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Silva Saarinen, Eevi Kaasinen,
Marja-Liisa Karjalainen-Lindsberg,
Kari Vesanen,
Mervi Aavikko,
Riku Katainen,
Minna Taskinen,
Soili Kytölä,
Sirpa Leppä,
Marja Hietala,
Pia Vahteristo,
Lauri A Aaltonen
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ABSTRACT: Primary mediastinal large B-cell lymphoma (PMBCL) is a subtype of diffuse large B-cell lymphoma (DLBCL) accounting for 2-4% of all non-Hodgkin lymphomas. We report a family of three siblings with PMBCL and their cousin with extranodal DLBCL. The histopathological characteristics of lymphomas of all four patients are similar, implying post germinal center differentiation and growth deregulation by other mechanisms than BCL2 mediated inhibition of apoptosis, and suggesting a shared biological background. We aimed to identify the genetic defect underlying lymphoma susceptibility in this family using exome sequencing and linkage analysis. The only variant segregating in all four patients and not reported in genetic databases was 5533C>A (His1845Asn) in the MLL gene. To our knowledge, this is the first time when familial clustering of PMBCL is reported. While we propose MLL as a candidate predisposition gene for this condition, this finding needs to be validated in additional cases.
Blood 03/2013; · 9.90 Impact Factor
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Eevi Kaasinen,
Mervi Aavikko,
Pia Vahteristo,
Toni Patama,
Yilong Li,
Silva Saarinen,
Outi Kilpivaara,
Esa Pitkänen,
Paul Knekt,
Maarit Laaksonen,
Miia Artama,
Rainer Lehtonen,
Lauri A Aaltonen,
Eero Pukkala
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ABSTRACT: Many cancer predisposition syndromes are rare or have incomplete penetrance, and traditional epidemiological tools are not well suited for their detection. Here we have used an approach that employs the entire population based data in the Finnish Cancer Registry (FCR) for analyzing familial aggregation of all types of cancer, in order to find evidence for previously unrecognized cancer susceptibility conditions. We performed a systematic clustering of 878,593 patients in FCR based on family name at birth, municipality of birth, and tumor type, diagnosed between years 1952 and 2011. We also estimated the familial occurrence of the tumor types using cluster score that reflects the proportion of patients belonging to the most significant clusters compared to all patients in Finland. The clustering effort identified 25,910 birth name-municipality based clusters representing 183 different tumor types characterized by topography and morphology. We produced information about familial occurrence of hundreds of tumor types, and many of the tumor types with high cluster score represented known cancer syndromes. Unexpectedly, Kaposi sarcoma (KS) also produced a very high score (cluster score 1.91, p-value <0.0001). We verified from population records that many of the KS patients forming the clusters were indeed close relatives, and identified one family with five affected individuals in two generations and several families with two first degree relatives. Our approach is unique in enabling systematic examination of a national epidemiological database to derive evidence of aberrant familial aggregation of all tumor types, both common and rare. It allowed effortless identification of families displaying features of both known as well as potentially novel cancer predisposition conditions, including striking familial aggregation of KS. Further work with high-throughput methods should elucidate the molecular basis of the potentially novel predisposition conditions found in this study.
PLoS ONE 01/2013; 8(1):e55209. · 4.09 Impact Factor
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Mervi Aavikko,
Song-Ping Li,
Silva Saarinen,
Pia Alhopuro, Eevi Kaasinen,
Ekaterina Morgunova,
Yilong Li,
Kari Vesanen,
Miriam J Smith,
D Gareth R Evans,
Minna Pöyhönen,
Anne Kiuru,
Anssi Auvinen,
Lauri A Aaltonen,
Jussi Taipale,
Pia Vahteristo
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ABSTRACT: Meningiomas are the most common primary tumors of the CNS and account for up to 30% of all CNS tumors. An increased risk of meningiomas has been associated with certain tumor-susceptibility syndromes, especially neurofibromatosis type II, but no gene defects predisposing to isolated familial meningiomas have thus far been identified. Here, we report on a family of five meningioma-affected siblings, four of whom have multiple tumors. No NF2 mutations were identified in the germline or tumors. We combined genome-wide linkage analysis and exome sequencing, and we identified in suppressor of fused homolog (Drosophila), SUFU, a c.367C>T (p.Arg123Cys) mutation segregating with the meningiomas in the family. The variation was not present in healthy controls, and all seven meningiomas analyzed displayed loss of the wild-type allele according to the classic two-hit model for tumor-suppressor genes. In silico modeling predicted the variant to affect the tertiary structure of the protein, and functional analyses showed that the activity of the altered SUFU was significantly reduced and therefore led to dysregulated hedgehog (Hh) signaling. SUFU is a known tumor-suppressor gene previously associated with childhood medulloblastoma predisposition. Our genetic and functional analyses indicate that germline mutations in SUFU also predispose to meningiomas, particularly to multiple meningiomas. It is possible that other genic mutations resulting in aberrant activation of the Hh pathway might underlie meningioma predisposition in families with an unknown etiology.
The American Journal of Human Genetics 09/2012; 91(3):520-6. · 10.60 Impact Factor
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Sari Tuupanen,
Jian Yan,
Mikko Turunen,
Alexandra E Gylfe, Eevi Kaasinen,
Li Li,
Charis Eng,
Daniel A Culver,
Matthew F Kalady,
Michael J Pennison, [......],
Sampsa Hautaniemi,
Hassan Askhtorab,
Duane Smoot,
Robert S Sandler,
Temitope Keku,
Sonia S Kupfer,
Nathan A Ellis,
Christopher A Haiman,
Jussi Taipale,
Lauri A Aaltonen
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ABSTRACT: Recent genome-wide association studies have identified multiple regions at 8q24 that confer susceptibility to many cancers. In our previous work, we showed that the colorectal cancer (CRC) risk variant rs6983267 at 8q24 resides within a TCF4 binding site at the MYC-335 enhancer, with the risk allele G having a stronger binding capacity and Wnt responsiveness. Here, we searched for other potential functional variants within MYC-335. Genetic variation within MYC-335 was determined in samples from individuals of European, African, and Asian descent, with emphasis on variants in putative transcription factor binding sites. A 2-bp GA deletion rs67491583 was found to affect a growth factor independent (GFI) binding site and was present only in individuals with African ancestry. Chromatin immunoprecipitation performed in heterozy-gous cells showed that the GA deletion had an ability to reduce binding of the transcriptional repressors GFI1 and GFI1b. Screening of 1,027 African American colorectal cancer cases and
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Sari Tuupanen,
Jian Yan,
Mikko Turunen,
Alexandra E Gylfe, Eevi Kaasinen,
Li Li,
Charis Eng,
Daniel A Culver,
Matthew F Kalady,
Michael J Pennison, [......],
Sampsa Hautaniemi,
Hassan Askhtorab,
Duane Smoot,
Robert S Sandler,
Temitope Keku,
Sonia S Kupfer,
Nathan A Ellis,
Christopher A Haiman,
Jussi Taipale,
Lauri A Aaltonen
[show abstract]
[hide abstract]
ABSTRACT: Recent genome-wide association studies have identified multiple regions at 8q24 that confer susceptibility to many cancers. In our previous work, we showed that the colorectal cancer (CRC) risk variant rs6983267 at 8q24 resides within a TCF4 binding site at the MYC-335 enhancer, with the risk allele G having a stronger binding capacity and Wnt responsiveness. Here, we searched for other potential functional variants within MYC-335. Genetic variation within MYC-335 was determined in samples from individuals of European, African, and Asian descent, with emphasis on variants in putative transcription factor binding sites. A 2-bp GA deletion rs67491583 was found to affect a growth factor independent (GFI) binding site and was present only in individuals with African ancestry. Chromatin immunoprecipitation performed in heterozygous cells showed that the GA deletion had an ability to reduce binding of the transcriptional repressors GFI1 and GFI1b. Screening of 1,027 African American colorectal cancer cases and 1,773 healthy controls did not reveal evidence for association (odds ratio: 1.17, 95% confidence interval: 0.97-1.41, P = 0.095). In this study, rs67491583 was identified as another functional variant in the CRC-associated enhancer MYC-335, but further studies are needed to establish the role of rs67491583 in the colorectal cancer predisposition of African Americans.
Cancer Genetics 01/2012; 205(1-2):25-33.
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Netta Mäkinen,
Miika Mehine,
Jaana Tolvanen, Eevi Kaasinen,
Yilong Li,
Heli J Lehtonen,
Massimiliano Gentile,
Jian Yan,
Martin Enge,
Minna Taipale,
Mervi Aavikko,
Riku Katainen,
Elina Virolainen,
Tom Böhling,
Taru A Koski,
Virpi Launonen,
Jari Sjöberg,
Jussi Taipale,
Pia Vahteristo,
Lauri A Aaltonen
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ABSTRACT: Uterine leiomyomas, or fibroids, are benign tumors that affect millions of women worldwide and that can cause considerable morbidity. To study the genetic basis of this tumor type, we examined 18 uterine leiomyomas derived from 17 different patients by exome sequencing and identified tumor-specific mutations in the mediator complex subunit 12 (MED12) gene in 10. Through analysis of 207 additional tumors, we determined that MED12 is altered in 70% (159 of 225) of tumors from a total of 80 patients. The Mediator complex is a 26-subunit transcriptional regulator that bridges DNA regulatory sequences to the RNA polymerase II initiation complex. All mutations resided in exon 2, suggesting that aberrant function of this region of MED12 contributes to tumorigenesis.
Science 08/2011; 334(6053):252-5. · 31.20 Impact Factor
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Silva Saarinen,
Mervi Aavikko,
Kristiina Aittomäki,
Virpi Launonen,
Rainer Lehtonen,
Kaarle Franssila,
Heli J Lehtonen, Eevi Kaasinen,
Peter Broderick,
Jussi Tarkkanen,
Barbara J Bain,
Frédéric Bauduer,
Ali Ünal,
Anthony J Swerdlow,
Rosie Cooke,
Markus J Mäkinen,
Richard Houlston,
Pia Vahteristo,
Lauri A Aaltonen
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ABSTRACT: A strong clustering of Hodgkin lymphoma in certain families has been long acknowledged. However, the genetic factors in the background of familial Hodgkin lymphoma are largely unknown. We have studied a family of 4 cousins with a rare subtype of the disease, nodular lymphocyte predominant Hodgkin lymphoma. We applied exome sequencing together with genome-wide linkage analysis to this family and identified a truncating germline mutation in nuclear protein, ataxia-telangiectasia locus (NPAT) gene, which segregated in the family. We also studied a large number of samples from other patients with Hodgkin lymphoma, and a germline variation leading to the deletion of serine 724 was found in several cases suggesting an elevated risk for the disease (odds ratio = 4.11; P = .018). NPAT is thus far the first gene implicated in nodular lymphocyte predominant Hodgkin lymphoma predisposition.
Blood 05/2011; 118(3):493-8. · 9.90 Impact Factor
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ABSTRACT: Genomewide association studies have identified 10 low-penetrance loci that confer modestly increased risk for colorectal cancer (CRC). Although they underlie a significant proportion of CRC in the general population, their impact on the familial risk for CRC has yet to be formally enumerated. The aim of this study was to examine the combined contribution of the 10 variants, rs6983267, rs4779584, rs4939827, rs16892766, rs10795668, rs3802842, rs4444235, rs9929218, rs10411210, and rs961253, on familial CRC.
The population-based series of CRC samples included in this study consisted of 97 familial cases and 691 sporadic cases. Genotypes in the 10 loci and clinical data, including family history of cancer verified from the Finnish Cancer Registry, were available. The overall number of risk alleles (0-20) was determined, and its association with familial CRC was analyzed. Excess familial risk was estimated using cancer incidence data from the first-degree relatives of the cases.
A linear association between the number of risk alleles and familial CRC was observed (P = 0.006). With each risk-allele addition, the odds of having an affected first-degree relative increased by 1.16 (95% confidence interval, 1.04-1.30). The 10 low-penetrance loci collectively explain approximately 9% of the variance in familial risk for CRC.
This study provides evidence to support the previous indirect estimations that these low-penetrance variants account for a relatively small proportion of the familial aggregation of CRC.
Our results emphasize the need to characterize the remaining molecular basis of familial CRC, which should eventually yield in individualized targeting of preventive interventions.
Cancer Epidemiology Biomarkers & Prevention 06/2010; 19(6):1478-83. · 4.12 Impact Factor
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ABSTRACT: Right atrial isomerism (RAI) is a heterotaxy syndrome with disturbances in the left-right axis development, resulting in complex heart malformations and abnormal lateralization of other thoracic and abdominal organs. Although autosomal-recessive inheritance of heterotaxy syndrome is seen in multiple families, underlying gene defects have remained unknown. Here we identify the molecular genetic basis of a kindred with five siblings with RAI. Linkage analysis and positional candidate gene approach showed that the affected children were compound heterozygotes for truncating mutations in the growth/differentiation factor 1 (GDF1) gene. Individuals heterozygous for the mutations were clinically healthy. This finding, supported by the similar phenotype in Gdf1 knockout mouse, provides firm evidence that RAI can occur as a recessively inherited condition, with GDF1 as the culprit gene. The results will shed light on the biological basis of human laterality defects and facilitate molecular diagnosis of RAI.
Human Molecular Genetics 04/2010; 19(14):2747-53. · 7.64 Impact Factor
