Mahdi Fallah

TERT promoter mutations in bladder cancer affect patient survival and disease recurrence through modification by a common polymorphism

Significance This study shows that the telomerase reverse transcriptase (TERT) promoter mutations, which create de novo E-twenty six/ternary complex factors (Ets/TCF) transcription binding sites, besides being the most common somatic genetic lesions, influence both survival and disease recurrence in bladder cancer patients. The effect of the TERT promoter mutations on both survival and recurrence is modified by a common polymorphism within the preexisting Ets binding site in the TERT promoter. The data were supported by the results from reporter assays carried out in two urothelial carcinoma cell lines. The findings of the study suggest that the TERT promoter mutations in conjunction with the common polymorphism have potential of being used as clinical biomarkers in bladder cancer. The telomerase reverse transcriptase (TERT) promoter, an important element of telomerase expression, has emerged as a target of cancer-specific mutations. Originally described in melanoma, the mutations in TERT promoter have been shown to be common in certain other tumor types that include glioblastoma, hepatocellular carcinoma, and bladder cancer. To fully define the occurrence and effect of the TERT promoter mutations, we investigated tumors from a well-characterized series of 327 patients with urothelial cell carcinoma of bladder. The somatic mutations, mainly at positions −124 and −146 bp from ATG start site that create binding motifs for E-twenty six/ternary complex factors (Ets/TCF), affected 65.4% of the tumors, with even distribution across different stages and grades. Our data showed that a common polymorphism rs2853669, within a preexisting Ets2 binding site in the TERT promoter, acts as a modifier of the effect of the mutations on survival and tumor recurrence. The patients with the mutations showed poor survival in the absence [hazard ratio (HR) 2.19, 95% confidence interval (CI) 1.02–4.70] but not in the presence (HR 0.42, 95% CI 0.18–1.01) of the variant allele of the polymorphism. The mutations in the absence of the variant allele were highly associated with the disease recurrence in patients with Tis, Ta, and T1 tumors (HR 1.85, 95% CI 1.11–3.08). The TERT promoter mutations are the most common somatic lesions in bladder cancer with clinical implications. The association of the mutations with patient survival and disease recurrence, subject to modification by a common polymorphism, can be a unique putative marker with individualized prognostic potential.

Clinical significance of glutamic acid decarboxylase antibodies in patients with epilepsy.

Purpose:  Glutamic acid decarboxylase antibodies (GADAs) have been detected in patients with epilepsy, but the clinical determinants of epilepsy associated with GADA have not been defined.

Metastatic sites and survival in lung cancer.

OBJECTIVES Population-based data on metastatic sites and survival in site-specific metastases are lacking for lung cancer and for any cancer because most cancer registries do not record metastases. This study uses a novel population-based approach to identify metastases from both death certificates and national inpatient data to describe metastatic pathways in lung cancer patients. MATERIALS AND METHODS 17,431 deceased lung cancer patients diagnosed 2002-2010 were identified from the nationwide Swedish Cancer Registry, which is based on compulsory reports. The influence of age at diagnosis, sex, and histological subtype on metastatic spread was investigated. Survival in metastatic lung cancer was assessed by histology and metastatic site. RESULTS The most frequent metastatic sites were the nervous system, bone, liver, respiratory system, and adrenal gland. Liver (35%) and nervous system (47%) metastases were common in patients with metastases from small cell lung cancer, and bone (39%) and respiratory system (22%) metastases in adenocarcinoma. Women (43% vs. 35%) and younger patients had more metastases to the nervous system. Median survival after diagnosis was 13 months for non-metastatic and five months for metastatic lung cancer. In this novel data, liver metastases conferred the worst prognosis (three months), especially for large cell histology. Bone metastases also featured poor survival, whereas survival in respiratory and nervous system metastases was better. CONCLUSION Metastatic sites and survival in metastatic lung cancer is influenced by sex, histological subtype, and age at diagnosis. Liver and bone metastases signal poor survival, compared with nervous system metastases.

Autoimmune diseases associated with non-Hodgkin lymphoma: a nationwide cohort study

BACKGROUND The cumulative risk of non-Hodgkin lymphoma (NHL) in Sweden by age 80 years has increased to 1.1 in women and 1.6% in men in 2011. Increased risk of NHL associated with personal histories of some autoimmune diseases (ADs) is known. It is unclear whether there are other NHL-related ADs and whether this association holds across different sex, age and year of diagnosis, or NHL histological subtypes. PATIENTS AND METHODS Over an average of 9.4-year (maximum 47 years) follow-up of 878 161 patients diagnosed in 1964-2010 with 33 different ADs, 3096 subsequent NHL were diagnosed (data: Swedish Cancer Registry). RESULTS Of 33 studied ADs, 21 showed significantly increased risk of NHL; 6 of them tended to increase the risk and none significantly decreased it. The overall standardized incidence ratio (SIR) for NHL after ADs was 1.6 [novel findings: immune thrombocytopenic purpura (ITP) = 7.5, polymyositis/dermatomyositis = 4.1, primary biliary cirrhosis = 3.9, myasthenia gravis = 2.2, Behcet = 1.7, rheumatoid fever = 1.7, ulcerative colitis = 1.5, polymyalgia rheumatica = 1.4, and chronic rheumatic heart disease = 1.4; confirmatory findings: autoimmune hemolytic anemia = 27.2, Sjögren = 4.9, Celiac = 4.8, systemic lupus erythematosus = 4.4, polyarteritis nodosa = 2.9, discoid lupus erythematosus = 2.7, sarcoidosis = 2.6, Crohn = 2.1, systemic sclerosis = 2.1, rheumatoid arthritis = 2.0, and Hashimoto/hypothyroidism and psoriasis = 1.4]. SIR for NHL diagnosis before age 60 (2.2) was significantly higher than that in older ages (age ≥60: 1.5). The SIRs in women or men and in period 1993-2010 or 1964-1992 were similar. Risk of all common NHL histology subtypes significantly increased after ADs (cutaneous/peripheral T cell and anaplastic large T and null cell = 2.2; small B-cell lymphocytic = 1.7; diffuse large B cell = 1.6; follicular and mantel cell = 1.3). CONCLUSION Many of 33 studied ADs (except for ankylosing spondylitis, diabetes type I graves/hyperthyroidism, multiple sclerosis, chorea minor, and pernicious anemia), especially when diagnosed at younger ages, were associated with higher risk of NHL. However, the absolute risk of NHL in many ADs is still small.

Familial risk of early and late onset cancer: nationwide prospective cohort study

Objective To determine whether familial risk of cancer is limited to early onset cases. Design Nationwide prospective cohort study. Setting Nationwide Swedish Family-Cancer Database. Participants All Swedes born after 1931 and their biological parents, totalling >12.2 million individuals, including >1.1 million cases of first primary cancer. Main outcome measures Familial risks of the concordant cancers by age at diagnosis. Results The highest familial risk was seen for offspring whose parents were diagnosed at an early age. Familial risks were significantly increased for colorectal, lung, breast, prostate, and urinary bladder cancer and melanoma, skin squamous cell carcinoma, and non-Hodgkin’s lymphoma, even when parents were diagnosed at age 70-79 or 80-89. When parents were diagnosed at more advanced ages (≥90), the risk of concordant cancer in offspring was still significantly increased for skin squamous cell carcinoma (hazard ratio 1.9, 95% confidence interval 1.4 to 2.7), colorectal (1.6, 1.2 to 2.0), breast (1.3, 1.0 to 1.6), and prostate cancer (1.3, 1.1 to 1.6). For offspring with a cancer diagnosed at ages 60-76 whose parents were affected at age <50, familial risks were not significantly increased for nearly all cancers. Conclusion Though the highest familial risks of cancer are seen in offspring whose parents received a diagnosis of a concordant cancer at earlier ages, increased risks exist even in cancers of advanced ages. Familial cancers might not be early onset in people whose family members were affected at older ages and so familial cancers might have distinct early and late onset components.

The population impact of familial cancer, a major cause of cancer

The population attributable fraction (PAF) defines the proportion of a disease that would be prevented if the exposure to a particular risk factor was avoided. Familial risk is a known risk factor for many cancers, but an unbiased estimation of the PAF for familial risk requires a large study population to include rare cancers. PAFs and their corresponding standardized incidence ratios (SIRs) were calculated for familial relative risk among first‐degree relatives (FDRs) and second‐degree relatives (SDRs) diagnosed with the same (concordant) invasive or in situ cancers. Calculations were based on the Swedish Family‐Cancer Database considering 8,148,737 individuals. To assess environmental effects, PAFs were also calculated for concordant cancers among spouses. Almost all cancers showed a significant familial risk. The highest PAFs were found for the common cancers of the prostate (13.94%), breast (7.46%) and colorectum (6.78%) among the FDRs. In the FDRs, the overall PAF for any concordant cancer was 4.20%, but in the SDRs, it was only 0.34%. The overall PAFs for in situ cancers were 0.86% and 0.56% for the FDRs and SDRs, respectively. The overall independent familial PAF was 5.96% for the invasive and in situ cancers in the FDRs and SDRs. The cancers between spouses yielded an overall PAF of 0.14%. For esophageal cancer, the risk among spouses was higher than the familial risk. Our study shows that the overall familial PAF of 5.96%, although underestimated for sex‐specific cancers, ranks as the third most common population burden after tobacco smoking and unhealthy diet.

Risk of thyroid cancer in first-degree relatives of patients with non-medullary thyroid cancer by histology type and age at diagnosis: a joint study from five Nordic countries

Background We aimed to estimate lifetime cumulative risk of thyroid cancer (CRTC) in first-degree relatives of patients with non-medullary thyroid cancers (NMTC), including papillary (PTC)/follicular/oxyphilic/anaplastic thyroid carcinoma, by histology and age at diagnosis in patients and their relatives. Design A population-based cohort of 63 495 first-degree relatives of 11 206 NMTC patients diagnosed in 1955–2009 in Nordic countries was followed for cancer incidence. Standardised incidence ratios (SIRs) were calculated using histology-specific, age-specific, sex-specific, period-specific and country-specific incidence rates as reference. Results The 0–84-year CRTC in female relatives of a patient with PTC was 2%, representing a threefold increase over the general population risk (SIR=2.9, 95% CI 2.4 to 3.4; Men: CRTC=1%, SIR=2.5, 95% CI 1.9 to 3.3). When there were ≥2 PTC patients diagnosed at age <60 years in a family, CRTC for female relatives was 10% (male 24%). Twins had a 23-fold increased risk of concordant PTC. Family history of follicular/oxyphilic/anaplastic carcinoma increased CRTC in relatives to about 1–2%. Although no familial case of concordant oxyphilic/anaplastic carcinoma was found, familial risks of discordant histology types of NMTC were interchangeably high for most of the types, for example, higher risk of PTC when a first-degree relative had follicular (SIR=3.0, 95%CI 1.7 to 4.9) or anaplastic (SIR=3.6, 95% CI 1.2 to 8.4) carcinoma. The earlier a patient was diagnosed with PTC in a family, the higher was the SIR in his/her younger relatives. There was a tendency towards concordant age at diagnosis of thyroid cancer among relatives of PTC patients. Conclusions This study provides clinically relevant risk estimates for family members of NMTC patients.

Hodgkin lymphoma after autoimmune diseases by age at diagnosis and histological subtype

BACKGROUND Increased risk of Hodgkin lymphoma (HL) associated with personal history of several autoimmune diseases (ADs), such as rheumatoid arthritis, systemic lupus erythematosus, sarcoidosis, and immune thrombocytopenic purpura, are known. Whether there are other HL-related ADs and whether the increased risk of HL after ADs holds across sex, age, year of diagnosis, or HL histological subtype is unclear. PATIENTS AND METHODS We systematically analyzed the risk of HL in 878 161 Swedish patients diagnosed with 33 different ADs in 1964-2010. During ∼10-year follow-up of ADs patients, 371 incident HL cases were diagnosed. RESULTS Significantly increased overall standardized incidence ratio (SIR) for HL after ADs was 2.0 (95% confidence interval: 1.8-2.2); AD-specific SIRs: autoimmune hemolytic anemia 19.9 (7.2-43.6), sarcoidosis 10.3 (7.8-13.4), systemic lupus erythematosus 8.4 (5.2-12.9), immune thrombocytopenic purpura 7.0 (3.2-13.3), polyarteritis nodosa 6.6 (1.2-19.5), polymyositis/dermatomyositis 6.3 (2.0-14.9), Behcets disease 5.6 (2.7-10.3), Sjögrens syndrome 5.0 (2.1-9.8), rheumatoid arthritis 3.2 (2.6-3.9), polymyalgia rheumatica 2.2 (1.4-3.5), and psoriasis 1.9 (1.3-2.6). Men with AD had slightly higher risk of HL (2.4, 2.0-2.7) compared with women (1.8, 1.5-2.0). Only 23% of ADs were diagnosed before age 35 years and the overall SIR for HL diagnosis before age 35 [1.4, (1.0-1.8)] was lower than that in older ages [35 ≤ age < 50: 2.1 (1.6-2.7); age ≥ 50: 2.2 (2.0-2.5)], except for sarcoidosis [age < 35: 19.3 (10.5-32.5); 35 ≤ age < 50: 10.4 (5.7-17.5); age ≥ 50: 8.4 (5.6-12.1)]. Risks of all classical HLs significantly increased after ADs: lymphocyte depletion 3.7 (1.5-7.6), lymphocyte-rich 3.7 (2.3-5.9), mixed cellularity 2.4 (1.8-3.2), and nodular sclerosis 1.7 (1.3-2.1). CONCLUSION Several, but not all ADs (11/33), had a positive association with all classical histological subtypes of HL. Higher risks of classical HL after polyarteritis nodosa, polymyositis/dermatomyositis, Behcets disease, Sjögrens syndrome, polymyalgia rheumatica, and psoriasis were novel findings of this study.BACKGROUND Increased risk of Hodgkin lymphoma (HL) associated with personal history of several autoimmune diseases (ADs), such as rheumatoid arthritis, systemic lupus erythematosus, sarcoidosis, and immune thrombocytopenic purpura, are known. Whether there are other HL-related ADs and whether the increased risk of HL after ADs holds across sex, age, year of diagnosis, or HL histological subtype is unclear. PATIENTS AND METHODS We systematically analyzed the risk of HL in 878 161 Swedish patients diagnosed with 33 different ADs in 1964-2010. During ∼10-year follow-up of ADs patients, 371 incident HL cases were diagnosed. RESULTS Significantly increased overall standardized incidence ratio (SIR) for HL after ADs was 2.0 (95% confidence interval: 1.8-2.2); AD-specific SIRs: autoimmune hemolytic anemia 19.9 (7.2-43.6), sarcoidosis 10.3 (7.8-13.4), systemic lupus erythematosus 8.4 (5.2-12.9), immune thrombocytopenic purpura 7.0 (3.2-13.3), polyarteritis nodosa 6.6 (1.2-19.5), polymyositis/dermatomyositis 6.3 (2.0-14.9), Behcets disease 5.6 (2.7-10.3), Sjögrens syndrome 5.0 (2.1-9.8), rheumatoid arthritis 3.2 (2.6-3.9), polymyalgia rheumatica 2.2 (1.4-3.5), and psoriasis 1.9 (1.3-2.6). Men with AD had slightly higher risk of HL (2.4, 2.0-2.7) compared with women (1.8, 1.5-2.0). Only 23% of ADs were diagnosed before age 35 years and the overall SIR for HL diagnosis before age 35 [1.4, (1.0-1.8)] was lower than that in older ages [35 ≤ age < 50: 2.1 (1.6-2.7); age ≥ 50: 2.2 (2.0-2.5)], except for sarcoidosis [age < 35: 19.3 (10.5-32.5); 35 ≤ age < 50: 10.4 (5.7-17.5); age ≥ 50: 8.4 (5.6-12.1)]. Risks of all classical HLs significantly increased after ADs: lymphocyte depletion 3.7 (1.5-7.6), lymphocyte-rich 3.7 (2.3-5.9), mixed cellularity 2.4 (1.8-3.2), and nodular sclerosis 1.7 (1.3-2.1). CONCLUSION Several, but not all ADs (11/33), had a positive association with all classical histological subtypes of HL. Higher risks of classical HL after polyarteritis nodosa, polymyositis/dermatomyositis, Behcets disease, Sjögrens syndrome, polymyalgia rheumatica, and psoriasis were novel findings of this study.

Population Landscape of Familial Cancer.

Public perception and anxiety of familial cancer have increased demands for clinical counseling, which may be well equipped for gene testing but less prepared for counseling of the large domain of familial cancer with unknown genetic background. The aim of the present study was to highlight the full scope of familial cancer and the variable levels of risk that need to be considered. Data on the 25 most common cancers were obtained from the Swedish Family Cancer Database and a Poisson regression model was applied to estimate relative risks (RR) distinguishing between family histories of single or multiple affected first-degree relatives and their diagnostic ages. For all cancers, individual risks were significantly increased if a parent or a sibling had a concordant cancer. While the RRs were around 2.00 for most cancers, risks were up to 10-fold increased for some cancers. Familial risks were even higher when multiple relatives were affected. Although familial risks were highest at ages below 60 years, most familial cases were diagnosed at older ages. The results emphasized the value of a detailed family history as a readily available tool for individualized counseling and its preventive potential for a large domain of non-syndromatic familial cancers.

Search for familial clustering of multiple myeloma with any cancer

Multiple myeloma (MM) is a disease of immunoglobulin-producing plasma cells, which reside mainly in the bone marrow. Family members of MM patients are at a risk of MM, but whether other malignancies are in excess in family members is not established and is the aim of this study. MM patients (24 137) were identified from the Swedish Cancer Registry from years 1958 to 2012. Relative risks (RRs) were calculated for MM defined by any cancer diagnosed in first-degree relatives and compared with individuals whose relatives had no cancer. MM was reliably associated with relative’s colorectal, breast and prostate cancers, non-thyroid endocrine tumors, leukemia and cancer of unknown primary; in addition, MM was associated with subsites of bone and connective tissue tumors and of non-Hodgkin lymphoma, including lymphoplasmacytic lymphoma/Waldenström macroglobulinema (RR 3.47). MM showed a strong association (RR 1.91) in colorectal cancer families, possibly as part of an unidentified syndrome. All the associations of MM with discordant cancers are novel suggesting that MM shares genetic susceptibility with many cancers. The associations of MM bone and connective tissue tumors were supported by at least two independent results. Whether the results signal bone-related biology shared by MM and these tumors deserves further study.