MODERN PATHOLOGY _MYOD1_ MUTATIONS IN RHABDOMYOSARCOMA Among the long-recognized embryonal, alveolar, and pleomorphic subtypes, spindle-cell and sclerosing rhabdomyosarcoma are now

recognized as specific clinical and molecular subtypes. Rekhi and colleagues demonstrated in a series of 21 sclerosing (_n_ = 9) and spindle-cell (_n_ = 12) rhabdomyosarcomas that a

characteristic _MYOD1_ L122R mutation is common: 78% in sclerosing and 25% in spindle-cell. These mutations were not seen in the embryonal (_n_ = 10) and alveolar (_n_ = 17) subtypes tested

or in the single tested pleomorphic rhabdomyosarcoma. The _MYOD1_ mutations correlated with more intense MyoD1 expression by immunohistochemistry. Moreover, _MYOD1_ L122R mutations in the

genetic alterations in prostate cancer. Lahdensuo _et al_ used ERG and PTEN immunohistochemistry as surrogates for these events to investigate two large cohorts of patients with prostate

cancer (_N_ = 815) for which Gleason score, stage, and other prognostic variables currently provide suboptimal predictive power. The authors found that PTEN loss was associated with poor

outcomes and more secondary treatment, particularly in ERG-negative cases. In addition, the absence of both PTEN and ERG stratified Gleason 7 patients into two distinct prognostic groups by

outcome and secondary treatments. Patients in whom androgen receptor (AR) showed high immunoreactivity with combined PTEN and ERG absence fared even more poorly. These results suggest that

the addition of PTEN and ERG immunohistochemistry to standard AR expression studies can provide significant discriminatory power beyond that of traditional grading, staging, and other

prognostic variables. LABORATORY INVESTIGATION EATING WORMS TO AMELIORATE FIBROSIS Some of us may have sung from time to time as kids, “Nobody likes me, everybody hates me, I guess I'll

go eat worms.” This might not a bad idea if you have pulmonary fibrosis, according to recent work by Yang _et al._ Earthworm extract (from the genus _Lumbricus_) has been reported to be

protective against inflammation, oxidation, and apoptosis. The best characterized active ingredient is lumbokinase, which has fibrinolytic activity. Using a mouse model of occupational

pulmonary fibrosis caused by silica inhalation, the authors demonstrated reduced lung inflammation and fibrosis. In silica-treated cell lines, earthworm extract inhibited oxidative stress,

the mitochondrial apoptotic pathway, and epithelial–mesenchymal transition. Mechanistically, they determined that activation of nuclear factor erythroid 2–related factor 2 (Nrf2), a

transcription factor that can induce antioxidant pathways, mediates these effects, at least in part. They did not report on the taste quality of earthworm extract in humans. PKC IN THE

PATHOGENESIS OF BULLOUS PEMPHIGOID Bullous pemphigoid is a chronic inflammatory subepidermal blistering disorder. Immunoglobulin G (IgG) autoantibodies to an intracellular component of the

hemidesmosome, type XVII collagen, mediate the disease. When keratinocytes are exposed to IgG from bullous pemphigoid patients, they internalize collagen 17 (COL17) decorated with IgG via

macropinocytosis. This process, which depletes local stores of COL17, is part of the pathogenesis of bullous pemphigoid. Iwata _et al_ discovered that they could partially disrupt

macropinocytosis by inhibiting the small GTPase family members Rac1, Cdc42, and Rho. Internalization of COL17-IgG complexes was also associated with increased intracellular calcium levels

and rapid phosphorylation of COL17 by protein kinase C (PKC). This phosphorylation of the intracellular tail of COL17 by PKC seems to be required for COL17 internalization, as inhibiting PKC

also prevented internalization. PKC could thus play an important, previously unrecognized role in the pathogenesis of bullous pemphigoid. NATURE.COM/PATHOLOGY MICROSATELLITE INSTABILITY

ACROSS 18 TCGA CANCER TYPES Microsatellite instability (MSI) is common in colorectal and endometrial carcinomas but seen at lower levels in other tumors. Cancers with MSI often have

different clinical properties; recently, MSI colorectal carcinomas were shown to respond dramatically to immune checkpoint inhibitors in contrast to microsatellite stable colorectal tumors.

In standard DNA-based testing for MSI, a few of the many genomic microsatellites (stretches of mono- or dinucleotide repeats) that are altered in size when DNA mismatch repair proteins are

deficient. This handful of microsatellites (usually 5 to 12 sites are tested) is optimized for colorectal samples. Hause _et al_ used TCGA data from 18 cancer types (5,930 exomes). They

examined more than 200,000 microsatellites per case and demonstrated varying degrees of MSI in 14 cancer types. Pertinent for clinical molecular testing, specific microsatellites showing MSI

varied across cancer types, suggesting that colorectal consensus microsatellites may not be appropriate for all cancer types. This has important implications for oncologists screening

cancers for immunotherapy trials dependent on MSI. _Nature Medicine_, published online 3 October 2016; doi:10.1038/nm.4191 RECURRENT MUTATIONS IN IMMUNOTHERAPY RESPONSE Immune checkpoint

inhibition has transformed treatment paradigms for metastatic disease in several cancer types. Little is understood of the discrete molecular determinates of response. Mutational loads,

immune microenvironmental constituent cells, and expression of immune checkpoint proteins all appear to have some influence. As recently reported in _Nature Genetics_, Riaz _et al_ found

that somatic mutations in _SERPINB3_ and _SERPINB4_ were associated with survival following treatment with anti-CTLA4 immunotherapy in two large cohorts of melanoma patients. Mutations in

these two genes correlated somewhat with total mutational loads, although they were more discriminatory for response than mutational load. The mutations remained predictive in settings of

relatively low mutational loads. Intriguingly, serpin proteins are associated with autoimmunity. A single mutation so strongly associated with immune checkpoint response will certainly evoke

additional mechanistic characterization. _Nature Genetics_ published online 26 September 2016; doi:10.1038/ng.3677 GERMLINE INFLUENCES ON APOBEC-SIGNATURE MUTATIONS IN CANCER Several

mutational signatures have been defined in cancers, some with clear etiologies such as aging, smoking, and other environmental influences. A less-understood signature is associated with

activity of the AID/APOBEC (apolipoprotein B mRNA editing enzyme, catalytic-peptide-like) family of cytodine amidases. Some researchers suggest that this signature is related to viral

infection or tissue inflammation, although mechanistic understanding is lacking. This APOBEC signature is present in more than 20 cancer types and is particularly prevalent in cervical and

bladder cancers. Middlebrooks _et al_ explored the role of two common changes in various _APOBEC3_ region genes. Using the genotypes for 5,832 bladder cases and 10,791 controls from the

NCI-GWAS1 and 2 studies, the single-nucleotide polymorphism rs1014971 was associated with not only bladder cancer risk but also increased _APOBEC3B_ expression and APOBEC-signature

mutations. Another germline _APOBEC3_ variant was associated with breast cancer risk and APOBEC signatures. This suggests tissue specificity for the oncogenic triggers of these mutational

signatures. _Nature Genetics_ published online 19 September 2016; doi:10.1038/ng.3670 RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Inside the USCAP

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