Skin Tumors Induced by Sorafenib; Paradoxic RAS–RAF Pathway Activation and Oncogenic Mutations of HRAS, TP53, and TGFBR1

Conclusion:

Sorafenib induces keratinocyte proliferation in vivo and a time- and dose-dependent activation of the MAP kinase pathway in vitro. It is associated with a spectrum of lesions ranging from benign follicular cystic lesions to KA-like SCC. Additional and potentially preexisting somatic genetic events, like UV-induced mutations, might influence the evolution of benign lesions to more proliferative and malignant tumors.

press release: UCSF-led team decodes evolution of skin and ovarian cancer cells (squamous cell/serous cell)

"They worked with a type of skin cancer known as cutaneous squamous cell carcinoma, which has among the highest numbers of mutations of any cancer, and also with a common type  (blogger's note: assumption - serous cell type) of ovarian cancer."


"Using the new technique, the researchers were able to identify not just the mutations that differentiate two types of human cancer from normal cells, but the actual order in which some of the most key mutations occurred."
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Temporal Dissection of Tumorigenesis in Primary Cancers

The article, "Temporal Dissection of Tumorigenesis in Primary cancers" is authored by Steffen Durinck, Christine Ho, Nicholas J. Wang, Wilson Liao, Lakshmi R. Jakkula, Eric A. Collisson, Jennifer Pons, Sai-Wing Chan, Ernest T. Lam, Catherine Chu, Kyunghee Park, Sung-woo Hong, Joe S. Hur, Nam Huh, Isaac M. Neuhaus, Siegrid S. Yu, Roy C. Grekin, Theodora M. Mauro, James E. Cleaver, Pui-Yan Kwok, Philip E. LeBoit, Gad Getz, Kristian Cibulskis, Jon C. Aster, Haiyan Huang, Elizabeth Purdom, Jian Li, Lars Bolund, Sarah T. Arron, Joe W. Gray, Paul T. Spellman, and Raymond J. Cho.
It appears in the July 2011 issue of the journal Cancer Discovery. See: http://dx.doi.org/10.1158/2159-8290.CD-11-0028

"Ovarian cancers generally show more complex karyotypic abnormalities than do cSCCs (13)." 

"We sought to validate our observations in an additional
cancer type. Recently, full genomic sequence and copy number
changes were determined for 10 ovarian serous adenocarcinomas
by The Cancer Genome Atlas Project. Ovarian
cancers generally show more complex karyotypic abnormalities
than do cSCCs (13). In the 3 samples with a clear, informative
CN-LOH event at 17p, we again found solid evidence
for complete loss of TP53 as the earliest event (Fig. 1D). These
initial events in ovarian tumorigenesis could not have been
determined through sequencing of precursor lesions and invasive cancers (1, 14), as the asymptomatic nature of early
disease precludes tissue collection." 

Long-Term Doxorubicin Linked to Secondary Oral Cancers

".......Four patients who received long-term PLD for advanced-stage ovarian cancer developed malignant and/or premalignant lesions of the tongue and/or oral cavity. Dr. Cannon points out that there were only about 16 patients who received PLD for an extended period of time, "so 4 out of 16 patients is quite high."
All 4 of the patients had received maintenance therapy with PLD for at least 3 years. Of this group, 3 women were subsequently diagnosed with squamous cell carcinoma (SCC) of the tongue and/or oral cavity, and 1 patient was diagnosed with sublingual mucosa high-grade dysplasia. All 3 cases of SCCs were negative for human papillomavirus.

Of note, said Dr. Cannon, was a patient who presented with 3 separate lesions of SCC of the oral cavity.

"I don't think this is a coincidence, that 4 of 16 patients receiving this treatment developed oral cancers," he said. "If this treatment for ovarian cancer becomes more popular, then this is something that should become known. Early dental screening would need to be initiated, and the treatment may need to be stopped after a certain time period."

It is relatively uncommon for ovarian cancer patients to receive PLD for this length of time.......cont'd

also: see chart