まずゲノム屋としてはとても興味を引かれるのがNature Geneticsの二つの論文である。
Nature Genetics 44, 642–650 (2012)
Received 12 September 2011
Accepted 09 April 2012
Published online 06 May 2012
Detectable clonal mosaicism from birth to old age and its relationship to cancer
Department of Biostatistics, University of Washington, Seattle, Washington, USA.
We detected clonal mosaicism for large chromosomal anomalies (duplications, deletions and uniparental disomy) using SNP microarray data from over 50,000 subjects recruited for genome-wide association studies. This detection method requires a relatively high frequency of cells with the same abnormal karyotype (>5–10%; presumably of clonal origin) in the presence of normal cells. The frequency of detectable clonal mosaicism in peripheral blood is low (<0.5%) from birth until 50 years of age, after which it rapidly rises to 2–3% in the elderly. Many of the mosaic anomalies are characteristic of those found in hematological cancers and identify common deleted regions with genes previously associated with these cancers. Although only 3% of subjects with detectable clonal mosaicism had any record of hematological cancer before DNA sampling, those without a previous diagnosis have an estimated tenfold higher risk of a subsequent hematological cancer (95% confidence interval = 6–18).Nature Genetics 44, 642–650 (2012)
Received 29 September 2011
Accepted 09 April 2012
Published online 06 May 2012
Detectable clonal mosaicism and its relationship to aging and cancer
Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), Rockville, Maryland, USA.
In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10−8). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10−11). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.☆☆☆☆☆☆☆☆☆☆☆☆☆☆☆☆☆☆☆☆
次はBRAF基盤の分子標的治療の最新情報：大腸癌を初めとする消化器癌への展開を期待するがゆえに注目しているのだが・・・
NEJM, June 4, 2012
Improved Survival with MEK Inhibition in BRAF-Mutated Melanoma
Background
Activating mutations in serine–threonine protein kinase B-RAF (BRAF) are found in 50% of patients with advanced melanoma. Selective BRAF-inhibitor therapy improves survival, as compared with chemotherapy, but responses are often short-lived. In previous trials, MEK inhibition appeared to be promising in this population.
Methods
In this phase 3 open-label trial, we randomly assigned 322 patients who had metastatic melanoma with a V600E or V600K BRAF mutation to receive either trametinib, an oral selective MEK inhibitor, or chemotherapy in a 2:1 ratio. Patients received trametinib (2 mg orally) once daily or intravenous dacarbazine (1000 mg per square meter of body-surface area) or paclitaxel (175 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to receive trametinib. Progression-free survival was the primary end point, and overall survival was a secondary end point.
Results
Median progression-free survival was 4.8 months in the trametinib group and 1.5 months in the chemotherapy group (hazard ratio for disease progression or death in the trametinib group, 0.45; 95% confidence interval [CI], 0.33 to 0.63; P<0.001). At 6 months, the rate of overall survival was 81% in the trametinib group and 67% in the chemotherapy group despite crossover (hazard ratio for death, 0.54; 95% CI, 0.32 to 0.92; P=0.01). Rash, diarrhea, and peripheral edema were the most common toxic effects in the trametinib group and were managed with dose interruption and dose reduction; asymptomatic and reversible reduction in the cardiac ejection fraction and ocular toxic effects occurred infrequently. Secondary skin neoplasms were not observed.
Conclusions
Trametinib, as compared with chemotherapy, improved rates of progression-free and overall survival among patients who had metastatic melanoma with a BRAF V600E or V600K mutation.以上の論文に関連してRAF活性型腫瘍へのTrametinibという分子標的薬剤の総説である
Editorial
Promises from Trametinib in RAF Active Tumors
☆☆☆☆☆☆☆☆☆☆☆☆☆☆☆☆☆☆
Wnt発見から30年を記念して「Wntと疾患」を巡ってのCell誌の総説である。Hans Cleversが書いた論考。この総説の最後に10個のテーマが述べられている。このテーマを眺めることがWntの現状把握には手っ取り早いと思えるのだ。小生がWntに興味があったわけではない。ただ、幹細胞特に癌幹細胞の基盤分子であるLgr4,5,6を追いかけていると、Wnt系にだんだん絡めとられていくのだ。この総説でもLgrは大きなサブテーマだ。
Cell, Volume 149, Issue 6, 1192-1205, 8 June 2012
Wnt/β-Catenin Signaling and Disease
Hans Clevers, Roel NusseBy reviewing the current status of Wnt signaling, we realized how many questions in this field remain unanswered. We highlight ten of those questions, hoping to inspire future research.
(1) What is the evolutionary origin of Wnt signals? Wnt genes and signaling components are found in all metazoan animals, including sponges. Given that Wnts are intercellular signals, it is not surprising that they are not present in unicellular organisms. Although the recently established Wnt-Fz structure has not yet pointed to a particular evolutionary origin, one can speculate that Wnts have a more ancient origin, possibly derived from enzymes secreted by prokaryotes.
(2) What is the nature of Wnt as a signal? Is the protein active by itself, or is it packaged in membranes, together with possible cofactors? The importance of “Wnt delivery” needs to be understood.
(3) Where does Wnt signaling take place in cells? Whereas Hedgehog signaling is located at the primary cilium, the subcellular location of Wnt signaling events remains unknown, though the endosomal compartment has been implicated as a signaling center.
(4) Besides the well-studied Frizzled and LRP receptors, there are other mechanisms for Wnt reception that involve the tyrosine kinases ROR and RYK. There is very little insight into the mechanisms of action of these receptors, and they deserve more intense study.
(5) How is the stabilized form of β-catenin ferried into the nucleus? Is there a role for active microtubule-based transport?
(6) How does Wnt signaling coordinate cell fate changes with changes in cell shape and polarity? This is a key question in many developmental contexts of Wnt signaling, including stem cells.
(7) Many different kinds of stem cells are controlled by Wnts, in such a way that self-renewal and the developmental potential of the cells are preserved by the Wnt signal. Is there a universal “stemness” property conferred to cells by Wnts?
(8) How much of the genome is Wnt controlled across various cell types? Given the broad effects of Wnt signaling and many Wnt target cells, the total number of Wnt-controlled genes could be significant.
(9) Are cancer stem cell behaviors controlled by Wnt signaling? The definition of cancer stem cells as being able to self-renew the tumorigenic state but also able to differentiate suggests that their behavior is dependent on external signals, such as Wnts.
(10) Can we identify bona fide and effective Wnt inhibitors? Though several molecules have been described to inhibit Wnt signaling in cells, there is a great need for additional reagents interfering with the Wnt pathway.
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