Two decades ago, we developed a congenic strain of Mus musculus, called b-congenic, by replacing the androgen-binding protein Abpa27a allele in the C3H/HeJ genome with the Abpa27b allele from DBA/2J. We and other researchers used this b-congenic strain and its C3H counterpart, the a-congenic strain, to test the hypothesis that, given the choice between signals from two strains with different a27 alleles on the same genetic background, test subjects would prefer the homosubspecific one. It was our purpose in undertaking this study to characterize the segment transferred from DBA to the C3H background in producing the b-congenic strain on which a role for ABPA27 in behavior has been predicated. We determined the size of the chromosome 7 segment transferred from DBA and the genes it contains that might influence preference. We found that the “functional" DBA segment is about 1% the size of the mouse haploid genome and contains at least 29 genes expressed in salivary glands, however, only three of these encode proteins identified in the mouse salivary proteome. At least two of the three genes Abpa27, Abpbg26 and Abpbg27 encoding the subunits of androgen-binding protein ABP dimers evolved under positive selection and the third one may have also. In the sense that they are subunits of the same two functional entities, the ABP dimers, we propose that their evolutionary histories might not be independent of each other.

The hypermobile Ehlers–Danlos syndrome (hEDS) GENE study is a multicenter, cohort study with the goal to identify genes associated with hypermobile EDS. Of the 148 people enrolled in the hEDS GENE study, 98 meet the 2017 hEDS criteria, 27 have a hypermobility spectrum disorder (HSD) and 23 are asymptomatic family members. More than 80% of participants are female with an average age of 41 years. Each participant has completed seven questionnaires to quantify disease‐related symptomatology. People with hypermobility experience a variety of physical and somatic symptoms, especially in the areas of fatigue, kinesiophobia, gastrointestinal, and autonomic function. These cause a significant decrease in health‐related quality of life. The frequency and severity of most symptoms were indistinguishable between participants with hEDS and HSD; however, there were significant differences in autonomic symptoms. Less than 20% of participants had autoantibodies known to be associated with dysautonomia. Subtle symptomatic differences in people meeting the 2017 diagnostic criteria suggest focusing further etiologic studies on autonomic pathways.

Background: The Arizona Cancer Registry has shown that in Pima County, AZ, breast cancer diagnosed in young Latinas increased 40% from 2004-2008, compared to 1999-2003, and Latinas more likely to die of their cancer. This study seeks to characterize genetic variation in women of Mexican ancestry with breast cancer using next generation sequencing, with the goal of providing prevalence information to help guide screening and cancer prevention efforts. Methods: The ELLA Binational Breast Cancer Study enrolled women of Mexican ancestry living in either U.S. or Mexico within 24 months of breast cancer diagnosis. Mexican women from the state of Jalisco were collected through collaboration with the Universidad de Guadalajara and women of Mexican ancestry were recruited from Tucson and Phoenix, AZ. Genomic DNA from 92 ELLA study participants (49 from the U.S. and 43 from Mexico) was enriched for breast cancer influencing gene sequence using the BROCA panel with standard techniques. Samples were sequenced with next generation sequencing and variants identified. Results: Sequencing of breast cancer risk genes in 92 Mexican and Mexican-American women with breast cancer revealed the presence of deleterious mutations in 15% of women (14/92). Five carry mutations in BRCA1, 5 in BRCA2, 2 in CHEK2, 1 in PALB2 and 1 in RAD51C. An additional 9% of participants (8/92) carry rare mutations of unknown functional consequence in the same genes. Four carry mutations in BRCA1 or BRCA2 at sites predicted to alter splice enhancers and four carry missense mutations in CHEK2 that are predicted to damage to kinase function. None of these variants appear in public databases or are characterized functionally in gene-specific databases. Dozens of women carry VUS or novel variants. Women carrying BRCA1 mutations are significantly more likely to have had triple negative pathology. Women carrying other mutations known or thought to be deleterious are also more likely to have been younger at diagnosis, to have more aggressive breast cancer or to report a family history of breast cancer. Table 1. Deleterious MutationsGeneEffectTotalBRCA1185delAG1BRCA12569delC2BRCA1Del Complete Gene1BRCA1Del Exons 9-121BRCA2c.658delGT1BRCA2c.3264insT2BRCA2c.5195delT1BRCA2c.6024insG1CHEK2R160G2PALB2S779 Stop1RAD51CDel Exons 4-91 Conclusion: Deleterious BRCA1 and BRCA2 gene mutations are common among women of Mexican ancestry diagnosed with breast cancer. Within this cohort, the prevalence of BRCA1/2 mutations is 11%, and 4% of women carry mutations in other genes increasing breast cancer risk. This is higher than the 10% mutation prevalence estimated for Ashkenazi Jewish women with breast cancer. An additional 9% of women carry variants likely to disrupt gene function and dozens of VUS and novel variants are found in these women. Further analysis of samples from the remaining 942 women using genetic sequencing will help further elucidate the role of genetic risk factors in women of Mexican ancestry with breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-07-05.

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Background: One in 8 women will develop breast cancer over the course of her lifetime, making it the most common cancer affecting women and the 2nd leading cause of cancer death. 20% of women with breast cancer have 1 or more family members who have also been diagnosed. In 25% of familial cases, cancer occurs in both the breast and ovaries and is attributable to deleterious mutations in BRCA1/BRCA2 DNA repair genes. A woman with a BRCA gene mutation has an 85% lifetime risk for developing breast cancer and 20-60% risk for ovarian cancer. The remaining 75% of susceptibility is polygenic in nature and a large number of low-penetrance genes are involved. This project builds on the discovery of new breast cancer influencing genes that interact with BRCA1 and BRCA2 to function in DNA repair. Here, we utilize next generation parallel sequencing techniques to determine if 89 genes of interest thought to play a role in breast cancer susceptibility are found in women with strong family histories of breast cancer enrolled in the University of Arizona Cancer Center High Risk Breast Cancer Genetics Clinic (UACC BCGC). Methods: The UACC BCGC is a unique and well-developed resource that is vital to the success of this translational project. The purpose of the high risk breast cancer genetics clinic is to provide cancer risk assessment and to manage surveillance and risk-reduction strategies in a cohort of high-risk women. This University of Arizona IRB-approved registry for epidemiologic and medical record information has been accruing for the past five years, and 182 subjects are currently enrolled with additional women being regularly recruited. Fifty-one (28%) of current UACC BCGC registry participants have identified BRCA1 or BRCA2 mutations and this study seeks genetic risk factors for cancer in other registry participants. The 72% of participants in the UACC BCGC database without identified BRCA mutations fall into four categories: 1) untested for BRCA mutations, 2) affected relative tests negative for deleterious BRCA mutation, 3) unaffected participant tests negative for deleterious BRCA mutation, and 4) BRCA negative participant diagnosed with breast cancer or “pre cancer”. Participants in categories 1, 2, and 4 were recruited. Genomic DNA was captured from the initial cohort of BCGC samples using Agilent Technologies HaloPlex protocols to enable additional analysis of novel custom genes of interest in addition to the University of Washington developed BROCA panel. Captured library DNA was denatured and subjected to cluster amplification on a Paired End Flow Cell in paired-end libraries with ~200 bp insert size, and sequenced on an Illumina HiSeq2000 instrument with 100 bp read lengths. Results: We expect that our preliminary analysis will show variation within these 89 genes may explain up to 50% of breast cancer risk in families with a strong pattern of breast cancer enrolled in the UACC BCGC. It is our hope that discovering the genetic risk factors at work in high risk families will help clarify individual risk and that this genetic information can be utilized to improve the management of at-risk women. Population frequency of variation is a major thrust of this project and future studies will probe penetrance. Long terms goals include expanding our recruitment of patients and their family members to allow prospective analysis to determine if these heritable mutations correlate with development of other types of cancer. Discussion: Women with strong personal and family histories of breast cancer are routinely tested for mutations in the BRCA1 and BRCA2 genes, but other gene testing is not generally available or offered. Researchers continue to study the genetic basis of the remaining familial breast cancer cases, and mutations in more than a dozen additional breast cancer risk genes have been identified. Some of these genes are highly penetrant with effect sizes similar to BRCA1 and BRCA2 (>5x increased lifetime risk), while others confer more moderate breast cancer risk (2-5x). Testing for most of these gene mutations is not yet available clinically and information in mutation status is difficult to interpret because we lack knowledge of the degree of risk conferred and/or the prevalence of these mutations in the general population. Discovering genetic risk factors at work in high risk families using our expanded panel at the UACC BCGC will help clarify individual risk and this genetic information can be utilized to improve the management of at-risk women. Identifying these patients is important because we can suggest specific cancer prevention options based on genetics. We can increase the chance of identifying cancer early and at a more treatable non-invasive stage by using intensive screening, recommending preventive medication, and/or risk reducing surgery to decrease the chance of developing invasive breast cancer in high risk individuals. Citation Format: Ateefa Chaudhury, Corina Mauss, Joanne Jeter, Christina Laukaitis. Genomic evaluation of inherited predisposition to breast cancer in women from the University of Arizona Cancer Center High Risk Breast Cancer Genetics Clinic. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A018.