Ashkenazi Research Articles

On the Dissemination of the Babylonian Talmud and the Origins of Ashkenazi Jewry

On the Dissemination of the Babylonian Talmud and the Origins of Ashkenazi Jewry Robert Brody The stimulus for this essay was provided by the recent proposals of Haym Soloveitchik concerning the origins of medieval Ashkenazi Jewry, which were first presented publicly in a lecture at the World Congress of Jewish Studies conducted in Jerusalem in the summer of 2013 and later published in more detailed form in the second volume of Soloveitchik's collected essays.1 I discussed many aspects of these proposals with Professor Soloveitchik several years earlier, and he acknowledged these conversations in his publication and even credited me for specific suggestions,2 but I was unable to convince him that his suggestions with regard to connections between the "founding fathers" of Ashkenaz and the contemporaneous Jewish community of Babylonia were highly problematic. Now that these proposals have appeared in print, and in view of Prof. Soloveitchik's repeated assertions that he is no expert in geonica and requests for specialists in the field to evaluate his suggestions,3 I have [End Page 265] taken it upon myself to do so. I am grateful for the opportunity that Soloveitchik's fresh approach to this topic has provided for me to clarify, both for myself and for my readers, my thoughts on several related questions, as well as to explore some possibilities I had not previously considered. I will begin by attempting to place Soloveitchik's theory in perspective by describing the central questions with regard to the establishment of the medieval Jewish community of Ashkenaz, other recent attempts to explain the data, and the similarities and differences between these theories and Soloveitchik's. Simply stated, early medieval Ashkenaz presents something of a conundrum: on the one hand, already the earliest known halakhists of Ashkenaz declared their allegiance to the Babylonian halakhic heritage as expressed in the Babylonian Talmud; on the other hand, Ashkenazi Jewry maintained a number of practices that were incompatible with this Talmud, some of which can be demonstrated to have Palestinian origins.4 How did such a state of affairs come about? The prevailing approach to this question for the last several decades has been to hypothesize that the initial Jewish settlement in medieval Ashkenaz was affiliated with Palestinian tradition—a notion that found some support in reports of the very early arrival of members of the Kalonymos family from Italy, which had close and long-standing ties with Palestine—and that Babylonian influence gradually overcame the initial Palestinian orientation but was unable (or perhaps saw no need to) eradicate all traces of the earlier Palestinian heritage.5 So it happened that Ashkenazi Jews preserved certain practices as ancestral customs despite their incompatibility with the Babylonian Talmud; some of these customs were ultimately of Palestinian origin (whether or not later generations were aware of their Palestinian roots). In essence, Soloveitchik accepts [End Page 266] the notion of a Palestinian substrate that eventually was overcome by the Babylonian Talmud but was not completely eliminated, although he attempts to minimize its scope and significance.6 In my opinion he is clearly right in his critique of several scholars who exaggerated the extent of Palestinian influence on Ashkenazi halakhah, although it sometimes seems that he goes a bit too far in the opposite direction.7 What is revolutionary about Soloveitchik's proposals is the historical model that he offers in order to explain the transition from a Palestinian-inspired Jewish culture to one dominated by the Babylonian Talmud, its study, and interpretation. In Soloveitchik's view, the earliest, Palestinian-oriented settlers were not talmudists, so that the Babylonian Talmud did not have to overcome an entrenched Palestinian Talmud when it arrived on the Ashkenazi scene. More importantly and controversially, the Babylonian Talmud was brought to Ashkenaz a few decades after the initial wave of settlement by immigrants from Babylonia who had studied at hitherto unknown talmudic academies.8 It is the latter hypothesis on which I will focus. For the purposes of this discussion I will accept the basic framework used by Soloveitchik and accepted by David Berger and Avraham Grossman, according to which the roots of medieval Ashkenazi culture go back only to about 9179...

Genome and transcriptome analysis highlights the association of rs2180341 variant with breast cancer

Abstract In 2008, a breast cancer genetic variant rs2180341 in 6q22.33 was first identified in Ashkenazi Jews population with P=2.90E-08. However, other studies reported controversial findings. Here, we conducted a three-stage analysis. In stage 1, we used the genome-wide association study datasets and candidate gene study datasets to evaluate the potential association between rs2180341 and breast cancer. In stage 2, we conducted an expression quantitative trait loci (eQTLs) analysis to further evaluate whether rs2180341 is associated with the expression of nearby genes. In stage 3, we evaluated the potential different expression of these nearby genes using case-control gene expression dataset. Our findings showed significant heterogeneity in all these selected genome-wide association study datasets and candidate gene study datasets. The breast cancer variant rs2180341 identified in Ashkenazi Jews population may not be directly replicated in other populations. Meanwhile, eQTLs analysis provides strong evidence implicating rs2180341 as a risk variant regulating the expression of nearby genes involved in kinds of cancers. However, few nearby genes showed significant different expression in breast cancer cases and controls.

Religious In-group Preference: A Replication and Extension into the Domain of Identity

Jewish success has led to questions of how Jews may differ from non-Jews. There is clear evidence that Ashkenazi Jews have greater general cognitive ability. There is more recent evidence that U.S. Jews differ in personality; specifically that they have a higher general factor of personality. Most recently it was also found that U.S. Jews exhibit high levels of in-group preference, despite having a low level of religiosity (itself being strongly positively correlated with in-group preference). In the current investigation this finding is replicated using data from the Wisconsin Longitudinal Study and inquiry extended to examine differences in personal identity. Consistent with the previous findings, Jews showed high levels of in-group preference and low levels of religiosity. Additionally, Jews put more importance on ethnic, and possibly political, identity. These results are interpreted as Jews conflating identifying as a religious and as an ethnic group. A clear limitation of the study is the small Jewish sample. It is recommended that future research test the replicability of the findings of differences in personal identity.

On Kosher Hamburgers, Yiddish Tangos, and Non-Affiliated Jews: Writing Jewish Latin America into the Americas

On Kosher Hamburgers, Yiddish Tangos, and Non-Affiliated Jews:Writing Jewish Latin America into the Americas Raanan Rein (bio) and Adriana M. Brodsky (bio) During his visit to the United States in 2018 while watching a Miami Heat basketball game, the president of the legendary soccer club Boca Juniors, Daniel Angelici, was impressed by the possibility of eating kosher food at the stadium. It was then that he decided to bring that novel idea to the "Bombonera" (the nickname for Boca Juniors' stadium). In August 2018, a kosher food stand was opened.1 Now, Jews and non-Jews alike will be able to enjoy a kosher version of the choripán, the quintessential and popular sausage snack.2 The inauguration of such a stand in one of Argentina's most renowned soccer temples received worldwide attention. Due to the importance and visibility of the Jewish community in Buenos Aires, and its long-standing involvement in Argentina's national sport, however, this should be no surprise. Indeed, one of the recent trends in Jewish-Latin American historiography precisely highlights how national cultures in the region influenced the elaboration of Jewish identities, and, simultaneously, how Jews ethnicized the larger society. This essay looks at some of the innovative contributions and challenges of Jewish Latin American historiography and what these studies can offer scholars focusing primarily on the Jewish experience in the United States. Current studies of Jewish history in Latin America insist on the importance of comparative studies, both within nations across different ethnic groups, and also across national borders within the Americas. The largest immigration to Latin America, which counted hundreds of thousands of Jews, took place between 1880 and 1930. [End Page 345] These were mainly Ashkenazi Jews driven away by pogroms, poverty, and discrimination. There was also a smaller number of Sephardi immigrants. Argentina, for example, counted only 6,085 Jews in its 1895 census, although the number was probably higher; by the 1930s, there were likely more than 200,000. In Brazil, the 1900 census listed 819 Jews. By the early 1930s, that number rose to around 30,000. And in Mexico, the official number of Jews increased from 134 in the early twentieth century to 9,000 in 1930.3 The richness of Jewish life in Latin America, which currently amounts to at least 500,000 Jews,4 has proved relevant to national histories, the Jewish world, and to the study of the relocation and movement of people and ideas, contributing to the reconfiguration of our understanding of Jewish geographies. While traditional historiography has tended to compare US Jewish experiences with European ones, attention to Jewish Latin America will better highlight the particular and unique in their case studies and what is in fact part of broader New World patterns as far as the social integration of Jews into their new host/home lands. The field of Jewish Latin American studies is a relatively new one compared to US Jewish studies, and it is therefore less bound by tradition when it comes to the historiography of organized Jewish communities and their internal dynamics. The exponential growth of this field, in particular since the foundation of the Latin American Jewish Studies Association (LAJSA) in 1982, does not allow us to refer to most of the studies published on different aspects of Jewish life in this hemisphere. Since there is little continuity between the Jewish experiences during the colonial period and the communities established during the years of Jewish mass migration to the Americas from the late nineteenth century onwards, this essay focuses on the modern period, and leaves the experience of Jews during the colonial period and the Anusim (those forced to convert and their descendants) for another discussion. When possible, we have given priority to material available in English and accessible to the readers of the American Jewish History. We have also mostly focused on historiography, as the existing body of work in literature and cultural studies is vast and deserves its own essay. And since previous historiography overemphasized the supposed importance of antisemitism in the region, this text will refer mostly to studies about [End Page 346] Jewish integration in and contribution to the many societies...

The Image of the Fragile Ashkenazi Jew

The Image of the Fragile Ashkenazi Jew

On the Third Yeshivah of Bavel: A Response to Robert Brody

On the Third Yeshivah of Bavel:A Response to Robert Brody Haym Soloveitchik For Alfred Haverkamp i Let me begin by thanking Professor Brody for the attention that he has given to my essay "The 'Third Yeshivah of Bavel' and the Cultural Origins of Ashkenaz—A Proposal" (his essay in response appears in this issue of JQR).1 He himself is a renowned expert on geonica and has further drawn on the expertise of many equally distinguished scholars: the medieval Jewish historian of Ashkenaz and unquestioned authority of Jewish-Christian polemics, David Berger2; the authority on rabbinic chronology and master of the editing of rabbinic texts, Chaim Milikowsky; [End Page 289] Daniel Schwartz, a leading historian on the Jews and Judaism of the Second Commonwealth whose broad range of knowledge extends down to Wissenschaft des Judentums in the nineteenth and early twentieth centuries; and Beryl Septimus, an authority on medieval Spain and Provence who has equally made serious contributions to the study of Mishneh Torah. I feel honored to have drawn the attention of so many distinguished scholars and challenged by their concentrated critical fire. Professor Brody drew on the expertise of numerous colleagues; the formulations, however, are his. He naturally assumes full responsibility for the end product and signed his name on the critique, and it is to him that I address my reply. ________ I must admit at the outset my perplexity. Many of the things attributed to me I never said, and for many of the things I did say, Brody simply registers his disagreement with no reason given for his dissent. Brody opens: I will begin by attempting to place Soloveitchik's theory in perspective by describing the central questions with regard to the establishment of the medieval Jewish community of Ashkenaz, other recent attempts to explain the data, and the similarities and differences between these theories and Soloveitchik's. Simply stated, early medieval Ashkenaz presents something of a conundrum: on the one hand, already the earliest known halakhists of Ashkenaz declared their allegiance to the Babylonian halakhic heritage as expressed in the Babylonian Talmud; on the other hand, Ashkenazi Jewry maintained a number of practices that were incompatible with this Talmud, some of which can be demonstrated to have Palestinian origins. How did such a state of affairs come about? (RB 266) I never addressed this problem in my essay. Nor would I, as the conundrum is illusory. No culture is monolithic; all cultures are composites, rich mosaics with one or two components being dominant. To give only one salient example from a later and far more crystalized and internally consistent culture than that of primeval Ashkenaz of the hazy ninth and tenth centuries: In the lighting of the Hanukkah candelabra, Ashkenaz (R. Moshe Isserles) follows Maimonides' dictum and Sefarad (R. Yosef Karo, the Meḥabber) follows that of the tosafists.3 Brody proceeds: [End Page 290] The prevailing approach to this question for the last several decades has been to hypothesize that the initial Jewish settlement in medieval Ashkenaz was affiliated with Palestinian tradition—a notion that found some support in reports of the very early arrival of members of the Kalonymos family from Italy, which had close and long-standing ties with Palestine—and that Babylonian influence gradually overcame the initial Palestinian orientation but was unable (or perhaps saw no need to) eradicate all traces of the earlier Palestinian heritage. So it happened that Ashkenazi Jews preserved certain practices as ancestral customs despite their incompatibility with the Babylonian Talmud; some of these customs were ultimately of Palestinian origin (whether or not later generations were aware of their Palestinian roots). In essence, Soloveitchik accepts the notion of a Palestinian substrate that eventually was overcome by the Babylonian Talmud but was not completely eliminated, although he attempts to minimize its scope and significance. (RB 266–67) I never "accepted the notion of a Palestinian substrate that eventually was overcome by the Babylonian Talmud." Quite the contrary, I argued in a preceding essay in the volume (and which Brody addresses, as we will see in the next paragraph) that to the extent that we can document what was the practice of the earliest known...

When Sonia Met Boris: An Oral History of Jewish Life Under Stalin by Anna Shternshis

Reviewed by: When Sonia Met Boris: An Oral History of Jewish Life Under Stalin by Anna Shternshis Jarrod Tanny Anna Shternshis. When Sonia Met Boris: An Oral History of Jewish Life Under Stalin. New York: Oxford University Press, 2017. Xii + 264 pp. Cloth $34.95. ISBN 0190223103. Who gets to tell the story? In Anna Shternshis’s When Sonia Met Boris it is 474 Ashkenazi Jews, all born in the Russian Empire or the Soviet Union between 1906 and 1928, Soviet citizens who came of age during the Stalin era and experienced the attendant social upheavals and cataclysmic events that marked this tumultuous era. Through oral histories, Shternshis seeks to uncover the daily lives of her subjects, how work, home, family, and migration patterns intersected with being Jewish in a time of modernization, famine, terror, war, and, antisemitism. The collapse of the USSR engendered a massive wave of Jewish emigration. Shternshis conducted her interviews in the United States, Canada, Germany, and Russia over the course of the first decade of the twenty-first century. The result is an informative, sophisticated, and lively account of Soviet Jewish history, one that “fleshes out and revises the historical record” (21) because “some events in Soviet Jewish history simply cannot . . . be understood properly without oral histories.” (9) When Sonia Met Boris is divided into three parts. In part one, Shternshis reflects on the practice of oral history, its strengths, and its limitations. She illustrates the techniques she used to get her interviewees to voice their histories, fully cognizant that hindsight, location, and her own role as an intermediary might severely compromise the stories they tell. In parts two and three, Shternshis examines Soviet Jewish family life and Jews in the Soviet workplace. In the eight chapters that make up these two sections, she strikes a delicate balance between a chronological thematic approach, periodically returning to topics already discussed—marriage, education, internal migration in search of work, fear of shame and arrest during Stalin’s purges—because such is the nature of human memory. The author tries to go where her subjects take her, letting them articulate their past as they remember it. But ever aware of her own role as mediator, Shternshis regularly tells the reader when her subjects’ responses surprised her, undermined her previous assumptions, or resonated with her as a scholar and—one may speculate—as a Soviet Jewish émigré. “Teachers were my favorite narrators,” writes Shternshis. “They were the most articulate, usually recalled events of the past with remarkable detail, were amazing storytellers, spoke loudly and clearly, and made sure the interviewer understood their point,” even though “they quickly recognized the interviewer’s agenda and sometimes exaggerated.” (123) Such personal interjections strengthen Shternshis’s work, because they remind the reader that the collector and interpreter of oral histories is not (and can never be) an impartial conveyer of unfiltered material. Although Shternshis’s composite picture of “the first Soviet Jewish generation” offers insight into many questions typically raised by scholars, two conclusions stand out. First, the final period of Stalin’s reign, 1948–53—what is commonly referred to as “the black years of Soviet Jewry” because of the [End Page 94] sharp uptick in state-sponsored antisemitism—was in fact a turning point in the lives of most of her subjects. “Whoever forgot that he was as a Jew, or didn’t know, learned about it in 1948!” (122) stated countless interviewees to Shternshis, because being Jewish became a liability; it prompted an enduring awareness that antisemitism could lead to obstructed professional mobility, public ridicule, and even arrest. But “these stories of antisemitism are not solely tales of victimhood,” (108) cautions Shternshis, because her subjects presented them as “quests,” as challenges that they needed to face and surmount, much as “one beats a disease, succeeding despite being burdened by misfortune.” (188) Shternshis may not be the first historian to reach this conclusion, but her use of oral testimony allows us to see how Soviet Jews perceived their changing relationship to the state and to their non-Jewish neighbors. It reveals the many secrets people kept and it fills in the spaces of silence historians encounter in archival and printed sources...

A Man Fighting a Lion: A Christian 'Theme' in Yiddish Epics

During the medieval and early modern periods, lions served as a common motif in Ashkenazic Jewish culture, bearing diverse symbolism. Also in literature written in Yiddish, the vernacular language of Ashkenazic Jews, lions were often mentioned. In this article, three songs about a man fighting a lion – Samson, David, and Benaiah – found within early modern Yiddish epics, are presented. An analysis of these songs' similar content and form suggests that they are short epic songs which have been initially orally transmitted, and later incorporated into the written long epics in Yiddish which have come down to us. In two of the songs the hero holds the lion's mouth with both hands, shortly before subduing him, an image common in Jewish art but lacking any basis in Jewish texts. This study identifies a Christian background to this image, namely that Samson's battle with the lion foreshadows the Harrowing of Hell and Jesus' releasing mankind’s souls from eternal damnation. The study points to the close cultural ties between Jews and Christians in the medieval and early modern eras, which were possible in the sphere of vernacular Yiddish literature. This closeness brought about influences which do not seem to exist in Hebrew literature.

The sequencing and interpretation of the genome obtained from a Serbian individual.

Recent genetic studies and whole-genome sequencing projects have greatly improved our understanding of human variation and clinically actionable genetic information. Smaller ethnic populations, however, remain underrepresented in both individual and large-scale sequencing efforts and hence present an opportunity to discover new variants of biomedical and demographic significance. This report describes the sequencing and analysis of a genome obtained from an individual of Serbian origin, introducing tens of thousands of previously unknown variants to the currently available pool. Ancestry analysis places this individual in close proximity to Central and Eastern European populations; i.e., closest to Croatian, Bulgarian and Hungarian individuals and, in terms of other Europeans, furthest from Ashkenazi Jewish, Spanish, Sicilian and Baltic individuals. Our analysis confirmed gene flow between Neanderthal and ancestral pan-European populations, with similar contributions to the Serbian genome as those observed in other European groups. Finally, to assess the burden of potentially disease-causing/clinically relevant variation in the sequenced genome, we utilized manually curated genotype-phenotype association databases and variant-effect predictors. We identified several variants that have previously been associated with severe early-onset disease that is not evident in the proband, as well as putatively impactful variants that could yet prove to be clinically relevant to the proband over the next decades. The presence of numerous private and low-frequency variants, along with the observed and predicted disease-causing mutations in this genome, exemplify some of the global challenges of genome interpretation, especially in the context of under-studied ethnic groups.

Carriers of both GBA and LRRK2 mutations, compared to carriers of either, in Parkinson's disease: Risk estimates and genotype-phenotype correlations

IntroductionThe clinical characteristics of Parkinson's disease (PD) associated with both the LRRK2 p.G2019S mutation and a GBA variant (LRRK2-GBA-PD) have not yet been determined. MethodsIn this retrospective observational study of Ashkenazi-Jewish (AJ) PD patients, we describe the clinical course and characteristics of LRRK2-GBA-PD and estimate the risk to develop PD for the double mutation carriers. Odds ratios (OR) were estimated using published data on frequencies of GBA and LRRK2 mutations. Demographic and clinical data was retrieved from medical records and from rating at last visit. ResultsOur analysis included 236 PD patients, divided into four groups: LRRK2-PD (n = 66), GBA-PD (n = 78), GBA-LRRK2-PD (n = 12) and mutation-negative PD (MNPD, n = 80 randomly selected). The estimated ORs in different models for GBA-LRRK2 PD were 15–28 (95% CI 6.7–72.0, p < 0.0001), compared to AJ controls. Using logistic regression (while controlling for sex, age at onset and PD duration), we found that probable REM-sleep behavior disorder (RBD) was significantly more common for GBA-PD than for LRRK2-PD, while none of the GBA-LRRK2-PD patients reported RBD. Dementia was significantly more common for GBA-PD than for the LRRK2-PD and MNPD. Psychosis was the most common for GBA-PD and least common for LRRK2-GBA-PD. ConclusionsWhile GBA-PD is characterized by higher rates of dementia, probable RBD and psychosis, it seems that compared to the other groups, these features are less common for LRRK2-GBA-PD. This may imply to a possible protective effect of LRRK2 p.G2019S mutation among GBA variant carriers.

Some Dietary Factors Among Ashkenazi and Sephardic Jews: An Ecological Study based on the Literature

In Israel, the multiple sclerosis (MS) prevalence was nearly two - fold in European / American immigrants (mostly Ashkenazim Jews) (53.7 per 100,000) in comparison to African / Asian immigrants (mostly Sephardim Jews) (27.9 per 100,000) in 2000. In the present study, a comparison of both populations with respect to the preservation methods of meat was made by an evaluation of totally 48 cookery books used as literary sources. It was shown that smoking of meat was much more common in Ashkenazi than Sephardic cookery (Yates’ corrected four - fold table test: chi² = 28.49; p &lt; 0.0001). In contrast, the percentage of vegetables (e.g. onions; parsley; garlic) did not differ between both groups. The findings hold for recommendations that might be given to all MS patients, although they are founded on experimental data so far.

Leucine rich repeat kinase 2 (LRRK2) GLY2019SER mutation is absent in a second cohort of Nigerian Africans with Parkinson disease.

To date the LRRK2 p.G2019S mutation remains the most common genetic cause of Parkinson disease (PD) worldwide. It accounts for up to 6% of familial and approximately 1.5% of sporadic cases. LRRK2 has a kinase enzymatic domain which provides an attractive potential target for drug therapies and LRRK2 kinase inhibitors are in development. Prevalence of the p.G2019S has a variable ethnic and geographic distribution, the highest reported among Ashkenazi Jews (30% in patients with familial PD, 14% in sporadic PD, 2.0% in controls) and North African Berbers (37% in patients with familial PD, 41% in sporadic PD, and 1% in controls). Little is known about the frequency of the LRRK2 p.G2019S among populations in sub-Saharan Africa. Our group and others previously reported that the p.G2019S is absent in a small cohort of Nigerian PD patients and controls. Here we used Kompetitive Allele Specific PCR (KASP) assay to screen for the p.G2019S in a larger cohort of Black African PD patients (n = 126) and healthy controls (n = 54) from Nigeria. Our analysis confirmed that all patients and controls are negative for the p.G2019S mutation. This report provides further evidence that the LRRK2 p.G2019S is not implicated in PD in black populations from Nigeria and support the notion that p.G2019S mutation originated after the early human dispersal from sub-Saharan Africa. Further studies using larger cohorts and advance sequencing technology are required to underpin the genetic causes of PD in this region.

Prenatal Diagnosis of Tay-Sachs Disease.

Tay-Sachs disease (TSD) is an autosomal recessive lysosomal storage disorder caused by mutations of the HEXA gene resulting in the deficiency of hexosaminidase A (Hex A) and subsequent neuronal accumulation of GM2 gangliosides. Infantile TSD is a devastating and fetal neurodegenerative disease with death before the age of 3-5years. A small proportion of TSD patients carry milder mutations and may present juvenile or adult onset milder disease. TSD is more prevalent among Ashkenazi Jewish (AJ) individuals and some other genetically isolated populations with carrier frequencies of approximately ~1:27 which is much higher than that of 1:300 in the general population. Carrier screening and prenatal testing for TSD are effective in preventing the birth of affected fetuses greatly diminishing the incidence of TSD. Testing of targeted HEXA mutations by genotyping or sequencing can detect 98% of carriers in AJ individuals; however, the detection rate is much lower for most other ethnic groups. When combined with enzyme analysis, above 98% of carriers can be reliably identified regardless of ethnic background. Multiplex PCR followed by allele-specific primer extension is one method to test for known and common mutations. Sanger sequencing or other sequencing methods are useful to identify private mutations. For prenatal testing, only predefined parental mutations need to be tested. In the event of unknown mutational status or the presence of variants of unknown significance (VUS), enzyme analysis must be performed in conjunction with DNA-based assays to enhance the diagnostic accuracy. Enzymatic assays involve the use of synthetic substrates 4-methylumbelliferyl-N-acetyl-β-glucosamine (4-MUG) and 4-methylumbelliferyl-6-sulfo-2-acetamido-2-deoxy-β-D-glucopyranoside (4-MUGS) to measure the percentage Hex A activity (Hex A%) and specific Hex A activity respectively. These biochemical and molecular tests can be performed in both direct specimens and cultured cells from chorionic villi sampling or amniocentesis.

The rate of the recurrent MSH6 mutations in Ashkenazi Jewish breast cancer patients.

Whether breast cancer (BC) should be considered within the spectrum of tumors in Lynch syndrome (LS) is unsettled. Recently, MSH6 and PMS2 germline mutations have reportedly been associated with an increased BC risk and with hereditary breast and ovarian cancer (HBOC) phenotype. We assessed the rates of the recurring Ashkenazi Jewish (AJ) mutations in the MSH6 gene (c.3984_3987dupGTCA and c.3959_3962delCAAG) in AJ cases with seemingly sporadic BC or HBOC phenotype, who were negative for the founder AJ BRCA1/2 mutations. All AJ individuals, affected with BC ≤ 70years and/or ovarian cancer at any age who were counseled, genotyped and tested negative for the BRCA1/2 founder mutations between January 2010 and February 2018 at the Oncogenetics unit, Sheba Medical Center, were genotyped for the AJ mutations in MSH6. Of 1016 genotyped participants (815 BC cases, 132 ovarian cancer cases, and 69 with more than one cancer), five carriers (0.49%) of the recurring AJ mutations in MSH6 were identified. All had BC, and two had personal history of additional cancers (pancreatic, endometrial, colorectal). The rate of MSH6 mutations was 0.93% (4/429) when considering only cases with a personal or first-degree relative with LS-related cancer, and 0.17% (1/587) of cases with second-degree relative or no family history of LS-related cancers (p = 0.087). Our data suggest the spectrum of genotyped mutations in AJ BC patients with a personal or family history of LS-related cancers should be expanded. These data should be validated in other populations with a similar phenotype.

Uterine cancer in Jewish Israeli BRCA1/2 mutation carriers.

BRCA1/2 mutation carriers have an increased risk of developing ovarian cancer, leading to the recommendation of risk-reducing salpingo-oophorectomy (RRSO) at 35-40 years of age. The role, if any, that BRCA mutations play in conferring uterine cancer risk, is unresolved. Jewish Israeli women, carriers of one of the predominant Jewish mutations in BRCA1/2 from 1998 to 2016, were recruited. Cancer diagnoses were determined through the Israeli National Cancer Registry. Uterine cancer risk was assessed by computing the standardized incidence ratio of observed-to-expected number of cases, using the exact 2-sided P value of Poisson count. Overall, 2627 eligible mutation carriers were recruited from 1998 to 2016, 2312 (88%) of whom were Ashkenazi Jews (1463 BRCA1, 1154 BRCA2 mutation carriers, 10 double mutation carriers). Among these participants, 1310 underwent RRSO without hysterectomy at a mean (± standard deviation) age of 43.6 years (± 4.4 years). During 32,774 women-years of follow up, 14 women developed uterine cancer, and the observed-to-expected rate of all histological subtypes was 3.98 (95% confidence interval [CI], 2.17-6.67; P < .001). For serous papillary (n = 5), the observed-to-expected ratio was 14.29 (95% CI, 4.64-33.34; P < .001), and for sarcoma (n = 4) it was 37.74 (95% CI, 10.28-96.62). These rates were also higher than those detected in a group of 1844 age- and ethnicity-matched women (53% with breast cancer). Israeli BRCA1 or BRCA2 mutation carriers are at an increased risk for developing uterine cancer, especially serous papillary and sarcoma. These elevated risks of uterine cancer should be discussed with BRCA carriers.

Prevalence of nonfounder BRCA1/2 mutations in Ashkenazi Jewish patients presenting for genetic testing at a hereditary breast and ovarian cancer center.

Genetic assessment in Ashkenazi Jewish (AJ) patients often is limited to BRCA1/2 founder mutation testing. With access to time-efficient and cost-efficient multigene panel testing, some advocate expanding genetic testing in this population. However, to the best of the authors' knowledge, rates of nonfounder BRCA1/2 mutations and mutations in cancer-associated genes other than BRCA1/2 among AJ are not known. In the current study, the authors sought to assess the prevalence of mutations other than BRCA1/2 founder mutations among AJ patients undergoing genetic assessment. The authors reviewed the medical records for all AJ patients who underwent genetic assessment at a single institution between June 2013 and December 2016. Mutations were categorized as 1) BRCA1/2 AJ founder mutations (BRCA1 185delAG, BRCA1 5382insC, or BRCA2 6174delT); 2) nonfounder BRCA1/2 mutations; or 3) mutations in non-BRCA1/2 cancer-associated genes. A total of 732 AJ patients underwent genetic assessment. Of these, 371 patients (51%) had a personal history of breast or ovarian cancer, 540 patients (73.8%) had a family history of breast cancer, and 132 patients (18%) had a family history of ovarian cancer. In the study population, 101 patients (13.8%) were found to have a pathogenic mutation, 78 patients (10.7%) had a BRCA1/2 founder mutation, 3 patients (0.4%) had a nonfounder BRCA1/2 mutation, and 20 patients (2.7%) had a mutation in a non-BRCA1/2 cancer-associated gene. Non-BRCA1/2 cancer-associated genes harboring mutations included RAD51D, TP53, mutS homolog 6 (MSH6), checkpoint kinase 2 (CHEK2), adenomatous polyposis coli (APC), and Fanconi anemia group C protein (FANCC). Among AJ patients found to have a pathogenic mutation on genetic assessment, approximately 22.8% had a mutation that would be missed with BRCA1/2 AJ founder mutation testing. Comprehensive multigene panel sequencing can provide clinically relevant genetic information for AJ patients and should be considered for genetic assessment in this population.

The Impact of Inflammatory Bowel Disease in Canada 2018: Epidemiology.

1. Canada continues to have among the highest prevalence of IBD in the world.2. Today, approximately 270,000 Canadians live with IBD. By 2030 it is estimated that nearly 403,000 Canadians will have a diagnosis of IBD.3. Inflammatory bowel disease has become a worldwide disease with increasing rates in Asia, Africa, and South America-continents where IBD was rarely diagnosed prior to 1990.4. The causes of IBD are unknown, but the high rates of disease over the past 60 years in Western countries and the emergence of disease in developing countries suggest that factors associated with urbanization, modernization, or Western diets may be pertinent to understanding the pathogenesis of the disease.5. Many of the leading hypotheses as to the causes of IBD tie in with alteration of the gut microbiome, the suite of organisms that reside in the bowel and maintain bowel health throughout life. 1. The incidence (the number of new diagnoses annually) of IBD rose throughout the 20th century in Canada and then stabilized at the turn of the 21st century.2. The prevalence (the total number of diagnosed persons in the population) of IBD in Canada is among the highest in the world.3. Today, 270,000 (0.7%, or 7 in 1000) Canadians are estimated to live with IBD. By 2030, that number is expected to rise to 403,000 Canadians (1% or 1 in 100).4. Inflammatory bowel disease can be diagnosed at any age. However, the age groups that are most likely to be diagnosed are adolescents and young adults from 20 to 30 years of age.5. Inflammatory bowel disease in Canada affects the lives of Canadians of all ethnicities, including known high-risk groups such as Ashkenazi Jews, and those thought previously to be at low risk, such as first-generation offspring of South Asian immigrants.6. Canadian health policy makers will need to prepare the Canadian health care system for the rising burden of IBD.7. As newly industrialized countries in Asia, Africa, and South America are transitioning to a Westernized society, IBD has emerged and its incidence in these countries is rising rapidly.8. The gut microbiome includes microorganisms that maintain digestive health. Thus, changes in the microbiome, which may change the immune system's response to triggers, may be important in initiating and perpetuating IBD.9. A number of factors can alter the gut microbiome and early childhood may be a particularly important time such that breastfeeding, early life diet, use of antibiotics, infections, and other environmental exposures may impact the gut microbiome in such a way that facilitates developing IBD.10. Smoking is associated with an increased risk and worsening disease course of Crohn's disease. Quitting smoking is associated with an increased risk of developing ulcerative colitis. Therefore, never initiating smoking can mitigate the risk for IBD. Educational programs aimed at those at-risk for IBD should emphasize the risk of starting to smoke tobacco.11. Modifying exposure to environmental risk factors associated with the Westernization of society (e.g., Western diet and lifestyles) may provide an avenue for reducing the risk of IBD in Canada and worldwide. 1. While the incidence of IBD appears to be stabilizing in some regions in Canada, IBD may be occurring more frequently in certain populations such as in children, South Asians, Ashkenazi Jews, and immigrants. Future research should focus on the changing demographics of IBD in Canada.2. The prevalence of IBD will rise steadily over the next decade. To enable better health care system planning and to respond adequately to the increasing burden of IBD, ongoing surveillance of the epidemiology and health services utilization of IBD in Canada is necessary.3. Most studies have focused on the mortality associated with IBD. Future research is necessary to assess health-adjusted life expectancy and overall life expectancy for those living with IBD.4. Analyses of resources, infrastructure, and personnel need to be modeled into the future in order to prepare our health care system for the rising burden of IBD.5. Research on the interaction between genes, microbes, and our environment will inform our understanding of the pathogenesis of IBD, information necessary to prevent IBD in the future.

Hairy Cell Leukemia: Retrospective Analysis of Demographic Data and Outcome of 203 Patients from 12 Medical Centers in Israel.

In this retrospective study, we summarized the national Israeli experience with hairy cell leukemia (HCL) in a large cohort of patients with a long follow-up. Demographic data, and relevant laboratory and clinical parameters were analyzed, emphasizing the outcome after first-line treatment with cladribine. Data on 203 patients was collected from 12 medical centers during 1985-2015. Mean and median follow-up were 7.5 years and 5.18 years (interquartile range=0.1-40 years), and 5- and 10-year survival were 96% and 90.62%, respectively. The median age of diagnosis was 55.5 years for Jews and 49 years for Arabs (p=0.021), and most patients were males (81.77%); 52.2% were Ashkenazi Jews, 36.1% Sephardic Jews and 11.7% were Arab, Druze or other ethnicity. Cladribine was given to 159 patients (80.7%%) and most (62%) received intravenous (i.v.) and 38% received subcutaneous (s.c.) therapy. Overall survival and time to next treatment were not significantly different between the two schedules (i.v., s.c.). In univariate analysis of a variety of factors, only age >65 years had a negative impact on outcome, with shorter overall survival. It is of interest that Arab patients with HCL were diagnosed at an earlier age, but had a similar clinical course and outcome to both Ashkenazi and Sephardic Jews.

David I. Shyovitz. A Remembrance of His Wonders: Nature and the Supernatural in Medieval Ashkenaz. Philadelphia: University of Pennsylvania Press, 2017. 325 pp.

Reviewed by: A Remembrance of His Wonders: Nature and the Supernatural in Medieval Ashkenaz by David I. Shyovitz David Malkiel David I. Shyovitz. A Remembrance of His Wonders: Nature and the Supernatural in Medieval Ashkenaz. Philadelphia: University of Pennsylvania Press, 2017. 325 pp. doi:10.1017/S036400941800065X Historical scholarship of the past few decades has sought to liberate the image of medieval Ashkenazic Jewry from the grip of Wissenschaft thinking, which portrayed it as xenophobic and ignorant. David Shyovitz's A Remembrance of His Wonders takes this scholarly movement in a new direction. Shyovitz argues that far from shunning the natural order, the German Pietists reflected deeply on natural phenomena that inspire marvel because they appear to defy explanation. The Pietists, chiefly Judah the Pious, collected these wonders in texts that often begin with "a remembrance of His wonders" (Psalm 111:4), in order to derive theological conclusions from seemingly aberrant forces of nature. The theological import derived from remembrances revolves around God's existence and omnipotence, and typically is learned a minore ad maius, from the physical order to the recondite divine realm. Shyovitz interprets these lessons propounded by the Pietists as implying a powerful current of skepticism among the rank and file of medieval Ashkenaz, which also challenges the traditional historiographical image. Indeed, Jeremy Cohen and Avraham Grossman have put forward similar arguments in different contexts, and yet I can imagine the Pietists propagating material of this sort for the edification and spiritual well-being of their audience without conjuring an atmosphere involving a crisis of faith. The interrogation of nature through its wonders is a familiar trope from the travel writing of Gerald of Wales and others, which treats home-bound readers to descriptions of bizarre creatures encountered at the geographical limits of the world, liminal phenomena in liminal locales. Thinking about events and behaviors that lie at the edge of the natural realm offered a way to conceptualize the natural [End Page 465] order and where its boundaries fall. Thus, the interest the Pietists show in the workings of nature situates them squarely in the context of medieval science, which, as Lynn Thorndike has shown, did not distinguish between science and magic, the natural and occult. More startling is the Pietists' methodology, which combines observation and experimentation. They instruct readers how to produce certain results, and their thinking is refreshingly modern for not being rooted in the classical tomes of Aristotle, Galen, and others. Judah the Pious takes his place among Albert the Great and other medieval thinkers whose empiricism anticipated the scientific revolution. A Remembrance of His Wonders also posits a high degree of cultural integration, with knowledge of the natural order—including the occult—derived not only from rabbinic tradition (e.g., sources about magnets, salamanders, etc.), but also from contemporary Christian writings, including bestiaries, lapidaries, encyclopedias, and "books of secrets." Once again, the book confounds the image of Ashkenazic Jewry as insular, although Yitzhak Baer, Joseph Dan, and others have suggested possible connections to Berthold of Regensburg or Caesarius of Heisterbach and acknowledged the presence of Germanic folklore in the Pietists' writings. Remembrances from the natural world are the subject of the first chapter; the remaining four focus on the human being, especially the body. We are thus cautioned that the Pietists' well-known asceticism does not imply disdain for the body; rather, the idea of man as microcosm stimulates intense scrutiny of the body's form and processes, from which the Pietists derive practical advantage, such as for divination or to fashion a golem. This fascination with the human form seems to sit well with the Ashkenazic tradition of divine corporealism, a tradition closely associated with Moses Taku, though true also for Rabbi Abraham ben David of Posquières. Shyovitz's overall thesis of intense Ashkenazic acculturation is supported here by evidence that the microcosm idea circulated widely in twelfth-century Europe, at the cathedral school of Chartres or, closer to home, in the writings of Hildegard of Bingen. We are also treated to sources from visual art, including the Noah Window of the Chartres Cathedral (fig. 8). The Pietists' theory of the soul supports Shyovitz's argument about their interest in...

Reflex Testing for Germline BRCA1, BRCA2, PALB2, and ATM Mutations in Pancreatic Cancer: Mutation Prevalence and Clinical Outcomes From Two Canadian Research Registries.

We investigated the translational value of reflex testing for germline mutations in four homology-directed DNA repair predisposition genes (BRCA1, BRCA2, PALB2, and ATM) in consecutive patients with pancreatic adenocarcinoma. One hundred fifty patients with French-Canadian (FC) ancestry were evaluated for founder mutations, and 114 patients were subsequently assessed by full gene sequencing and multiplex ligation-dependent probe amplification for nonfounder mutations. Two hundred thirty-six patients unselected for ancestry were also assessed for mutations by full gene sequencing. The FC founder mutation prevalence among the 150 patients was 5.3% (95% CI, 2.6% to 10.3%), and the nonfounder mutation prevalence across the four genes among the 114 patients tested was 2.6% (95% CI, 0.6% to 7.8%). In the case series unselected for ancestry, 10.0% (95% CI, 2.7% to 26.4%) of patients reporting Ashkenazi Jewish (AJ) ancestry carried an AJ founder mutation, with no nonfounder mutations identified. The mutation prevalence among patients without FC/AJ ancestry was 4.9% (95% CI, 2.6% to 8.8%). Mutations were more frequent in patients diagnosed at ≤ 50 years of age (P = .03) and in patients with either two or more first- or second-degree relatives with pancreas, breast, ovarian or prostate cancer, or one such relative and a second primary of one of these cancer types (P < .001). BRCA1, BRCA2, and PALB2 carriers with late-stage (III or IV) disease had an overall survival advantage (P = .049), particularly if treated with platinum-based chemotherapies (P = .030). Considering these results, we recommend reflex founder mutation testing of patients with FC/AJ ancestry and full gene sequencing of patients who are ≤ 50 years or meet the identified family history criteria. Reflex testing of all incident patients for these four genes may become justified as full gene sequencing costs decline.