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Background Previous work has shown that young females, who present with genomically-stable, poorly-differentiated, diffuse gastric cancer harbor CLDN18/ARHGAP26 fusions more often than older individuals with intestinal type or non-diffuse gastric cancer histology. This fusion usually occurs between exon 5 of CLDN18 and exon 12 of ARHGAP26, is associated with a poor prognosis, and confers a propensity for metastasis. We investigated the prevalence of this fusion and characterized the fusion-positive patient population among gastric cancer patients whose tumor samples underwent OncoExtraTM assay testing. Methods Tumor and paired-normal samples from 171 gastric cancer patients aged 18-90 years were sequenced with the OncoExtraTM assay. This assay uses whole-exome DNA sequencing to detect somatic single base substitutions, indels, copy number alterations, and whole transcriptome RNA sequencing to detect gene fusions and alternative transcripts. The RNA sequencing data were used to identify CLDN18/ARHGAP26 fusions. Results The 171 patients were well balanced between sexes: 91 (53.2%) men, 80 (46.8%) women. Most patients were older: 44 (25.7%) ≤50 years old, 127 (74.3%) >50 years old. There were 6 (3.5%) patient samples with a CLDN18/ARHGAP26 fusion. The fusion was found more often in females (5 of 80, 6.3%) than males (1 of 91, 1.1%) and younger patients (3 of 44, 6.8%, ≤50 years; 3 of 127, 2.3%, >50 years). All 6 had diffuse histology by pathology, variably described as poorly differentiated, diffuse, or signet ring subtype. Notably, the 2 patients with mixed histology did not have metastases reported on the pathology report, while the 4 whose histology was described as diffuse or signet ring cell type were metastatic. In all cases the fusion involved exon 5 of CLDN18 and exon 12 of ARHGAP26. Further analysis revealed that five of the fusion-containing tumors had alterations in genes/pathways known to be oncogenic drivers of cell proliferation, specifically 1 ERBB2 (2 mutations present), 1 SWI/SNF pathway (ARID1A and PBRM1 both altered), 2 MET (both amplifications), and 1 PI3K pathway (PI3KCA altered). The sixth tumor sample possessed no obvious driver alterations: only TP53 and WRN were altered. Five of the 6 tumors had low tumor mutational burden (TMB) and were microsatellite stable, the sixth had intermediate TMB, and none had evidence for genomic instability. No CLDN18 fusions were found in any other solid tumors (7050 samples). Conclusions The OncoExtraTM assay detected gastric cancer CLDN18/ARHGAP26 fusions at a frequency (3.5%) similar to previous reports. The majority were female and of younger age compared to patients lacking this fusion. Five of the 6 tumors had additional oncogenic alterations associated with cell proliferation. Given its frequency in poorly differentiated gastric cancer with metastatic potential, as well as its prevalence in a relatively young cohort, this fusion is an attractive target for ongoing drug development. Citation Format: Deborah Josefson, David W. Hall, Jess Hoag, Ariane Kemkes, Janine LoBello, Snehal G. Thakkar, Gargi Basu. CLDN18/ARHGAP26 fusions in gastric cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2150.

This prospective phase II clinical trial (Side Out 2) explored the clinical benefits of treatment selection informed by multi‐omic molecular profiling (MoMP) in refractory metastatic breast cancers (MBCs). Core needle biopsies were collected from 32 patients with MBC at trial enrollment. Patients had received an average of 3.94 previous lines of treatment in the metastatic setting before enrollment in this study. Samples underwent MoMP, including exome sequencing, RNA sequencing (RNA‐Seq), immunohistochemistry, and quantitative protein pathway activation mapping by Reverse Phase Protein Microarray (RPPA). Clinical benefit was assessed using the previously published growth modulation index (GMI) under the hypothesis that MoMP‐selected therapy would warrant further investigation for GMI ≥ 1.3 in ≥ 35% of the patients. Of the 32 patients enrolled, 29 received treatment based on their MoMP and 25 met the follow‐up criteria established by the trial protocol. Molecular information was delivered to the tumor board in a median time frame of 14 days (11–22 days), and targetable alterations for commercially available agents were found in 23/25 patients (92%). Of the 25 patients, 14 (56%) reached GMI ≥ 1.3. A high level of DNA topoisomerase I (TOPO1) led to the selection of irinotecan‐based treatments in 48% (12/25) of the patients. A pooled analysis suggested clinical benefit in patients with high TOPO1 expression receiving irinotecan‐based regimens (GMI ≥ 1.3 in 66.7% of cases). These results confirmed previous observations that MoMP increases the frequency of identifiable actionable alterations (92% of patients). The MoMP proposed allows the identification of biomarkers that are frequently expressed in MBCs and the evaluation of their role as predictors of response to commercially available agents. Lastly, this study confirmed the role of MoMP for informing treatment selection in refractory MBC patients: more than half of the enrolled patients reached a GMI ≥ 1.3 even after multiple lines of previous therapies for metastatic disease., This prospective trial assessed the role of multi‐omic molecular profiling in informing treatment selection for metastatic breast cancer patients. Molecular profiles were collected in 14 business days and targetable alterations for commercial agents were identified in 92% of patients; 56% of patients reached a growth modulation index ≥ 1.3 after multiple lines of previous therapies. This work confirms the unique role for multi‐omic molecular profiling in guiding treatment selection for metastatic patients.

Based on the U.S. Federal Mortality Schedules from the years 1850–1880 infant deaths

The present research investigates the moderating role of the "child factor" in impression formation. 307 university students (148 males, 159 females) were asked to assess 14 traits related to physical attractiveness, resource accruing potential, and emotional stability. The stimulus person was either accompanied by a child or shown individually. As expected, targets depicted with children were believed to be more family-committed and to possess greater parenting skills. The child factor also favourably biased respondents' assessments in terms of honesty, faithfulness, and maturity. Women with children were assumed to be less ambitious, while men with children were believed to be more generous and possess higher status and financial security. All results are discussed within the greater evolutionary context of kin selection and the "good-parent process". It is hypothesized that the negative stereotyping of the voluntary childfree is a by-product of cues that infer prosocial behaviour--similar to those used in mate selection.

The observation that declines in the human secondary sex ratio (SSR) may be linked to stressful periconceptional periods has received considerable attention (Catalano [2003] Hum Reprod 18:1972–1975; Catalano et al. [2005] Int J Epidemiol 34:944–948, [2005] Hum Reprod 20:1221–1227, [2005] Paediatr Perinat Epidemiol 19:413–420). For the purpose of testing the external validity of this phenomenon, birth records from four German village genealogies (N = 1,048) were analyzed to study the impact of the French Revolutionary Wars (1787–1802) on the proportion of male births. All births were subdivided into three cohorts (prewar, 1787–1792; war, 1792–1797; and postwar, 1797–1802). Differences in SSR between cohorts achieved statistical significance (χ2 = 7.695; df = 2; P = 0.021). In addition, changes in SSR before, during, and after the wars were monitored by risk analysis. Using the SSR of the prewar period as a control, the results of the war cohort failed to achieve statistical significance (regression coefficient, −0.257; Exp(B) = 0.773; P = 0.118), while the odds reduction of 32.3% in the postwar period proved to be statistically significant (regression coefficient, −0.390; Exp(B) = 0.677; P = 0.006). It is hypothesized that the experience of postwar economic hardship (attributable to lowered food availability paired with dietary changes) represents the most likely proximate cause. The study also finds evidence of a parental sex ratio manipulation strategy meant to offset the female-biased SSR after the wars. It is argued that from an evolutionary perspective both the decline in SSR in response to stress as well as parental manipulation of the tertiary sex ratio convey reproductive advantages. Am. J. Hum. Biol. 18:806–821, 2006. © 2006 Wiley-Liss, Inc.

Recently, a method which estimates the sex of unknown skeletal remains by discriminant function analysis of the patella has received much recognition. With seven simple measurements and a sexing accuracy of almost 84% this morphometric approach would be very suitable both in the forensic and anthropological context. In order to put this method to the test, 52 unfractured and non-pathological left and right patellae (26 males, 26 females) from a prehistoric skeletal sample were analyzed. In addition, 30 patellae were randomly selected which were not part of the original reference series. The first 15 (4 males, 11 females) had the same sample origin as the 30 target specimen but were of mediocre preservational state. The second 15 belonged to an archaeological sample of different provenience (8 males, 7 females). The results of the current study indicate that the morphometric assessment of this sesamoid is indeed well-suited as the results of the previous study could be duplicated, when sample size was not taken into consideration (85%). However, when the issue of small sample size was systematically addressed via a jack-knife procedure or the calculation of Delta-value, the resultant accuracies dropped to 78 and 74%, respectively. It is suggested that two confounding factors--age and sex of the individual--may be held accountable. There are slight, whilst not statistically significant tendencies to misclassify female and older specimen.

The current surge in childlessness is often seen as an alternative lifestyle amidst growing pluralism and individualism. The results of this study indicate that several subgroups of childless women need to be differentiated: those who actively decide to forgo children in favour of other life pursuits and those who merely defer the decision. Both have accumulated a high degree of human capital in their education or career-building paths. Thus, the increase of a woman's time invested in education or career formation takes its toll on the time available for childrearing. A survey performed among female academics (N=193) brought to light that among childless women, many merely mean to postpone motherhood until their career prospects are established. Differences between those who outwardly reject motherhood and those who defer the decision can be seen in a variety of job- and career-related aspects. However, due to misconceptions about fertility, many of those who merely intended to postpone children may inevitably end up ‘involuntarily childless’. As this trend is most likely to increase in the near future, the resolution of this conflict will be an important milestone in the development of modern industrialized countries. As can be seen from this survey, financial benefits will not induce women to enter into motherhood. Rather, societal and infrastructural changes have to be brought about in order to induce women to enter into motherhood.

Marked denominational mortality differentials have been documented for various time periods and geographic locations. From a historical perspective, death rates among Catholics are often found to be higher than those among Protestants or Jews. Using a conceptual model based on the life history approach, biomedical and sociocultural factors of causation are extrapolated. In total, 5513 historical entries from family reconstitution were available. Selection of data was guided by the inclusion of information about religious affiliation. Only married couples with children as well as single mothers were considered. Of these, 1855 entries were of Roman Catholic (C), 1143 of Lutheran/Protestant (L/P), and 609 of Reformed Calvinist (R) denomination. With a focus on both adult and subadult mortality, this study attempted to document that the cultural patterns associated with religious behavior are merely proximate determinants, while the ultimate causes are biological in nature. Survival prospects depended on demographic and familial characteristics such as age-at-first-birth, spacing and stopping behavior, infant care, and targeted sibship size, rather than religiosity.

The medico-legal investigation of skeletons is a trans-disciplinary effort by forensic scientists as well as physical anthropologists. The advent of DNA extraction and amplification from bones and teeth has led to the assumption that morphological assessment of skeletal remains might soon become obsolete. But despite the introduction and success of molecular biology, the analysis of skeletal biology will remain an integral part of the identification process. This is due to the fact, that the skeletal record allows relatively fast and accurate inferences about the identity of the victim. Moreover, a standard biological profile may be established to effectively narrow the police investigator's search parameters. The following study demonstrates how skeletal biology may collaborate in the forensic investigation and support DNA fingerprinting evidence. In this case, the information gained from standard morphological methods about the unknown person's sex, age and heritage immediately led the police to suspect, that the remains were that of a young man from Vietnam, who had been missing for 2.5 years. The investigation then quickly shifted to prove the victim's identity via DNA extraction and mtDNA sequence analysis and biostatistical calculations involving questions of kinship [4].

The majority of palaeodemographic analyses shows a demonstrable deficit of female skeletons in archaeological samples. The obvious question remains, whether this is merely an artifact produced by method or sample inherent deficiencies or whether this underrepresentation of females can be attributed to past sociocultural or ethnohistoric factors. Due to the overwhelming critiques and controversies surrounding palaeodemographic studies, each sample needs to be put under close scrutiny to evaluate any such bias. Furthermore, the time frame of the sample in question - and thus the economic, social and religious conditions - need to be explored. Past living conditions may prove to hold the key of unravel this phenomenon.

SummaryBased on a 1900 census sample of 34,166 post-reproductive females (≥45 years), the birth month effect was put to the test, for both lifetime fertility as well as child survival, controlling for maternal birth cohort (1826–1835, 1836–1845, 1846–1855), Duncan's SEI, urbanity, nativity, literacy and marital duration. Testing for potential cohort effects did not indicate a temporal trend in fertility by maternal birth month (seasonal Mann-Kendall test, p=0.578), while a minute increase in offspring survival was detected (pF11, 33606=1809.0, pF538, 33606=2.2, pη2=0.40. Planned contrasts revealed that birth-month-specific differences in fertility achieved statistical significance (F11, 31798=1712.9, pF157, 3467=26.3, pF182, 10299=75.5, pF199, 19859=137.9, p

Recent advances in the methods of skeletal age estimation have rekindled interest in their applicability to paleodemography. The current study contributes to the discussion by applying several long established as well as recently developed or refined aging methods to a subsample of 121 adult skeletons from the early medieval cemetery of Lauchheim. The skeletal remains were analyzed by 13 independent observers using a variety of aging techniques (complex method and other multimethod approaches, Transition Analysis, cranial suture closure, auricular surface method, osteon density method, tooth root translucency measurement, and tooth cementum annulation counting). The age ranges and mean age estimations were compared and results indicate that all methods showed smaller age ranges for the younger individuals, but broader age ranges for the older age groups.

According to recent studies in evolutionary anthropology, firstborn daughters influence both parity progression and sibling survival by acting as so-called helpers at the nest. Based on 534 sets of household data from family reconstitution, the current analysis fails to show that offspring sex had any direct impact on maternal fertility, sibling survivorship, birth spacing, or reproductive span. Instead, the results indicate that fertility decisions were heavily affected by proximate factors such as child mortality and gender preferences. Families who had experienced child death were swift to substitute the loss with another pregnancy—a phenomenon known as replacement strategy. Similarly, a surplus of daughters acted as a strong impulse for parity progression, not because of potential helping effects but in an attempt to conceive additional sons. This is particularly apparent when the odds of grandmultiparity are considered.

Recently, a metric approach to skeletal sex determination was published by Paiva and Segre which is based on the summation of two triangular areas defined by three distinct craniometric landmarks: Porion, Mastoidale, and Asterion. According to the authors, values for the total triangle > or =1447.40 mm(2) are characteristic for male crania, while values < or =1260.36 mm(2) are indicative of female skulls (95% confidence). In order to evaluate the method's validity, two sex- and age-documented samples of different provenience were analyzed (N=197). The results show that while the indicated measurements display significant sex differences, the technique is of little practical meaning where a single individual must be independently classified. It is hypothesized that differences in the expression of sexual dimorphism as well as a population-specific variability of the asterion location undermine the value of the mastoid triangle as a sex determinant.

It has long been observed that tall people display longer life spans. The current data were employed to verify this association within the bioarchaeological context. To this end, stature and its association with age-at-death were analyzed in a pooled sample of 2,923 skeletons. Height was estimated from proxy indicators based on the maximum length of the humerus, radius, femur, and tibia. Stature estimation followed the procedure outlined by Pearson ([1899] Philos. Trans. R. Soc. Lond. [A] 192:169-244), incorporating minor modifications by Rosing ([ 1988] Handbuch der vergleichenden Biologie des Menschen; Stuttgart: Gustave Fischer, p 586-600). Individual age estimates were classified into three mutually exclusive age groups: 20-39 years (591 males, 667 females), 40-59 years (876 males, 499 females), and 60+ years (171 males, 119 females). The results document that both sexes display a statistically significant inverse relationship between adult height and age-at-death (males, P < 0.01; females, P < 0.05). Taking an epidemiological approach, the risk model implies that the estimated odds of survival beyond age 40 improve by approximately 16% for 1 SD in bone length. However, not all bones may be equally adept at displaying the association. The radius failed to support the positive association between stature and longevity, which may be indicative of a relatively greater contribution of environmental factor to radius length. Overall, the relationship between body height and longevity is not causal but coincidental: mitigated by diverse environmental factors such as nutrition, socioeconomic stressors, and disease load.

Based on a set of 2,371 family related entries dating from 1688 to 1921, the current study tried to verify longevity differentials due to interspousal age difference. For the purpose of the analysis, age-heterogamy was operationalized in terms of sample-specific marital age gap (3.2 years) with a standard deviation of 6.1 years. Based on this, five marriage groups were isolated. Female mean age at marriage experienced a slight increase over time, while the male mean at marriage decreased. This led to an appreciable narrowing of the spousal age gap. Age-homogamous unions were most prevalent in the lower socio-economic class (day-laborers, industrial workers) (p0.01). In both husband-older and wife-older unions, the interspousal gap increased with marriage order. In accord with previous studies, mean age at death varied significantly by marriage group. Females, who married younger men, died later than females, who married older men. In contrast, male longevity was most depressed within age-similar marriages, while those who married older or younger wives displayed higher life spans. Overall, marriage to a younger spouse seemed to increase longevity prospects (p0.05). These differentials were not exclusively a function of the marital age gap, but were affected by diverse confounders such as reproductive output and socio-economic status.

Family studies provide support for a modest genetic influence on offspring life span, although the magnitude of these correlations is small.The study aimed to clarify the relative contributions of parental age at birth and overall parental longevity on offspring lifespan, and to identify the biological and cultural mechanisms.Information was derived from two village genealogies (1650-1927) encompassing 9979 births (5315 males, 4664 females). Data selection was guided by the inclusion of information about parental age at birth and lifespan, offspring lifespan and cohort-specific life expectancy.Parental age at reproduction displayed a negative association with offspring survivability, which was caused by a host of biological as well as environmental factors. In contrast, parental lifespan was positively associated with offspring age at death. These effects differed by parent's and child's sex.The maternal age effect on female progeny is thought to be indicative of a preferential genetic load. From an evolutionary point of view, direct selection for maternal lifespan may be an adaptive strategy to enhance child survival prospects.

Using a conceptual model that integrates both social and biomedical factors of causation, this paper tries to delineate the pathways through which the reproductive characteristics of a multidenominational community are characterized. In total, 5513 historical entries from family reconstitution were available. Selection of data was guided by the inclusion of information about religious affiliation. Only married couples with children as well as single mothers with the relevant information were considered. Of these, 1855 entries were of Roman Catholic (C), 1143 of Lutheran/Protestant (L/P2), and 609 of Reformed Calvinist (R) denomination. The analysis documented differential nuptiality and fertility patterns, which at first glance may be interpreted along religious lines. However, the paper attempts to show that these various sociocultural patterns associated with religious behavior are merely proximate determinants, while the ultimate causes are biological in nature (i.e., differential parental age at marriage or birth, different parity progression regimes, differences in median interpregnancy interval, as well as highly variable sibship size within the denominational groups).

5523 Background: Patients with p53 wildtype head and neck squamous cell carcinoma (HNSCC) tend to be HPV-positive, which associates with better prognosis. The purpose of this study was to explore biomarker expression profiles for insight into molecular differences in HNSCC patients based on p53 status. Methods: TP53 gene sequencing using the AmpliChip p53 microarray (Roche Molecular Systems, Inc.) was attempted on 61 HNSCC patients previously tested with Caris Target Now tumor profiling service. DNA was extracted from a FFPE sample, amplified and processed on the AmpliChip p53 microarray to detect single base pair substitution and deletion mutations in exons 2 - 11 and their flanking splice sites in the TP53 gene (GenBank X54156). EGFR FISH , HER2 IHC and 22 other predictive biomarkers, e.g. TS, TOPO2A, MGMT, etc., were assayed and retrospectively analyzed. All tests were performed in a CLIA-certified lab and interpreted by board-certified pathologists or cytogeneticists. Statistical analysis was performed using SPSS (PASW statistics17) for parametric and non-parametric tests of independence. Results: 52 cases provided sufficient quality DNA for p53 analysis and results revealed a mutation rate of 25% in HNSCC patients. Interestingly, only EGFR FISH and HER2 IHC (p=.002 and p=.004, respectively) were differentially expressed in wildtype vs. mutated p53. Matched-pair analysis in the p53 mutated subgroup (n=13) showed no significant trend regarding EGFR status (p=.763) but a slight trend towards HER-2 negativity (p=.020). In the p53 wildtype subgroup (n=39), a strong association with EGFR FISH non-amplification (n=28, 71.8%, p

e21153 Background: Testing for HER2 has revolutionized the management of breast cancer and, now, gastro-esophageal junction cancer. The purpose of this study was to capture the relative frequency a...

The importance of steroid hormone receptors to the biology of breast cancer was recognized over 40 years ago. New insights into hormone receptor biology and the increasing array of proteins that can modify their function have already translated into better therapies for breast cancer. The responsiveness of a tumor to hormone therapy is an important parameter in cancer management. Besides breast cancer, other cancers also express steroid hormone receptors. Hence, the purpose of this study was to capture the relative distribution of hormone receptors in all types of cancer including breast cancer. In a total cohort of 9,491 patient samples, hormone receptors ER, PR and AR were assayed by immunohistochemistry on a Ventana platform using antibodies ER (SP 1), PR (I E 2) and AR (AR 27). The slides were read manually by pathologists using the cutoff of (>=1+ and >=10% as positive) for AR, PR and ER. Based on these cutoffs, samples were deemed positive or negative. Our preliminary observations indicate that the frequency of ER is highest in breast (40.8%), followed by ovary (25.0%), and uterus (14.9%), with marginal frequencies in lung (4.0%) and peritoneum (2.2%). The most common cancer types with negative ER expression are lung (14.7%), colon (13.3%), pancreas (10.5%), breast (9.4%) and skin (4.2%) The cancer distribution of PR mimics that of ER, albeit with a slightly lower prevalence (breast 25.5%, ovary 22.0%, uterus 13.3%, lung 5.6%, and pancreas 3.9%). The most common cancer types in which PR was negatively expressed are lung (14.0%), colon (12.6%), breast (12.2%), pancreas (9.5%) and ovary (7.6%) The frequency of AR, surprisingly, is higher in breast cancers (45.7%) as opposed to prostate cancer (5.8%). Other cancer types with overexpression of AR are ovary (18.5%), uterus (3.4%) and lung (3.0%). In contrast, low expression of AR is most often found in lung (14.3%), colon (12.0%), pancreas (9.7%), breast (9.6%), and skin (3.7%). All distributional differences by HR status were analyzed by Pearson's chi-square (χ2) test and showed statistical significance (p< 0.001). To our knowledge, this is the first study involving a large patient pool in which hormone receptors have been investigated in a single clinical laboratory with standardized IHC. Cancer is a heterogeneous disease with different molecular drivers regulating its growth, survival and response to therapy. This study shows that hormone receptors are frequently expressed in cancer types outside of breast, which merits the inclusion of therapeutic strategies using hormone therapy in such tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3152. doi:10.1158/1538-7445.AM2011-3152

HER2 overexpression occurs in approximately 15-20% of patients with breast cancer and is associated with aggressive disease and decreased survival. HER2 status is predictive of response to trastuzumab and lapatinib. Given the importance of HER2 positive disease, accurate evaluation of HER2 status is essential. The aim of this study is to provide insights into the relationship between HER2 expression by immunohistochemistry, DNA microarray and FISH in a large cohort of 1,032 Breast cancers. HER2 protein expression was determined using antibody clones (4B5) and interpreted per ASCO/CAP scoring criteria. Samples scored as equivocal (>2+;> 10% to Investigation of two-way comparisons using qualitative (categorial) outcome measure (overexpressed, underexpressed, equivocal) yielded statistically significant results but demonstrated poor kappa values, showing only moderate to slight agreement between the assays (IHC/FISH K=.096, p To conclude, our data suggest that – due to poor inter-assay agreement – Breast cancers with HER2 IHC and HER2 FISH equivocal results cannot be resolved by DNA Microarray. Protein expression by IHC is the most robust and cost effective way to test for HER2 expression when performed per ASCO/CAP guidelines and it correlates well with gene amplification by FISH. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3143. doi:10.1158/1538-7445.AM2011-3143