FUS-P525L Juvenile Amyotrophic Lateral Sclerosis and Intellectual Disability: Evidence for Association and Oligogenic Inheritance.

Background and Objectives: Amyotrophic lateral sclerosis (ALS) is characterized by upper and lower motor neuron degeneration, with juvenile ALS (jALS) defined as disease with age at onset (AAO) before 25 years. We aimed to identify the genetic basis of 2 unrelated patients with jALS with very rapid deterioration and early age intellectual disability (ID) and to assess association of genetic findings with both phenotypes in a large cohort of patients with ALS and controls, and in the literature. Methods: Exome sequencing was performed in 2 unrelated probands and their parents. Trio analyses included de novo, rare homozygosity, and compound heterozygosity analyses. A TaqMan genotyping assay was used to genotype ALS cohorts. A systematic literature review was conducted and additional information from authors obtained to assess prevalence of fused in sarcoma (FUS)-ALS associated with ID. Results: A de novo mutation FUS-P525L was identified in both patients. Additional variations were identified in other genes related to intellectual disabilities. Among 8 additional unrelated juvenile patients, one carried the same FUS mutation and had a similar medical history of mild ID and fulminant ALS, whereas the others did not carry any FUS coding mutations and had no reported learning or intellectual disabilities (p = 0.0083). In addition, 486 patients with ALS with AAO ≥25 years were negative for this mutation. An extensive literature review showed that among all patients with FUS-related ALS with full phenotype reports, 10.3% exhibited additional learning/intellectual disabilities. Discussion: FUS-P525L mutation was identified in 3 among 10 patients with jALS (30%) in our clinical cohort, all with a very aggressive disease course and ID. Together with literature reports, these results support a novel association between mutations in FUS and early life ID. Additional variations identified in genes related to ID and brain development in our patients (GPT2, DNAH10, and SCUBE2) may suggest a complex oligogenic inheritance for this phenotype. We propose that this mutation should be screened in patients with ALS with very early AAO, aggressive disease course, and sporadic occurrence, especially when ALS is accompanied by ID.

Clinical Observation: Effect of a Second Transpositioned Variant in a Family with Autosomal Dominant Ryanodine Receptor-1-Related Disease.

Mutations in the ryanodine receptor-1 ( RYR1 ) may cause disorders inherited in an autosomal dominant/recessive fashion. Sequencing of RYR1 in an infant of Ashkenazi Jewish descent with severe hypotonia, dislocation of hip, torticollis and scoliosis, and paternal family history of autosomal dominant mild disease. The child was compound heterozygote for a missense variant c.7042G > A inherited from her father associated with autosomal dominant disease, and a missense variant of unknown significance c.5309C > T inherited from an asymptomatic mother. This case raises the possibility of a dominant disease complicated by a second variant in the other allele serving as a modifier.

Single cell dissection of plasma cell heterogeneity in symptomatic and asymptomatic myeloma.

Multiple myeloma, a plasma cell malignancy, is the second most common blood cancer. Despite extensive research, disease heterogeneity is poorly characterized, hampering efforts for early diagnosis and improved treatments. Here, we apply single cell RNA sequencing to study the heterogeneity of 40 individuals along the multiple myeloma progression spectrum, including 11 healthy controls, demonstrating high interindividual variability that can be explained by expression of known multiple myeloma drivers and additional putative factors. We identify extensive subclonal structures for 10 of 29 individuals with multiple myeloma. In asymptomatic individuals with early disease and in those with minimal residual disease post-treatment, we detect rare tumor plasma cells with molecular characteristics similar to those of active myeloma, with possible implications for personalized therapies. Single cell analysis of rare circulating tumor cells allows for accurate liquid biopsy and detection of malignant plasma cells, which reflect bone marrow disease. Our work establishes single cell RNA sequencing for dissecting blood malignancies and devising detailed molecular characterization of tumor cells in symptomatic and asymptomatic patients.

Genetic markers of Restless Legs Syndrome in Parkinson disease.

INTRODUCTION: Several studies proposed that Restless Legs Syndrome (RLS) and Parkinson disease (PD) may be clinically and/or etiologically related. To examine this hypothesis, we aimed to determine whether the known RLS genetic markers may be associated with PD risk, as well as with PD subtype. METHODS: Two case-control cohorts from Tel-Aviv and New-York, including 1133 PD patients and 867 controls were genotyped for four RLS-related SNPs in the genes MEIS1, BTBD9, PTPRD and MAP2K5/SKOR1. The association between genotype, PD risk and phenotype was tested using multivariate regression models. RESULTS: None of the tested SNPs was significantly associated with PD risk, neither in any individual cohort nor in the combined analysis after correction for multiple comparisons. The MAP2K5/SKOR1 marker rs12593813 was associated with higher frequency of tremor in the Tel-Aviv cohort (61.0% vs. 46.5%, p = 0.001, dominant model). However, the risk allele for tremor in this gene has been associated with reduced RLS risk. Moreover, this association did not replicate in Tremor-dominant PD patients from New-York. CONCLUSION: RLS genetic risk markers are not associated with increased PD risk or subtype in the current study. Together with previous genetic, neuropathological and epidemiologic studies, our results further strengthen the notion that RLS and PD are likely to be distinct entities.

Role of α5-containing nicotinic receptors in neuropathic pain and response to nicotine.

Nicotinic receptors in the central nervous system (nAChRs) are known to play important roles in pain processing and modulate behavioral responses to analgesic drugs, including nicotine. The presence of the α5-neuronal nicotinic accessory subunit in the nicotinic receptor complex is increasingly understood to modulate reward and aversive states, addiction, and possibly pathological pain. In the current study, using α5-knockout (KO) mice and subunit-specific antibodies, we assess the role of α5-containing neuronal nicotinic receptors in neuropathic pain and in the analgesic response to nicotine. After chronic constriction injury (CCI) or partial sciatic nerve ligation (PSNL), no differences in mechanical, heat, or cold hyperalgesia were found in wild-type (WT) versus α5-KO littermate mice. The number of α5-containing nAChRs was decreased (rather than increased) after CCI in the spinal cord and in the thalamus. Nevertheless, thermal analgesic response to nicotine was marginally reduced in CCI α5-KO mice at 4 days after CCI, but not at later timepoints or after PSNL. Interestingly, upon daily intermittent nicotine injections in unoperated mice, WT animals developed tolerance to nicotine-induced analgesia to a larger extent than α5-KO mice. Our results suggest that α5-containing nAChRs mediate analgesic tolerance to nicotine but do not play a major role in neuropathic pain.

Higher frequency of certain cancers in LRRK2 G2019S mutation carriers with Parkinson disease: a pooled analysis.

IMPORTANCE: Patients with Parkinson disease (PD) who harbor LRRK2 G2019S mutations may have increased risks of nonskin cancers. However, the results have been inconsistent across studies. OBJECTIVES: To analyze pooled data from 5 centers to further examine the association between LRRK2 G2019S mutation and cancer among patients with PD and to explore factors that could explain discrepancies. DESIGN, SETTING, AND PARTICIPANTS: Clinical, demographic, and genotyping data as well as cancer outcomes were pooled from 1549 patients with PD recruited across 5 movement disorders clinics located in Europe, Israel, and the United States. Associations between LRRK2 G2019S mutation and the outcomes were examined using mixed-effects logistic regression models to estimate odds ratios (ORs) and 95% CIs. Models were adjusted for age and ethnicity (Ashkenazi Jewish vs others) as fixed effects and study center as a random effect. MAIN OUTCOMES AND MEASURES: All cancers combined, nonskin cancers, smoking-related cancers, hormone-related cancers, and other types of cancer. RESULTS: The overall prevalence of the LRRK2 G2019S mutation was 11.4% among all patients with PD. Mutation carriers were younger at PD diagnosis and more likely to be women (53.1%) and of Ashkenazi Jewish descent (76.8%) in comparison with individuals who were not mutation carriers. The LRRK2 G2019S mutation carriers had statistically significant increased risks for nonskin cancers (OR, 1.62; 95% CI, 1.04-2.52), hormone-related cancers (OR, 1.87; 95% CI, 1.07-3.26) and breast cancer (OR, 2.34; 95% CI, 1.05-5.22) in comparison with noncarriers. There were no associations with other cancers. There were no major statistically significant differences in the results when the data were stratified by Ashkenazi Jewish ethnicity; however, there was some evidence of heterogeneity across centers. CONCLUSIONS AND RELEVANCE: This multinational study from 5 centers demonstrates that LRRK2 G2019S mutation carriers have an overall increased risk of cancer, especially for hormone-related cancer and breast cancer in women. Larger prospective cohorts or family-based studies investigating associations between LRRK2 mutations and cancer among patients with PD are warranted to better understand the underlying genetic susceptibility between PD and hormone-related cancers.

CHRNB3 c.-57A>G functional promoter change affects Parkinson's disease and smoking.

Cigarette smoking is protective in Parkinson's disease (PD), possibly because of nicotine action on brain nicotinic-acetylcholine receptors. The ß3 nicotinic-acetylcholine receptor subunit (encoded by CHRNB3) is depleted in the striatum of PD patients and associated with nicotine dependence. Herein, the CHRNB3 gene was sequenced, and the c.-57G allele frequency was 0.31 and 0.26 among patients (n = 596) and controls (n = 369), respectively (p = 0.02, odds ratio = 1.33, 95% confidence interval = 1.03-1.73). The c.-57G allele was strongly associated with smoking in patients, as 48.4% of c.-57G carriers compared with 32.6% of noncarriers reported smoking history (p < 0.0001). The transcription factor Oct-1 binding was almost eliminated in lymphoblasts with the c.-57G/G genotype, to only 6.5% percent, and the CHRNB3 promoter activity was reduced in cells with the c.-57G/G genotype by 96%-70%. These findings suggest that the CHRNB3 c.-57A>G alteration affects the promoter activity and is associated with PD and smoking in PD patients. It is therefore possible that nicotine may be valuable for patients who carry this alteration and beneficial in PD only for patients with specific genotypes.

Variable clinical presentation of an MUC1 mutation causing medullary cystic kidney disease type 1.

BACKGROUND AND OBJECTIVES: The genetic cause of medullary cystic kidney disease type 1 was recently identified as a cytosine insertion in the variable number of tandem repeat region of MUC1 encoding mucoprotein-1 (MUC1), a protein that is present in skin, breast, and lung tissue, the gastrointestinal tract, and the distal tubules of the kidney. The purpose of this investigation was to analyze the clinical characteristics of families and individuals with this mutation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Families with autosomal dominant interstitial kidney disease were referred for genetic analysis over a 14-year period. Families without UMOD or REN mutations prospectively underwent genotyping for the presence of the MUC1 mutation. Clinical characteristics were retrospectively evaluated in individuals with the MUC1 mutation and historically affected individuals (persons who were both related to genetically affected individuals in such a way that ensured that they could be genetically affected and had a history of CKD stage IV or kidney failure resulting in death, dialysis, or transplantation). RESULTS: Twenty-four families were identified with the MUC1 mutation. Of 186 family members undergoing MUC1 mutational analysis, the mutation was identified in 95 individuals, 91 individuals did not have the mutation, and111 individuals were identified as historically affected. Individuals with the MUC1 mutation suffered from chronic kidney failure with a widely variable age of onset of end stage kidney disease ranging from 16 to >80 years. Urinalyses revealed minimal protein and no blood. Ultrasounds of 35 individuals showed no medullary cysts. There were no clinical manifestations of the MUC1 mutation detected in the breasts, skin, respiratory system, or gastrointestinal tract. CONCLUSION: MUC1 mutation results in progressive chronic kidney failure with a bland urinary sediment. The age of onset of end stage kidney disease is highly variable, suggesting that gene-gene or gene-environment interactions contribute to phenotypic variability.

A founder mutation causing a severe methylenetetrahydrofolate reductase (MTHFR) deficiency in Bukharian Jews.

Methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive disorder. A novel homozygous MTHFR c.474A>T (p.G158G) mutation was detected in two unrelated children of Jewish Bukharian origin. This mutation generates an abnormal splicing and early termination codon. A carrier frequency of 1:39 (5/196) was determined among unrelated healthy Bukharian Jews. Given the disease severity and allele frequency, a population screening for individuals of this ancestry is warranted in order to allow prenatal, or preimplantation diagnosis.

Tnfα, Cox2 and AdipoQ adipokine gene expression levels are modulated in murine adipose tissues by both nicotine and nACh receptors containing the ß2 subunit.

Studies have provided evidences for the effects of nicotine on adipose tissues, as well as in inflammatory response. We hypothesized that nicotine affects adipokine gene expression in adipose tissues via specific neuronal nicotinic acetylcholine receptors (nAChRs). First, we described the expression of multiple nAChR subunit genes in mouse white and brown adipose tissues (WAT and BAT), and detected differential expression in WAT and BAT (α2>α5>ß2 and α2>ß2>ß4, respectively). Additionally, when nicotine was administered to wild-type mice, it significantly affected the expression of adipokine genes, such as Tnfα, AdipoQ, Haptoglobin and Mcp1 in WAT. Next, we demonstrated that in mice deficient for the ß2 nAChR subunit (ß2-/- mice), the expression levels of Cox2 and Ngfß genes in WAT, and Leptin, Cox2, AdipoQ and Haptoglobin in BAT, were significantly altered. Furthermore, interactions between mouse ß2 subunit and nicotine treatment affected the expression levels of the adipokine genes Tnfα, Cox2 and AdipoQ in WAT and of AdipoQ in BAT. Finally, analysis of a cellular model of cultured adipocytes demonstrated that application of nicotine after silencing of the ß2 nAChR subunit significantly elevated the expression level of Cox2 gene. Together, our data suggest a molecular link between the ß2 nACh receptor subunit and the expression levels of specific adipokines, which is also affected by nicotine.

HIF1A C1772T polymorphism leads to HIF-1α mRNA overexpression in prostate cancer patients.

Hypoxia-inducible factor 1α (HIF-1α) gene polymorphisms have been investigated for a possible role in mediating genetic predisposition to cancer. Our previous data show that men homozygous to C1772T polymorphism had 4-fold risk to develop prostate cancer. Therefore, we studied the effects of C1772T polymorphism on HIF-1α expression. HIF-1α mRNA expression levels were significantly higher in peripheral blood leukocytes of prostate cancer patients with the TT genotype compared with the CC genotype. Expression of C1772T HIF-1α in HIF-1α knockout cancer cells showed higher expression levels and stabilization of HIF-1α mRNA compared with the wild-type. Mutated HIF-1α protein half-life was similar to that of the wild-type. Hence, our data provide evidence that C1772T polymorphism causes activation of HIF-1α as a gain-of-function mechanism driven by stabilization of HIF-1α mRNA. These findings may also explain the increased risk of men homozygous to this mutation to develop prostate cancer.

Sperm epidermal growth factor receptor (EGFR) mediates α7 acetylcholine receptor (AChR) activation to promote fertilization.

To attain fertilization the spermatozoon binds to the egg zona pellucida (ZP) via sperm receptor(s) and undergoes an acrosome reaction (AR). Several sperm receptors have been described in the literature; however, the identity of this receptor is not yet certain. In this study, we suggest that the α7 nicotinic acetylcholine receptor (α7nAChR) might be a sperm receptor activated by ZP to induce epidermal growth factor receptor (EGFR)-mediated AR. We found that isolated ZP or α7 agonists induced the AR in sperm from WT but not α7-null spermatozoa, and the induced AR was inhibited by α7 or EGFR antagonists. Moreover, α7-null sperm showed very little binding to the egg, and microfluidic affinity in vitro assay clearly showed that α7nAChR, as well as EGFR, interacted with ZP3. Induction of EGFR activation and the AR by an α7 agonist was inhibited by a Src family kinase (SFK) inhibitor. In conclusion we suggest that activation of α7 by ZP leads to SFK-dependent EGFR activation, Ca(2+) influx, and the acrosome reaction.

A genome-wide scan of Ashkenazi Jewish Crohn's disease suggests novel susceptibility loci.

Crohn's disease (CD) is a complex disorder resulting from the interaction of intestinal microbiota with the host immune system in genetically susceptible individuals. The largest meta-analysis of genome-wide association to date identified 71 CD-susceptibility loci in individuals of European ancestry. An important epidemiological feature of CD is that it is 2-4 times more prevalent among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Europeans (NJ). To explore genetic variation associated with CD in AJs, we conducted a genome-wide association study (GWAS) by combining raw genotype data across 10 AJ cohorts consisting of 907 cases and 2,345 controls in the discovery stage, followed up by a replication study in 971 cases and 2,124 controls. We confirmed genome-wide significant associations of 9 known CD loci in AJs and replicated 3 additional loci with strong signal (p<5×10⁻6). Novel signals detected among AJs were mapped to chromosomes 5q21.1 (rs7705924, combined p = 2×10⁻8; combined odds ratio OR = 1.48), 2p15 (rs6545946, p = 7×10⁻9; OR = 1.16), 8q21.11 (rs12677663, p = 2×10⁻8; OR = 1.15), 10q26.3 (rs10734105, p = 3×10⁻8; OR = 1.27), and 11q12.1 (rs11229030, p = 8×10⁻9; OR = 1.15), implicating biologically plausible candidate genes, including RPL7, CPAMD8, PRG2, and PRG3. In all, the 16 replicated and newly discovered loci, in addition to the three coding NOD2 variants, accounted for 11.2% of the total genetic variance for CD risk in the AJ population. This study demonstrates the complementary value of genetic studies in the Ashkenazim.

Predictive value of TP53 fluorescence in situ hybridization in cytogenetic subgroups of acute myeloid leukemia.

Acute myeloid leukemia (AML) with a complex karyotype (CK) has frequent alterations in TP53 and a very poor prognosis. We examined whether a prompt and simple fluorescence in situ hybridization (FISH) analysis for 17p13 deletion at diagnosis has a predictive value for response to therapy and overall survival in subgroups of AML. In 15 patients with a normal karyotype the TP53 FISH analysis was normal, whereas in 16 patients with CK 75% had only one copy of the TP53 allele. The deletion was also detected in 33% of six patients with monosomy or partial monosomy of chromosome 5, 7, 9, or 12. This loss of TP53 correlated significantly with a poor response to chemotherapy, and the median survival time of these patients was shorter. TP53 FISH analysis carried out at diagnosis has a predictive value with respect to chemotherapy response and can therefore facilitate a rapid decision on treatment strategies.

Large-scale population screening for spinal muscular atrophy: clinical implications.

PURPOSE: To determine the frequency of SMN1 deletion carriers in the Israeli population and to assess the feasibility of population screening for spinal muscular atrophy. METHODS: A total of 6394 individuals without family history of spinal muscular atrophy underwent genetic screening by multiplex ligation-dependent probe amplification, designed to detect SMN1 exon 7 and exon 8 copy number. RESULTS: One hundred fifty-nine individuals carried an SMN1 heterozygous exon 7 deletion, yielding a carrier frequency of 1:40. About 10.8% of individuals were found to carry two or more SMN1 exon 7 copies on the same chromosome (cis configuration). This implies that some deletion carriers may not be detected by multiplex ligation-dependent probe amplification or similar quantitative methods. The acceptance of spinal muscular atrophy screening among women undergoing testing for fragile X syndrome and cystic fibrosis reached 93%. CONCLUSIONS: Currently used molecular techniques cannot detect about 5% of spinal muscular atrophy carriers with a cis configuration or individuals with SMN1 sequence mutations and de novo deletions. Thus, it is estimated that the spinal muscular atrophy carrier detection rate is about 90%. Given the severity of spinal muscular atrophy, the relatively high carrier frequency, and the estimated detection rate, we conclude that population-based screening for spinal muscular atrophy is feasible and acceptable.

Activation of the cholinergic anti-inflammatory system by nicotine attenuates neuroinflammation via suppression of Th1 and Th17 responses.

The alpha7 nicotinic acetylcholine receptor (nAChR) was recently described as an anti-inflammatory target in both macrophages and T cells. Its expression by immune cells may explain the epidemiological data claiming a negative link between cigarette smoking and several inflammatory diseases. In this study, we determined the immunological effects of alpha7 nAChR activation by nicotine. Our results indicate that the alpha7 nAChR is expressed on the surface of CD4(+) T cells and that this expression is up-regulated upon immune activation. Nicotine reduced T cell proliferation in response to an encephalitogenic Ag, as well as the production of Th1 (TNF-alpha and IFN-gamma) and Th17 cytokines (IL-17, IL-17F, IL-21, and IL-22). IL-4 production was increased in the same setting. Attenuation of the Th1 and Th17 lineages was accompanied by reduced T-bet (50%) and increased GATA-3 (350%) expression. Overall, nicotine induced a shift to the Th2 lineage. However, alpha7(-/-)-derived T cells were unaffected by nicotine. Furthermore, nicotine reduced NF-kappaB-mediated transcription as measured by IL-2 and IkappaB transcription. In vivo, administration of nicotine (2 mg/kg s.c.) suppressed the severity of CD4(+) T cell-mediated disease experimental autoimmune encephalomyelitis. alpha7(-/-) mice were refractory to nicotine treatment, although disease severity in those animals was reduced, due to impairment in Ag presentation. Accordingly, CD4(+) and CD11b(+) cells infiltration into the CNS, demyelination, and axonal loss were reduced. Our data implicate a role for the alpha7 nAChR in immune modulation and suggest that alpha7 nAChR agonists may be effective in the treatment of inflammatory disorders.

Interspecies comparison of prostate cancer gene-expression profiles reveals genes associated with aggressive tumors.

Prostate cancer (PC) is a heterogeneous disease whose aggressive phenotype is the second leading cause of cancer-related death in men. The identification of key molecules and pathways that play a pivotal role in PC progression towards an aggressive form is crucial. A major effort towards this end has been taken by global analyses of gene expression profiles. However, the large body of data did not provide a definitive idea about the genes which are associated with the aggressive growth of PC. In order to identify such genes, we performed an interspecies comparison between several human data sets and high quality microarray data that we generated from the transgenic adenocarcinoma of mouse prostate (TRAMP) strain. The TRAMP PC mimics the histological and pathological appearance as well as the aggressive phenotype of human PC (huPC). Analysis of the microarray data, derived from microdissected TRAMP specimens removed at different stages of the disease yielded genetic signatures delineating the TRAMP PC development and progression. Comparison of the TRAMP data with a set of genes representing the core expression signature of huPC yielded a limited set genes. Some of these genes are known predictors of poor prognosis in huPC. Interestingly, the modulation of genes responsible for the invasive phenotype of huPC occurs in TRAMP already during the transition to prostate intraepithelial neoplasia (PIN) and onwards to localized tumors. We therefore suggest that critical oncogenic events leading to an aggressive phenotype of huPC can be studied in the PIN stage of TRAMP.

Dynamic modification strategy of the Israeli carrier screening protocol: inclusion of the Oriental Jewish Group to the cystic fibrosis panel.

PURPOSE: A retrospective population study was conducted to determine the carrier frequencies of recently identified mutations in Oriental Jewish cystic fibrosis patients. METHODS: Data were collected from 10 medical centers that screened the following mutations: two splice site mutations-3121-1G>A and 2751 + 1insT-and one nonsense mutation-the Y1092X in Iraqi Jews. One missense mutation, I1234V, was screened in Yemenite Jews. RESULTS: A total of 2499 Iraqi Jews were tested for one, two, or all three mutations. The 3121-1G>A, Y1092X, and 2751 + 1insT mutations had a carrier frequency of 1:68.5, 1:435, and 0, respectively. In 1435 Yemenite Jews screened, I1234V had a carrier frequency of 1:130. CONCLUSION: The 0.84% allele frequency of the three Iraqi founder mutations falls within the Israeli Society of Medical Geneticists' inclusion criteria for screening of 1:60 carrier frequency; hence, Iraqi Jews were added to the carrier screening policy with a panel including the three Iraqi founder mutations in addition to the five Ashkenazi mutations previously detected in Eastern Jews. 2751 + 1insT that was detected in patients only was included in the screening panel to increase the detection rate. I1234V does not meet the inclusion criteria but is now offered on a diagnostic basis and can be added to the screening panel for individuals whose mixed origin includes Yemenite, in addition to protocol-recommended origins. This study demonstrates the dynamic modifications of the Israeli carrier cystic fibrosis screening protocol based on newly detected founder mutations in a large cohort, taking into account mutation impact and intercommunal admixture.

Being 'at-risk' for developing cancer: cognitive representations and psychological outcomes.

This study investigated cognitive representations and psychological effects of being 'at-risk' for cancer. Perceived personal risk for cancer and causal attributions for cancer were measured in four groups: women identified as carriers of mutations in breast/ovarian cancer genes BRCA1 BRCA2, habitual smokers, X-ray technicians, and an average-risk group. Despite differences in awareness of their risk status and perceived risk for cancer, the groups did not differ in health anxiety, cancer worry interference, and self-assessed health. Motivated reasoning processes were identified as potential strategies used by individuals at-risk to regulate levels of psychological distress. Evidence for biased risk perceptions and unrealistic optimism were found among smokers, and patterns indicative of self-enhancement through self-assessments and defensive discounting of cancer causal attributions were found in the genetically susceptible group. These findings highlight the role of cognitive representations in adjustment to being at-risk for cancer.