Development of a Multivariable Model to Predict the Need for Bone Marrow Sampling in Persons With Monoclonal Gammopathy of Undetermined Significance : A Cohort Study Nested in a Clinical Trial.

BACKGROUND: Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic precursor conditions to multiple myeloma and related disorders. Smoldering multiple myeloma is distinguished from MGUS by 10% or greater bone marrow plasma cells (BMPC) on sampling, has a higher risk for progression, and requires specialist management. OBJECTIVE: To develop a multivariable prediction model that predicts the probability that a person with presumed MGUS has 10% or greater BMPC (SMM or worse by bone marrow criteria) to inform the decision to obtain a bone marrow sample and compare its performance to the Mayo Clinic risk stratification model. DESIGN: iStopMM (Iceland Screens, Treats or Prevents Multiple Myeloma), a prospective population-based screening study of MGUS. (ClinicalTrials.gov: NCT03327597). SETTING: Icelandic population of adults aged 40 years or older. PATIENTS: 1043 persons with IgG, IgA, light-chain, and biclonal MGUS detected by screening and an interpretable bone marrow sample. MEASUREMENTS: Monoclonal gammopathy of undetermined significance isotype; monoclonal protein concentration; free light-chain ratio; and total IgG, IgM, and IgA concentrations were used as predictors. Bone marrow plasma cells were categorized as 0% to 4%, 5% to 9%, 10% to 14%, or 15% or greater. RESULTS: The c-statistic for SMM or worse was 0.85 (95% CI, 0.82 to 0.88), and calibration was excellent (intercept, -0.07; slope, 0.95). At a threshold of 10% predicted risk for SMM or worse, sensitivity was 86%, specificity was 67%, positive predictive value was 32%, and negative predictive value was 96%. Compared with the Mayo Clinic model, the net benefit for the decision to refer for sampling was between 0.13 and 0.30 higher over a range of plausible low-risk thresholds. LIMITATION: The prediction model will require external validation. CONCLUSION: This accurate prediction model for SMM or worse was developed in a population-based cohort of persons with presumed MGUS and may be used to defer bone marrow sampling and referral to hematology. PRIMARY FUNDING SOURCE: International Myeloma Foundation and the European Research Council.

Association Between Autoimmune Diseases and Monoclonal Gammopathy of Undetermined Significance : An Analysis From a Population-Based Screening Study.

BACKGROUND: Monoclonal gammopathy of undetermined significance (MGUS) is a precursor of multiple myeloma (MM) and related conditions. In previous registry-based, retrospective studies, autoimmune diseases have been associated with MGUS. However, these studies were not based on a screened population and are therefore prone to ascertainment bias. OBJECTIVE: To examine whether MGUS is associated with autoimmune diseases. DESIGN: A cross-sectional study within iStopMM (Iceland Screens, Treats, or Prevents MM), a prospective, population-based screening study of MGUS. SETTING: Icelandic population of adults aged 40 years or older. PATIENTS: 75 422 persons screened for MGUS. MEASUREMENTS: Poisson regression for prevalence ratios (PRs) of MGUS among persons with or without an autoimmune disease, adjusted for age and sex. RESULTS: A total of 10 818 participants had an autoimmune disorder, of whom 599 had MGUS (61 with a prior clinical diagnosis and 538 diagnosed at study screening or evaluation). A diagnosis of an autoimmune disease was not associated with MGUS (PR, 1.05 [95% CI, 0.97 to 1.15]). However, autoimmune disease diagnoses were associated with a prior clinical diagnosis of MGUS (PR, 2.11 [CI, 1.64 to 2.70]). LIMITATION: Registry data were used to gather information on autoimmune diseases, and the homogeneity of the Icelandic population may limit the generalizability of these results. CONCLUSION: The study did not find an association between autoimmune disease and MGUS in a systematically screened population. Previous studies not done in systematically screened populations have likely been subject to ascertainment bias. The findings indicate that recommendations to routinely screen patients with autoimmune disease for MGUS may not be warranted. PRIMARY FUNDING SOURCE: The International Myeloma Foundation and the European Research Council.

Prior cancer and risk of monoclonal gammopathy of undetermined significance: a population-based study in Iceland and Sweden.

There is some evidence that a prior cancer is a risk factor for the development of multiple myeloma (MM). If this is true, prior cancer should be associated with a higher prevalence or increased progression rate of monoclonal gammopathy of undetermined significance (MGUS), the precursor of MM and related disorders. Those with a history of cancer might therefore constitute a target population for MGUS screening. This two-part study is the first study to evaluate a relationship between MGUS and prior cancers. First, we evaluated whether prior cancers were associated with having MGUS at the time of screening in the Iceland Screens Treats or Prevents Multiple Myeloma (iStopMM) study that includes 75,422 individuals screened for MGUS. Next, we evaluated the association of prior cancer and the progression of MGUS to MM and related disorders in a population-based cohort of 13,790 Swedish individuals with MGUS. A history of prior cancer was associated with a modest increase in the risk of MGUS (odds ratio=1.10; 95% confidence interval: 1.00-1.20). This excess risk was limited to prior cancers in the year preceding MGUS screening. A history of prior cancer was associated with progression of MGUS, except for myeloid malignancies which were associated with a lower risk of progression (hazard ratio=0.37; 95% confidence interval: 0.16-0.89; P=0.028). Our findings indicate that a prior cancer is not a significant etiological factor in plasma cell disorders. The findings do not warrant MGUS screening or different management of MGUS in those with a prior cancer.

Histopathology and levels of proteins in plasma associate with survival after colorectal cancer diagnosis.

BACKGROUND: The TNM system is used to assess prognosis after colorectal cancer (CRC) diagnosis. Other prognostic factors reported include histopathological assessments of the tumour, tumour mutations and proteins in the blood. As some of these factors are strongly correlated, it is important to evaluate the independent effects they may have on survival. METHODS: Tumour samples from 2162 CRC patients were visually assessed for amount of tumour stroma, severity of lymphocytic infiltrate at the tumour margins and the presence of lymphoid follicles. Somatic mutations in the tumour were assessed for 2134 individuals. Pre-surgical levels of 4963 plasma proteins were measured in 128 individuals. The associations between these features and prognosis were inspected by a Cox Proportional Hazards Model (CPH). RESULTS: Levels of stroma, lymphocytic infiltration and presence of lymphoid follicles all associate with prognosis, along with high tumour mutation burden, high microsatellite instability and TP53 and BRAF mutations. The somatic mutations are correlated with the histopathology and none of the somatic mutations associate with survival in a multivariate analysis. Amount of stroma and lymphocytic infiltration associate with local invasion of tumours. Elevated levels of two plasma proteins, CA-125 and PPP1R1A, associate with a worse prognosis. CONCLUSIONS: Tumour stroma and lymphocytic infiltration variables are strongly associated with prognosis of CRC and capture the prognostic effects of tumour mutation status. CA-125 and PPP1R1A may be useful prognostic biomarkers in CRC.

Immunohistochemical staining seems mandatory for individualizing and shortening follow-up in unilateral primary aldosteronism.

OBJECTIVE: The clinical significance of immunohistochemistry (IHC) for unilateral primary aldosteronism (PA) has been unclear. Individualized follow-up of PA patients could be in sight. Long-term outcomes of patients, classified based on IHC, need further investigation. We aimed to assess long-term clinical outcomes for unilateral PA, classifying patients based on IHC. DESIGN: A nationwide observational study, with up to 16 years follow-up, executed in 2007-2016 at Landspitali University Hospital, tertiary referral center. Patients were diagnosed and treated in line with the current guidelines. Haematoxylin and eosin (H&E) tissue slides were stained using CYP11B1 and -B2 antibodies. All cases were re-evaluated and classified according to the HISTALDO consensus. Outcomes were assessed using the PASO criteria. PATIENTS: All unilateral PA patients diagnosed in 2007-2016 in Iceland, 26 patients aged 28-73 years, who underwent adrenalectomy, were included. MEASUREMENTS: Aldosterone, renin, and cortisol values, use and dosage of antihypertensives, potassium supplementation, blood pressure and serum potassium pre-intervention and throughout follow-up, and histopathology results post-adrenalectomy. RESULTS: Following IHC, an aldosterone-producing nodule was seen in 12 adrenals, an aldosterone-producing adenoma in 10 and multiple aldosterone-producing micronodules in four. IHC altered histopathology from previous H&E diagnosis in 23% (6/26) of the patients. In total, 81% (21/26) of the patients had partial clinical success. Eight percent (2/26) of the patients needed potassium supplementation during follow-up. In the classical group, the AVS results were more determinative with significantly higher lateralization index (median 10.1 vs. 5.3, p = .04) and more contralateral suppression (median nondominant ratio 0.4 vs. 1.0, p = .03). One out of five patients with complete clinical success at 12 months post-op had severe relapse later, the other four were normotensive without antihypertensives for up to 10 years. CONCLUSIONS: We found IHC mandatory for accurate histopathologic diagnosis of PA. Our results support the importance of contralateral suppression when interpreting AVS results. Also, the study highlights the complicated assessment of clinical outcome and importance of aldosterone and renin measurements during follow-up.

Disease associations with monoclonal gammopathy of undetermined significance can only be evaluated using screened cohorts: results from the population-based iStopMM study.

Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic precursor condition that precedes multiple myeloma and related disorders but has also been associated with other medical conditions. Since systematic screening is not recommended, MGUS is typically diagnosed due to underlying diseases and most cases are not diagnosed. Most previous studies on MGUS disease associations have been based on clinical cohorts, possibly resulting in selection bias. Here we estimate this selection bias by comparing clinically diagnosed and screened individuals with MGUS with regards to demographics, laboratory features, and comorbidities. A total of 75,422 participants in the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study were screened for MGUS by serum protein electrophoresis, immunofixation and free light chain assay (clinicaltrials gov. Identifier: NCT03327597). We identified 3,352 individuals with MGUS, whereof 240 had previously been clinically diagnosed (clinical MGUS), and crosslinked our data with large, nationwide registries for information on comorbidities. Those with clinical MGUS were more likely to have at least one comorbidity (odds ratio=2.24; 95% confidence interval: 1.30-4.19), and on average had more comorbidities than the screened MGUS group (3.23 vs. 2.36, mean difference 0.68; 95% confidence interval: 0.46-0.90). They were also more likely to have rheumatological disease, neurological disease, chronic kidney disease, liver disease, heart failure, or endocrine disorders. These findings indicate that individuals with clinical MGUS have more comorbidities than the general MGUS population and that previous studies have been affected by significant selection bias. Our findings highlight the importance of screening data when studying biological and epidemiological implications of MGUS.

Keratinocytes secrete multiple inflammatory and immune biomarkers, which are regulated by LL-37, in a psoriasis mimicking microenvironment.

Psoriasis is an autoimmune disease driven by a Th17 response linked to the antimicrobial peptide (AMP) LL-37 that has been connected to the induction and chronicity of psoriasis. We show that keratinocytes secrete various immune biomarkers with a direct link to psoriasis immunopathogenesis. Under pro-inflammatory microenvironmental conditions, LL-37 was found to regulate keratinocyte secretion of various immune biomarkers (eg C-X-C motif chemokine ligand (CXCL)8 and interleukin (IL)-1ß) and alter extracellular signal-regulated kinase (ERK)1/2 signalling. However, during neutral conditions LL-37 induced a different pattern of keratinocyte immune biomarker secretion (eg vascular endothelial growth factor, CXCL8 and IL-6). Thus, an interesting pattern emerged regarding the immunomodulatory effects of LL-37 on keratinocytes; in general, expression of immune biomarkers that were upregulated in a Th1-like microenvironment was downregulated in the presence of LL-37. In contrast, LL-37 reinforced the Th17 response. In active psoriatic skin lesions, LL-37 expression was found to be significantly upregulated, which was also evident from the unique diffuse epidermic expression pattern not found in healthy skin. Finally, successful phototherapy of psoriasis patients converted this LL-37 inflammatory psoriatic skin pattern into a more localized basal layer expression as found in healthy controls. Thus, these findings demonstrate that LL-37 has a significant role in skin immune homeostasis and that its interplay with keratinocytes may have a more direct role in the immunopathogenesis of psoriasis than previously thought.

[Comparison of diagnosis and treatment of invasive breast cancer between Iceland and Sweden].

PURPOSE: As part of the implementation of quality registration in Iceland we used retrospective data to compare diagnosis and treatment of invasive breast cancer between Iceland and Sweden. MATERIALS AND METHODS: Information on all patients diagnosed with invasive breast cancer in Iceland 2016-2017 was obtained from the Icelandic Cancer Registry. Hospital records were used to register variables in an electronic form adapted from the Swedish quality registration, and compared with data from Sweden for the same period. A chi-square test was used to compare ratios. RESULTS: A total of 486 cases of breast cancer were diagnosed in Iceland and 15.325 in Sweden. A lower proportion of 40-69 year old women were diagnosed within the screening programme in Iceland (46%) compared to Sweden (60%) (p<0.01). Multidisciplinary tumor board meetings held before and after surgery were less frequent in Iceland (92% vs. 96%) compared to Sweden (98% vs. 99%) in 2016 (p<0,01) but no difference was seen in 2017. A sentinel node surgery was done in 69% of the cases in Iceland compared to 94% in Sweden (p<0,01). For cancers ≤30mm breast conserving surgery was done in 48% cases in Iceland but 80% in Sweden (p<0,01). In Iceland 87% of the cases had radiation therapy after breast conserving surgery but 94% in Sweden (p<0,01). Among mastectomy patients with lymph node metastases, 49% received radiation therapy in Iceland compared to 83% in Sweden (p<0,01). CONCLUSION: Differences were seen in several areas of diagnosis and treatment of invasive breast cancer between Iceland and Sweden. With quality registration it will be possible to monitor and set goals for the diagnosis and treatment, with the aim of providing the best treatment to as many patients as possible.

Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers.

BACKGROUND: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown. METHODS: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models. RESULTS: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94-1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85-1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06-1.48) and HR = 1.59 (95% CI: 1.08-2.33) per 5-kg/m2 increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (Pinteraction < 0.05). CONCLUSION: Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population.

Insertion of an SVA-E retrotransposon into the CASP8 gene is associated with protection against prostate cancer.

Transcriptional and splicing anomalies have been observed in intron 8 of the CASP8 gene (encoding procaspase-8) in association with cutaneous basal-cell carcinoma (BCC) and linked to a germline SNP rs700635. Here, we show that the rs700635[C] allele, which is associated with increased risk of BCC and breast cancer, is protective against prostate cancer [odds ratio (OR) = 0.91, P = 1.0 × 10(-6)]. rs700635[C] is also associated with failures to correctly splice out CASP8 intron 8 in breast and prostate tumours and in corresponding normal tissues. Investigation of rs700635[C] carriers revealed that they have a human-specific short interspersed element-variable number of tandem repeat-Alu (SINE-VNTR-Alu), subfamily-E retrotransposon (SVA-E) inserted into CASP8 intron 8. The SVA-E shows evidence of prior activity, because it has transduced some CASP8 sequences during subsequent retrotransposition events. Whole-genome sequence (WGS) data were used to tag the SVA-E with a surrogate SNP rs1035142[T] (r(2) = 0.999), which showed associations with both the splicing anomalies (P = 6.5 × 10(-32)) and with protection against prostate cancer (OR = 0.91, P = 3.8 × 10(-7)).

Oestrogen receptor status, treatment and breast cancer prognosis in Icelandic BRCA2 mutation carriers.

BACKGROUND: The impact of an inherited BRCA2 mutation on the prognosis of women with breast cancer has not been well documented. We studied the effects of oestrogen receptor (ER) status, other prognostic factors and treatments on survival in a large cohort of BRCA2 mutation carriers. METHODS: We identified 285 breast cancer patients with a 999del5 BRCA2 mutation and matched them with 570 non-carrier patients. Clinical information was abstracted from patient charts and pathology records and supplemented by evaluation of tumour grade and ER status using archived tissue specimens. Univariate and multivariate hazard ratios (HR) were estimated for breast cancer-specific survival using Cox regression. The effects of various therapies were studied in patients treated from 1980 to 2012. RESULTS: Among mutation carriers, positive ER status was associated with higher risk of death than negative ER status (HR=1.94; 95% CI=1.22-3.07, P=0.005). The reverse association was seen for non-carriers (HR=0.71; 95% CI: 0.51-0.97; P=0.03). CONCLUSIONS: Among BRCA2 carriers, ER-positive status is an adverse prognostic factor. BRCA2 carrier status should be known at the time when treatment decisions are made.

No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer.

OBJECTIVE: Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3' UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. METHODS: Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). RESULTS: We found no association with risk of ovarian cancer (OR=0.99, 95% CI 0.94-1.04, p=0.74) or breast cancer (OR=0.98, 95% CI 0.94-1.01, p=0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR=1.09, 95% CI 0.97-1.23, p=0.14, breast cancer HR=1.04, 95% CI 0.97-1.12, p=0.27; BRCA2, ovarian cancer HR=0.89, 95% CI 0.71-1.13, p=0.34, breast cancer HR=1.06, 95% CI 0.94-1.19, p=0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR=0.94, 95% CI 0.83-1.07, p=0.38), breast cancer (HR=0.96, 95% CI 0.87-1.06, p=0.38), and all other previously-reported associations. CONCLUSIONS: rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.

Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes.

We performed a genome-wide association scan to search for sequence variants conferring risk of prostate cancer using 1,501 Icelandic men with prostate cancer and 11,290 controls. Follow-up studies involving three additional case-control groups replicated an association of two variants on chromosome 17 with the disease. These two variants, 33 Mb apart, fall within a region previously implicated by family-based linkage studies on prostate cancer. The risks conferred by these variants are moderate individually (allele odds ratio of about 1.20), but because they are common, their joint population attributable risk is substantial. One of the variants is in TCF2 (HNF1beta), a gene known to be mutated in individuals with maturity-onset diabetes of the young type 5. Results from eight case-control groups, including one West African and one Chinese, demonstrate that this variant confers protection against type 2 diabetes.

Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24.

Prostate cancer is the most prevalent noncutaneous cancer in males in developed regions, with African American men having among the highest worldwide incidence and mortality rates. Here we report a second genetic variant in the 8q24 region that, in conjunction with another variant we recently discovered, accounts for about 11%-13% of prostate cancer cases in individuals of European descent and 31% of cases in African Americans. We made the current discovery through a genome-wide association scan of 1,453 affected Icelandic individuals and 3,064 controls using the Illumina HumanHap300 BeadChip followed by four replication studies. A key step in the discovery was the construction of a 14-SNP haplotype that efficiently tags a relatively uncommon (2%-4%) susceptibility variant in individuals of European descent that happens to be very common (approximately 42%) in African Americans. The newly identified variant shows a stronger association with affected individuals who have an earlier age at diagnosis.

A common variant associated with prostate cancer in European and African populations.

With the increasing incidence of prostate cancer, identifying common genetic variants that confer risk of the disease is important. Here we report such a variant on chromosome 8q24, a region initially identified through a study of Icelandic families. Allele -8 of the microsatellite DG8S737 was associated with prostate cancer in three case-control series of European ancestry from Iceland, Sweden and the US. The estimated odds ratio (OR) of the allele is 1.62 (P = 2.7 x 10(-11)). About 19% of affected men and 13% of the general population carry at least one copy, yielding a population attributable risk (PAR) of approximately 8%. The association was also replicated in an African American case-control group with a similar OR, in which 41% of affected individuals and 30% of the population are carriers. This leads to a greater estimated PAR (16%) that may contribute to higher incidence of prostate cancer in African American men than in men of European ancestry.

Psoriasis treatment: faster and long-standing results after bathing in geothermal seawater. A randomized trial of three UVB phototherapy regimens.

BACKGROUND: The combination of seawater baths and narrowband ultraviolet B (NB-UVB) is a known treatment for psoriasis. This study evaluates two treatment regimens that combine bathing in geothermal seawater and NB-UVB therapy in comparison with NB-UVB monotherapy. METHODS: Sixty-eight psoriasis patients were randomly assigned to outpatient bathing in geothermal seawater combined with NB-UVB therapy three times a week, intensive daily treatment involving bathing in geothermal seawater combined with NB-UVB therapy, or NB-UVB therapy alone three times a week; treatment period was 6 weeks. Disease severity [Psoriasis Area Severity Index (PASI) and Lattice System Physician's Global Assessment scores], quality of life (Dermatology Life Quality Index) and histological changes were evaluated before, during and after treatment. The primary end point was the proportion of patients who achieved PASI 75 at 6 weeks. RESULTS: At 6 weeks, the percentage of patients who achieved PASI 75 and PASI 90 was significantly greater for both regimens, bathing in geothermal seawater three times a week (68.1% and 18.2%, respectively) and intensive treatment with geothermal seawater (73.1% and 42.3%, respectively) than for NB-UVB monotherapy (16.7% and 0%, respectively) (P < 0.05 in all comparisons). Clinical improvement was paralleled by improvement in quality of life and histological score and a reduction in NB-UVB doses. CONCLUSION: Bathing in geothermal seawater combined with NB-UVB therapy in psoriasis induces faster clinical and histological improvement, produces longer remission time and permits lower NB-UVB doses than UVB therapy alone.

A Breast Cancer Candidate Locus at 6q Narrowed to 6q15-q21.

Although a number of high-risk breast cancer genes have been identified, including BRCA1 and BRCA2, the risk profile of many high-risk families cannot be explained using known breast cancer genes. Previously, we have shown strong indications of new breast cancer risk loci at chromosomes 2p, 6q, and 14q in a family of six generations including 10 breast cancer cases. In this study, we identified and traced four new family branches descending from siblings of the parents in the top generation of the studied family. One distantly related branch included four breast cancer cases, two of whom were diagnosed at age < 45 years. DNA samples from the cases were typed at selected polymorphic markers from all three chromosome loci, to test identical origin of the haplotypes. All four cases were shown to segregate a common 6q haplotype with a region identical to the previously identified 6q haplotype. The data strongly support a new breast cancer locus at 6q, and narrow it down to a 17 MB interval at 6q15-q21.

Tumour diploidy and survival in breast cancer patients with BRCA2 mutations.

It is not well known to what extent carrying a BRCA2 mutation affects the survival of women with breast cancer and prognostic factors among BRCA2-positive women warrant investigation. Using a record linkage approach we compared the long-term survival in carriers and noncarriers of an inherited BRCA2 founder mutation (999del5), and sought to identify prognostic factors among the BRCA2 mutation-positive subset, including markers of genetic instability (aneuploidy) and mitotic activity (S-phase fraction). We established the genetic status of 2,967 Icelandic breast cancer patients (215 mutation carriers and 2,752 noncarriers) diagnosed from 1955 to 2004, representing 72 % of all cases diagnosed in the country during this period. Tumour ploidy and S-phase fraction were assessed on tumour cells by DNA flow cytometry. Prognostic factors were assessed blindly with respect to mutation status. Univariate and multivariate hazard ratios (HR) were estimated for breast cancer-specific survival by BRCA2 status, using Cox regression. After a median follow-up of 9.5 years, BRCA2 mutation carriers had a higher risk of death from breast cancer than noncarriers (HR 1.64, 95 % CI 1.24-2.16, p < 0.001). The risk increase was restricted to women with diploid tumours (HR 3.03, 95 % CI 1.91-4.79, p < 0.001). Among breast cancer patients with aneuploid tumours, survival of carriers was similar to that of noncarriers (HR 0.76, 95 % CI 0.41-1.41, p = 0.38). Increased tumour size and a positive nodal status predicted worse prognosis in all patients, whereas the highly correlated prognostic factors diploidy, low proliferative activity and a positive estrogen receptor status had reverse effects in mutation carriers and noncarriers. Breast cancer patients who carry the Icelandic founder BRCA2 mutation have inferior long-term survival than noncarriers, but the adverse prognosis is restricted to mutation carriers with diploid, slowly proliferating tumours.

High Atlastin 2-2 (ATL2-2) Expression Associates with Worse Prognosis in Estrogen-Receptor-Positive Breast Cancer.

The disruption of endoplasmic reticulum (ER) homeostasis occurs in many human diseases. Atlastins (ATLs) maintain the branched network of the ER. The dysregulation of ATL2, located at ER network junctions, has been associated with cancer. ATL2 is necessary for lipid droplet formation in murine breast tissue. Thus, we analyzed whether ATL2 has a role in human breast cancer (BC) pathology. The expression of ATL2 variant ATL2-2 was analyzed in breast tumors from the BC cohorts of the TCGA, METABRIC, and two independent Icelandic cohorts, Cohort 1 and 2; its association with clinical, pathological, survival, and cellular pathways was explored. ATL2-2 mRNA and protein expression were higher in breast tumors than in normal tissue. ATL2-2 mRNA associated with tumor characteristics that indicate a worse prognosis. In METABRIC, high ATL2-2 mRNA levels were associated with shorter BC-specific survival (BCSS) in patients with estrogen-receptor-positive luminal breast tumors, which remained significant after correction for grade and tumor size (HR 1.334, CI 1.063-1.673). Tumors with high ATL2 mRNA showed an upregulation of hallmark pathways MYC targets v1, E2F targets, and G2M checkpoint genes. Taken together, the results suggest that high levels of ATL2-2 may support BC progression through key cancer driver pathways.

Prevalence of smoldering multiple myeloma based on nationwide screening.

Smoldering multiple myeloma (SMM) is an asymptomatic precursor to multiple myeloma. Here we define the epidemiological characteristics of SMM in the general population in Iceland. The iStopMM study (ClinicalTrials.gov ID: NCT03327597 ) is a nationwide screening study for multiple myeloma precursors where all residents in Iceland 40 years or older were invited to participate. SMM was defined as 10-60% bone marrow plasma cells and/or monoclonal (M) protein concentration ≥3 g dl-1, in the absence of myeloma-defining events. Of the 80,759 who gave informed consent to participate, 75,422 (93%) were screened. The prevalence of SMM in the total population was 0.53% (95% confidence interval (CI) = 0.49-0.57%) in individuals 40 years or older. In men and women, the prevalence of SMM was 0.67% (95% CI = 0.62-0.73%) and 0.39% (95% CI = 0.35-0.43%), respectively; it increased with age in both sexes. For the 193 individuals with SMM, median age was 70 years (range 44-92 years) and 60% were males. The mean M protein concentration of individuals with SMM was 0.62 g dl-1 (range 0.01-3.5 g dl-1) and 73% had 11-20% bone marrow plasma cell infiltration. The high prevalence of SMM has implications for future treatment policies in multiple myeloma as the evidence supporting treatment initiation at the SMM stage is emerging.