Exome Sequencing Identifies Recurrent Somatic Mutations in EIF1AX and SF3B1 in Uveal Melanoma with Disomy 3

Martin M, Maßhöfer L, Temming P, Rahmann S, et al. Nature Genetics. Jun 23 2013.

“Exome sequencing, identified recurrent somatic mutations in EIF1AX and SF3B1, specifically occurring in uveal melanomas with disomy 3, which rarely metastasize. Targeted resequencing showed that 24 of 31 tumors with disomy 3 (77%) had mutations in either EIF1AX (15; 48%) or SF3B1 (9; 29%). Mutations were infrequent (2/35; 5.7%) in uveal melanomas with monosomy 3, which are associated with poor prognosis.”

SF3B1 Mutations are Associated with Alternative Splicing in Uveal Melanoma

Furney SJ, Pedersen M, Gentien D, Dumont AG, et al. Cancer Discovery. Jul 16, 2013.

“Uveal melanoma, the most common eye malignancy causes severe visual morbidity and is fatal in about 50% of patients. Primary uveal melanoma can be cured by surgery or radiotherapy, but the metastatic disease is treatment refractory. To understand comprehensively uveal melanoma genetics, we performed SNP arrays and whole genome sequencing on 12 primary uveal melanomas. We observed only ~2000 predicted somatic single nucleotide variants per tumor and low levels of aneuploidy. We did not observe an ultraviolet radiation DNA-damage signature, but identified SF3B1 mutations in three samples and a further 15 mutations in an extension cohort of 105 samples. SF3B1 mutations were associated with good prognosis and were rarely coincident with BAP1 mutations. SF3B1 encodes a component of the spliceosome and RNA sequencing revealed that SF3B1 mutations were associated with differential alternative splicing of protein coding genes including ABCC5 and UQCC, and of the long non-coding RNA (lncRNA) CRNDE.”

Ipilimumab Could Treat Small Melanomas in the Brain

MedPage Today | Mar 30, 2012

A study in The Lancet shows that the drug ipilimumab could treat melanomas that have spread to the brain, particularly in people who do yet not have neurological symptoms. Of 51 such patients treated with ipilimumab, 12 had tumors in the brain that shrank or did not get worse and 14 had tumors outside the brain that shrank or did not get worse. Ipilimumab (Yervoy) is an immune system booster that the FDA has approved for treating advanced melanomas.

Primary source: http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2812%2970090-6/abstract

Drug Targets Two Common Melanoma Mutations

MedPage Today | Jun 8, 2012

An experimental drug could help control some melanomas that have BRAF or NRAS mutations, according to a report at an American Society of Clinical Oncology meeting. Tumors shrank or did not get worse in 8 out of 35 patients with the most common BRAF mutation (V600E), and in 6 out of 28 patients with NRAS mutations. This is the first targeted treatment for melanomas that have NRAS mutations. BRAF and NRAS mutations can activate a protein called MEK that is involved in cell division. The experimental drug, which is called MEK162, is a MEK inhibitor. The side effects of MEK162, which included diarrhea, rashes and swelling, were manageable.

Dabrafenib May Shrink Melanomas in the Brain

MedPage Today | May 18, 2012

An early stage clinical trial suggests that dabrafenib, a BRAF inhibitor, could treat melanomas that have spread to the brain. The study, reported in The Lancet, included 10 people with brain metastases of melanomas that had BRAF mutations. Tumors shrank in 9 patients and were not evident in 4 patients. This is a surprise because the drug had not been expected to cross the blood-brain barrier effectively. Indeed, melanoma patients with brain metastases have been routinely excluded from previous trials of vemurafenib (Zelboraf) and other BRAF inhibitors.

Primary source: http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2812%2970269-3/abstract

Trametinib Outperforms Chemotherapy for Melanomas with BRAF Mutations

MedPage Today | Jun 4, 2012

A New England Journal of Medicine study reports a promising new approach to treating melanomas with BRAF mutations, which often respond to BRAF inhibitors for just a short time. Melanoma patients treated with trametinib were stable (ie, did not get worse) for three times longer than those treated with dacarbazine, a conventional chemotherapy drug (4.8 vs. 1.5 months, respectively). Trametinib inhibits MEK, a protein that is activated by BRAF and is involved in cell division. The drug’s most common side effects were rash, diarrhea, and swelling in the legs, which could be controlled by periodically adjusting the dose.

Primary source: http://www.nejm.org/doi/full/10.1056/NEJMoa1203421

New Melanoma Mutation Frequent Enough for Routine Screening

Cancer Discovery | Jul 13, 2012

Researchers identified a new mutation (BRAF L597) in a melanoma patient and then tested for it in 49 other melanomas that had no known cancer-linked mutations, which account for about half of all melanomas. They found that BRAF L597 occurred in 4% of the other melanomas tested. The study, which appeared in Cancer Discovery, also showed that tumors with this mutation respond to a MEK inhibitor called TAK-733. The existence of a targeted treatment, coupled with the new mutation’s relatively high incidence, lead the researchers to suggest routinely screening melanomas for BRAF L597.

UK Health Institute Approves Vemurafenib and Ipilimumab for Melanomas

The Independent | Nov 2, 2012

The National Institute for Health and Clinical Excellence (NICE) recommends giving people in England and Wales access to vemurafenib and ipilimumab via the National Health Service (NHS). The FDA has already approved these drugs for treating metastatic melanoma in the U.S. Initially, the cost of these treatments was a stumbling block in the UK and the watchdog institute’s recommendation comes with the caveat that manufacturers must provide a discount to the NHS.

Vemurafenib Extends Life up to 3 Years in Melanoma Trial

Drugs.com | Nov 9, 2012

An ongoing clinical trial found that 26% of melanoma patients treated with vemurafenib (Zelboraf®) were alive at 3 years—far longer than the average survival time of 9 months with conventional chemotherapy. Vemurafenib is a BRAF inhibitor and this trial includes 32 people with the most common BRAF mutation (V600E). In addition, five people survived at 3 years and 4 months; three of them had no evidence of disease.