Merkel Cell Carcinoma In Situ Arising in Association With an Infundibular Cyst With Unusual Reticulated Infundibulocystic Proliferation.

ABSTRACT: Merkel cell carcinoma (MCC) is an uncommon aggressive primary cutaneous neuroendocrine tumor usually arising on sun exposed skin of older patients. Most Merkel cell carcinomas are diagnosed as invasive tumors with only rare cases of MCC in situ (MCCIS) reported. MCCs are often associated with other cutaneous neoplasms and more recently have been described in association with cystic lesions, albeit rarely. We present a unique case of an 80-year-old male with a slow growing nodular lesion on the right buttock that on excision demonstrated MCCIS arising within an infundibular cyst with unusual reticulated infundibulocystic proliferation. The MCCIS was intimately associated with the infundibulocystic proliferation and demonstrated immunopositivity for CK20, CD56, AE1/AE3, synaptophysin, and Merkel cell polyoma virus. The confinement of the MCC to the epithelium together with the Merkel cell polyoma virus positivity further supports the assumption that viral positive MCC may derive from epithelial linage.

The Genomic Impact of European Colonization of the Americas.

The human genetic diversity of the Americas has been affected by several events of gene flow that have continued since the colonial era and the Atlantic slave trade. Moreover, multiple waves of migration followed by local admixture occurred in the last two centuries, the impact of which has been largely unexplored. Here, we compiled a genome-wide dataset of ∼12,000 individuals from twelve American countries and ∼6,000 individuals from worldwide populations and applied haplotype-based methods to investigate how historical movements from outside the New World affected (1) the genetic structure, (2) the admixture profile, (3) the demographic history, and (4) sex-biased gene-flow dynamics of the Americas. We revealed a high degree of complexity underlying the genetic contribution of European and African populations in North and South America, from both geographic and temporal perspectives, identifying previously unreported sources related to Italy, the Middle East, and to specific regions of Africa.

Prehistoric migrations through the Mediterranean basin shaped Corsican Y-chromosome diversity.

The rarity of human remains makes it difficult to apprehend the first settlements in Corsica. It is admitted that initial colonization could have occurred during the Mesolithic period when glaciations would have shortened the open water travel distance from the continent. Mesolithic sites in Corsica show relatively short and irregular occupation, and suggest discontinuous settling of very mobile groups probably traveling by boat. Previous genetic studies on Corsican populations showed internal differentiation and a relatively poor genetic relationship with continental populations, despite intense historical contacts, however local Mesolithic-based genetic inheritance has never been properly estimated. The aim of this study was to explore the Corsican genetic profile of Y-chromosomes in order to trace the genetic signatures back to the first migrations to Corsica. This study included 321 samples from men throughout Corsica; samples from Provence and Tuscany were added to the cohort. All samples were typed for 92 Y-SNPs, and Y-STRs were also analyzed. Results revealed highly differentiated haplogroup patterns among Corsican populations. Haplogroup G had the highest frequency in Corsica, mostly displaying a unique Y-STR profile. When compared with Provence and Tuscany, Corsican populations displayed limited genetic proximity. Corsican populations present a remarkable Y-chromosome genetic mixture. Although the Corsican Y-chromosome profile shows similarities with both Provence and to a lesser extent Tuscany, it mainly displays its own specificity. This study confirms the high level of genetic diversity in Corsican populations and backs genetic contributions from prehistoric migrations associated with the Mesolithic, Neolithic and Metal Age eras, rather than from historical movements to Corsica, respectively attested by frequencies and TMRCA of haplogroups G2a-L91 and G2a-P15, J2a-M241 and J2-DYS445 = 6, R1b-U152 and R1b-U106. These results suggest that marine routes to reach the Corsican coast in many different points may have led to such a genetic heterogeneity.

Y-chromosome phylogeographic analysis of the Greek-Cypriot population reveals elements consistent with Neolithic and Bronze Age settlements.

BACKGROUND: The archeological record indicates that the permanent settlement of Cyprus began with pioneering agriculturalists circa 11,000 years before present, (ca. 11,000 y BP). Subsequent colonization events followed, some recognized regionally. Here, we assess the Y-chromosome structure of Cyprus in context to regional populations and correlate it to phases of prehistoric colonization. RESULTS: Analysis of haplotypes from 574 samples showed that island-wide substructure was barely significant in a spatial analysis of molecular variance (SAMOVA). However, analyses of molecular variance (AMOVA) of haplogroups using 92 binary markers genotyped in 629 Cypriots revealed that the proportion of variance among the districts was irregularly distributed. Principal component analysis (PCA) revealed potential genetic associations of Greek-Cypriots with neighbor populations. Contrasting haplogroups in the PCA were used as surrogates of parental populations. Admixture analyses suggested that the majority of G2a-P15 and R1b-M269 components were contributed by Anatolia and Levant sources, respectively, while Greece Balkans supplied the majority of E-V13 and J2a-M67. Haplotype-based expansion times were at historical levels suggestive of recent demography. CONCLUSIONS: Analyses of Cypriot haplogroup data are consistent with two stages of prehistoric settlement. E-V13 and E-M34 are widespread, and PCA suggests sourcing them to the Balkans and Levant/Anatolia, respectively. The persistent pre-Greek component is represented by elements of G2-U5(xL30) haplogroups: U5*, PF3147, and L293. J2b-M205 may contribute also to the pre-Greek strata. The majority of R1b-Z2105 lineages occur in both the westernmost and easternmost districts. Distinctively, sub-haplogroup R1b- M589 occurs only in the east. The absence of R1b- M589 lineages in Crete and the Balkans and the presence in Asia Minor are compatible with Late Bronze Age influences from Anatolia rather than from Mycenaean Greeks.

The phylogenetic and geographic structure of Y-chromosome haplogroup R1a.

R1a-M420 is one of the most widely spread Y-chromosome haplogroups; however, its substructure within Europe and Asia has remained poorly characterized. Using a panel of 16 244 male subjects from 126 populations sampled across Eurasia, we identified 2923 R1a-M420 Y-chromosomes and analyzed them to a highly granular phylogeographic resolution. Whole Y-chromosome sequence analysis of eight R1a and five R1b individuals suggests a divergence time of ∼25,000 (95% CI: 21,300-29,000) years ago and a coalescence time within R1a-M417 of ∼5800 (95% CI: 4800-6800) years. The spatial frequency distributions of R1a sub-haplogroups conclusively indicate two major groups, one found primarily in Europe and the other confined to Central and South Asia. Beyond the major European versus Asian dichotomy, we describe several younger sub-haplogroups. Based on spatial distributions and diversity patterns within the R1a-M420 clade, particularly rare basal branches detected primarily within Iran and eastern Turkey, we conclude that the initial episodes of haplogroup R1a diversification likely occurred in the vicinity of present-day Iran.

Afghan Hindu Kush: where Eurasian sub-continent gene flows converge.

Despite being located at the crossroads of Asia, genetics of the Afghanistan populations have been largely overlooked. It is currently inhabited by five major ethnic populations: Pashtun, Tajik, Hazara, Uzbek and Turkmen. Here we present autosomal from a subset of our samples, mitochondrial and Y- chromosome data from over 500 Afghan samples among these 5 ethnic groups. This Afghan data was supplemented with the same Y-chromosome analyses of samples from Iran, Kyrgyzstan, Mongolia and updated Pakistani samples (HGDP-CEPH). The data presented here was integrated into existing knowledge of pan-Eurasian genetic diversity. The pattern of genetic variation, revealed by structure-like and Principal Component analyses and Analysis of Molecular Variance indicates that the people of Afghanistan are made up of a mosaic of components representing various geographic regions of Eurasian ancestry. The absence of a major Central Asian-specific component indicates that the Hindu Kush, like the gene pool of Central Asian populations in general, is a confluence of gene flows rather than a source of distinctly autochthonous populations that have arisen in situ: a conclusion that is reinforced by the phylogeography of both haploid loci.

No evidence from genome-wide data of a Khazar origin for the Ashkenazi Jews.

The origin and history of the Ashkenazi Jewish population have long been of great interest, and advances in high-throughput genetic analysis have recently provided a new approach for investigating these topics. We and others have argued on the basis of genome-wide data that the Ashkenazi Jewish population derives its ancestry from a combination of sources tracing to both Europe and the Middle East. It has been claimed, however, through a reanalysis of some of our data, that a large part of the ancestry of the Ashkenazi population originates with the Khazars, a Turkic-speaking group that lived to the north of the Caucasus region ~1,000 years ago. Because the Khazar population has left no obvious modern descendants that could enable a clear test for a contribution to Ashkenazi Jewish ancestry, the Khazar hypothesis has been difficult to examine using genetics. Furthermore, because only limited genetic data have been available from the Caucasus region, and because these data have been concentrated in populations that are genetically close to populations from the Middle East, the attribution of any signal of Ashkenazi-Caucasus genetic similarity to Khazar ancestry rather than shared ancestral Middle Eastern ancestry has been problematic. Here, through integration of genotypes from newly collected samples with data from several of our past studies, we have assembled the largest data set available to date for assessment of Ashkenazi Jewish genetic origins. This data set contains genome-wide single-nucleotide polymorphisms in 1,774 samples from 106 Jewish and non-Jewish populations that span the possible regions of potential Ashkenazi ancestry: Europe, the Middle East, and the region historically associated with the Khazar Khaganate. The data set includes 261 samples from 15 populations from the Caucasus region and the region directly to its north, samples that have not previously been included alongside Ashkenazi Jewish samples in genomic studies. Employing a variety of standard techniques for the analysis of population-genetic structure, we found that Ashkenazi Jews share the greatest genetic ancestry with other Jewish populations and, among non-Jewish populations, with groups from Europe and the Middle East. No particular similarity of Ashkenazi Jews to populations from the Caucasus is evident, particularly populations that most closely represent the Khazar region. Thus, analysis of Ashkenazi Jews together with a large sample from the region of the Khazar Khaganate corroborates the earlier results that Ashkenazi Jews derive their ancestry primarily from populations of the Middle East and Europe, that they possess considerable shared ancestry with other Jewish populations, and that there is no indication of a significant genetic contribution either from within or from north of the Caucasus region.

Letter to the editor: Genetics and the archaeology of ancient Israel.

This letter is a call for DNA testing on ancient skeletal materials from the southern Levant to begin a database of genetic information of the inhabitants of this crossroads region. In this region, during the Iron I period traditionally dated to circa 1200-1000 BCE, archaeologists and biblical historians view the earliest presence of a group that called itself Israel. They lived in villages in the varied hill countries of the region, contemporary with urban settlements in the coastal plains, inland valleys, and central hill country attributed to varied indigenous groups collectively called Canaanite. The remnants of Egyptian imperial presence in the region lasted until around 1150 BCE, postdating the arrival of an immigrant group from the Aegean called the Philistines circa 1175 BCE. The period that follows in the southern Levant is marked by the development of territorial states throughout the region, circa 1000-800 BCE. These patrimonial kingdoms, including the United Kingdom of Israel and the divided kingdoms of northern Israel and Judah, coalesced varied peoples under central leadership and newly founded administrative and religious bureaucracies. Ancient DNA testing will give us a further refined understanding of the individuals who peopled the region of the southern Levant throughout its varied archaeological and historic periods and provide scientific data that will support, refute, or nuance our sociohistoric reconstruction of ancient group identities. These social identities may or may not map onto genetic data, but without sampling of ancient DNA we may never know. A database of ancient DNA will also allow for comparisons with modern DNA samples collected throughout the greater region and the Mediterranean littoral, giving a more robust understanding of the long historical trajectories of regional human genetics and the genetics of varied ancestral groups of today's Jewish populations and other cultural groups in the modern Middle East and Mediterranean.

Distinguishing the co-ancestries of haplogroup G Y-chromosomes in the populations of Europe and the Caucasus.

Haplogroup G, together with J2 clades, has been associated with the spread of agriculture, especially in the European context. However, interpretations based on simple haplogroup frequency clines do not recognize underlying patterns of genetic diversification. Although progress has been recently made in resolving the haplogroup G phylogeny, a comprehensive survey of the geographic distribution patterns of the significant sub-clades of this haplogroup has not been conducted yet. Here we present the haplogroup frequency distribution and STR variation of 16 informative G sub-clades by evaluating 1472 haplogroup G chromosomes belonging to 98 populations ranging from Europe to Pakistan. Although no basal G-M201* chromosomes were detected in our data set, the homeland of this haplogroup has been estimated to be somewhere nearby eastern Anatolia, Armenia or western Iran, the only areas characterized by the co-presence of deep basal branches as well as the occurrence of high sub-haplogroup diversity. The P303 SNP defines the most frequent and widespread G sub-haplogroup. However, its sub-clades have more localized distribution with the U1-defined branch largely restricted to Near/Middle Eastern and the Caucasus, whereas L497 lineages essentially occur in Europe where they likely originated. In contrast, the only U1 representative in Europe is the G-M527 lineage whose distribution pattern is consistent with regions of Greek colonization. No clinal patterns were detected suggesting that the distributions are rather indicative of isolation by distance and demographic complexities.

Landscape influences on headwater streams on Fort Stewart, Georgia, USA.

Military landscapes represent a mixture of undisturbed natural ecosystems, developed areas, and lands that support different types and intensities of military training. Research to understand water-quality influences of military landscapes usually involves intensive sampling in a few watersheds. In this study, we developed a survey design of accessible headwater watersheds intended to improve our ability to distinguish land-water relationships in general, and training influences, in particular, on Fort Stewart, GA. We sampled and analyzed water from watershed outlets. We successfully developed correlative models for total suspended solids (TSS), total nitrogen (TN), organic carbon (OC), and organic nitrogen (ON), which dominated in this blackwater ecosystem. TSS tended to be greater in samples after rainfall and during the growing season, and models that included %Wetland suggested a "build-and-flush" relationship. We also detected a positive association between TSS and tank-training, which suggests a need to intercept sediment-laden runoff from training areas. Models for OC showed a negative association with %Grassland. TN and ON both showed negative associations with %Grassland, %Wetland, and %Forest. Unexpected positive associations were observed between OC and equipment-training activity and between ON and %Bare ground + Roads. Future studies that combine our survey-based approach with more intensive monitoring of the timing and intensity of training would be needed to better understand the mechanisms for these empirical relationships involving military training. Looking beyond local effects on Fort Stewart streams, we explore questions about how exports of OC and nitrogen from coastal military installations ultimately influence estuaries downstream.

The coming of the Greeks to Provence and Corsica: Y-chromosome models of archaic Greek colonization of the western Mediterranean.

BACKGROUND: The process of Greek colonization of the central and western Mediterranean during the Archaic and Classical Eras has been understudied from the perspective of population genetics. To investigate the Y chromosomal demography of Greek colonization in the western Mediterranean, Y-chromosome data consisting of 29 YSNPs and 37 YSTRs were compared from 51 subjects from Provence, 58 subjects from Smyrna and 31 subjects whose paternal ancestry derives from Asia Minor Phokaia, the ancestral embarkation port to the 6th century BCE Greek colonies of Massalia (Marseilles) and Alalie (Aleria, Corsica). RESULTS: 19% of the Phokaian and 12% of the Smyrnian representatives were derived for haplogroup E-V13, characteristic of the Greek and Balkan mainland, while 4% of the Provencal, 4.6% of East Corsican and 1.6% of West Corsican samples were derived for E-V13. An admixture analysis estimated that 17% of the Y-chromosomes of Provence may be attributed to Greek colonization. Using the following putative Neolithic Anatolian lineages: J2a-DYS445 = 6, G2a-M406 and J2a1b1-M92, the data predict a 0% Neolithic contribution to Provence from Anatolia. Estimates of colonial Greek vs. indigenous Celto-Ligurian demography predict a maximum of a 10% Greek contribution, suggesting a Greek male elite-dominant input into the Iron Age Provence population. CONCLUSIONS: Given the origin of viniculture in Provence is ascribed to Massalia, these results suggest that E-V13 may trace the demographic and socio-cultural impact of Greek colonization in Mediterranean Europe, a contribution that appears to be considerably larger than that of a Neolithic pioneer colonization.

Lentiginous melanoma.

CONTEXT: Atypical lentiginous melanocytic lesions, particularly in older individuals, continue to pose a diagnostic challenge. Such lesions often show features intermediate between lentiginous nevus and melanoma in situ. We have recently defined within this group of lesions a histologic pattern of lentiginous melanoma, a slowly progressing variant of melanoma typically found on the trunk and proximal extremities of middle-aged and older individuals. OBJECTIVE: To review the clinical and histologic features of lentiginous melanoma and its histologic differential diagnosis. DATA SOURCES: Review of pertinent published literature and work in our laboratory. CONCLUSIONS: Lentiginous melanoma defines a subset of slowly progressing melanoma occurring in middle-aged and older patients. It is histologically characterized by a broad atypical lentiginous growth pattern of moderately atypical melanocytes showing focal nesting and pagetoid spread without significant dermal fibroplasia or alteration of the rete ridges. Lentiginous melanoma shows significant overlap in clinical and histologic features with atypical lentiginous nevus (of the elderly). Relationship between these entities requires further investigations. Given the risk of progression to invasive melanoma, all lesions showing features of lentiginous melanoma should be treated with adequately wide excision.

The performance of MelaFind: a prospective multicenter study.

OBJECTIVE: To demonstrate the safety and effectiveness of MelaFind, a noninvasive and objective computer-vision system designed to aid in detection of early pigmented cutaneous melanoma. DESIGN: A prospective, multicenter, blinded study. The diagnostic performance of MelaFind and of study clinicians was evaluated using the histologic reference standard. Standard images and patient information for a subset of 50 randomly selected lesions (25 melanomas) were used in a reader study of 39 independent dermatologists to estimate clinicians' biopsy sensitivity to melanoma. SETTING: Three academic and 4 community practices in the United States with expertise in management of pigmented skin lesions. PATIENTS: A total of 1383 patients with 1831 lesions enrolled from January 2007 to July 2008; 1632 lesions (including 127 melanomas-45% in situ-with median Breslow thickness of invasive lesions, 0.36 mm) were eligible and evaluable for the study end points. MAIN OUTCOME MEASURES: Sensitivity of MelaFind; specificities and biopsy ratios for MelaFind and the study investigators; and biopsy sensitivities of independent dermatologists in the reader study. RESULTS: The measured sensitivity of MelaFind was 98.4% (125 of 127 melanomas) with a 95% lower confidence bound at 95.6% and a biopsy ratio of 10.8:1; the average biopsy sensitivity of dermatologists was 78% in the reader study. Including borderline lesions (high-grade dysplastic nevi, atypical melanocytic proliferations, or hyperplasias), MelaFind's sensitivity was 98.3% (172 of 175), with a biopsy ratio of 7.6:1. On lesions biopsied mostly to rule out melanoma, MelaFind's average specificity (9.9%) was superior to that of clinicians (3.7%) (P=.02). CONCLUSION: MelaFind is a safe and effective tool to assist in the evaluation of pigmented skin lesions. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00434057.

A major Y-chromosome haplogroup R1b Holocene era founder effect in Central and Western Europe.

The phylogenetic relationships of numerous branches within the core Y-chromosome haplogroup R-M207 support a West Asian origin of haplogroup R1b, its initial differentiation there followed by a rapid spread of one of its sub-clades carrying the M269 mutation to Europe. Here, we present phylogeographically resolved data for 2043 M269-derived Y-chromosomes from 118 West Asian and European populations assessed for the M412 SNP that largely separates the majority of Central and West European R1b lineages from those observed in Eastern Europe, the Circum-Uralic region, the Near East, the Caucasus and Pakistan. Within the M412 dichotomy, the major S116 sub-clade shows a frequency peak in the upper Danube basin and Paris area with declining frequency toward Italy, Iberia, Southern France and British Isles. Although this frequency pattern closely approximates the spread of the Linearbandkeramik (LBK), Neolithic culture, an advent leading to a number of pre-historic cultural developments during the past ≤10 thousand years, more complex pre-Neolithic scenarios remain possible for the L23(xM412) components in Southeast Europe and elsewhere.