclusion We perform comprehensive mutational analysis of ASCC and characterize mutational features associated with CRT. Although many primary and recurrent tumors share driver events, we identify several unique examples of clonal evolution in response to treatment.

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“…Anal squamous cell carcinoma (ASCC) represents about 2% of all gastrointestinal malignancies, strongly associated with Human Papilloma Virus ‐ mostly HPV16 ‐, but with an increasing incidence and no effective therapies for advanced disease . In contrast with other squamous cell carcinomas and HPV‐related cancers, for which several large‐scale studies have defined the genetic and epigenetic processes involved in oncogenesis, the molecular landscape of ASCC is still poorly characterised . Nevertheless, all of these analyses have identified PI3K/AKT/mTOR as the pathway most commonly altered in ASCC.…”

Section: Introductionmentioning

confidence: 99%

Interaction between IGF2‐PI3K axis and cancer‐associated‐fibroblasts promotes anal squamous carcinogenesis

Cacheux

Lièvre

Richon

et al. 2019

Intl Journal of Cancer

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Anal squamous cell carcinoma (ASCC) is a rare tumour, but its incidence is increasing. Standard chemoradiotherapy fails to cure 20% of patients and no targeted therapy is currently approved for recurrent ASCC. The PI3K/Akt/mTOR pathway is frequently altered in this poorly characterised carcinoma. IGF2 was identified here as a key factor in ASCC oncogenesis, as IGF2 was shown to play a crucial role in the PI3K pathway with frequent (~60%) and mutually exclusive genomic alterations in IGF2, IGF1R, PTEN and PIK3CA genes. We also demonstrated that IGF2 expression is mainly due to cancer‐associated fibroblasts and that IGF2 secreted by cancer‐associated fibroblasts from ASCC samples promotes proliferation of a human ASCC cell line via IGF2 paracrine signalling. Altogether, these results highlight the key role of the IGF2/PI3K axis, and the major role of cancer‐associated fibroblasts in tumour growth via IGF2 secretion, suggesting a major role of IGF2/IGF1R inhibitors in ASCC therapies.

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Molecular biology of anal squamous cell carcinoma: implications for future research and clinical intervention

Cited by 64 publications

References 97 publications

A role for the vitamin D pathway in non-intestinal lesions in genetic and carcinogen models of colorectal cancer and in familial adenomatous polyposis

A role for the vitamin D pathway in non-intestinal lesions in genetic and carcinogen models of colorectal cancer and in familial adenomatous polyposis

Genomic Evolution after Chemoradiotherapy in Anal Squamous Cell Carcinoma

Interaction between IGF2‐PI3K axis and cancer‐associated‐fibroblasts promotes anal squamous carcinogenesis

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