Inherited susceptibility to uterine leiomyomas and renal cell cancer

Launonen, Virpi; Vierimaa, Outi; Kiuru, Maija; Isola, Jorma; Roth, Stephan; Pukkala, Eero; Sistonen, Pertti; Herva, Riitta; Aaltonen, Lauri A.

doi:10.1073/pnas.051633798

Cited by 596 publications

(539 citation statements)

References 18 publications

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“…A tumor-susceptibility gene for multiple cutaneous and uterine leiomyomatosis syndrome has been identified. 69,70 Characterization of the syndrome was almost immediately followed by identification of the susceptibility gene, fumarate hydratase.…”

Section: Discussionmentioning

confidence: 99%

Familial risk of cancer by site and histopathology

Hemminki

2002

Intl Journal of Cancer

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Familial risks for histopathology-specific cancers have not been determined. We used the nationwide Swedish FamilyCancer Database on 10.2 million individuals and 1 million tumors to calculate standardized incidence ratios (SIRs) for familial cancers of specific histology and morphology among 0-to 66-year-old offspring. We used histology codes for both offspring and parents, but because of the limited number of cases, the morphology-specific classification could be used only for offspring by all site-specific cancers in parents, resulting in inflated risk estimates. A number of novel findings emerged in the histopathology-specific analysis of familial risks, in addition to some known associations. Overall, specific histology showed an SIR of 2.07 for all cancers compared to an SIR of 2.00 for any histology. However, the small effect was due to breast and prostate cancers, which showed a negligible effect of specific histology. Familial risks of over 4.0 were found for serous papillary cystadenocarcinoma of the ovary, papillary thyroid cancer and low-grade astrocytoma. Familial risks of over 3.0 were found for signet-ring gastric cancer, various forms of ovarian cancer and squamous cell skin cancer. Also noteworthy were familial risks of hepatocellular carcinoma (2.48), pancreatic adenocarcinoma (1.92), large cell carcinoma and adenocarcinoma of the lung (2.29 and 2.18, respectively) and clear cell carcinoma of the kidney (2.73). Many of the findings were novel and could be revealed only by applying codes for specific histopathology. These data call for a closer description of familial aggregations and probing for the underlying genetic mechanisms.

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Section: Discussionmentioning

confidence: 99%

Familial risk of cancer by site and histopathology

Hemminki

2002

Intl Journal of Cancer

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“…2 A small proportion of families with MCUL also cluster renal cancer, either papillary renal type II cancer or renal collecting duct cancer. 1,[3][4][5][6] This disease variant has been referred to as hereditary leiomyomatosis and renal cancer (HLRCC, OMIM 605839). MCUL/HLRCC has been found to be caused by germline mutations in fumarate hydratase (FH) in the majority of screened cases.…”

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confidence: 99%

Missense Mutations in Fumarate Hydratase in Multiple Cutaneous and Uterine Leiomyomatosis and Renal Cell Cancer

Alam

Olpin

Rowan

et al. 2005

The Journal of Molecular Diagnostics

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Heterozygous germline mutations in fumarate hydratase (FH) predispose to the multiple cutaneous and uterine leiomyomatosis syndrome (MCUL), which, when co-existing with renal cancer, is also known as hereditary leiomyomatosis and renal cell cancer. Twenty-seven distinct missense mutations represent 68% of FH mutations reported in MCUL. Here we show that FH missense mutations significantly occurred in fully conserved residues and in residues functioning in the FH A-site, B-site, or subunit-interacting region. Of 24 distinct missense mutations, 13 (54%) occurred in the substrate-binding Asite, 4 (17%) in the substrate-binding B-site, and 7 (29%) in the subunit-interacting region. Clustering of missense mutations suggested the presence of possible mutational hotspots. FH functional assay of lymphoblastoid cell lines from 23 individuals with heterozygous FH missense mutations showed that A-site mutants had significantly less residual activity than B-site mutants, supporting data from Escherichia coli that the A-site is the main catalytic site. Missense FH mutations predisposing to renal cancer had no unusual features, and identical mutations were found in families without renal cancer, suggesting a role for genetic or environmental factors in renal cancer development In the autosomal dominant syndrome of multiple cutaneous and uterine leiomyomatosis (MCUL, Reed syndrome, leiomyomatosis cutis et uteri, multiple leiomyomatosis; OMIM 150800), affected females develop uterine leiomyomas and affected individuals of both sexes develop cutaneous leiomyomas. 1 Cutaneous leiomyomas are believed to be derived from the smooth muscle of the pilo-arrector apparatus. They generally present in the second, third, or fourth decades, typically as grouped papules or nodules on the trunk or limbs and are characteristically painful particularly in response to low temperatures or touch. Uterine leiomyomas or fibroids in MCUL are severely symptomatic with a large proportion of patients requiring symptom control by hysterectomy. 2 A small proportion of families with MCUL also cluster renal cancer, either papillary renal type II cancer or renal collecting duct cancer. 1,[3][4][5][6] This disease variant has been referred to as hereditary leiomyomatosis and renal cancer (HLRCC, OMIM 605839). MCUL/HLRCC has been found to be caused by germline mutations in fumarate hydratase (FH) in the majority of screened cases. 1,5,6 Forty-six distinct FH mutations have been reported to date in MCUL/HLRCC. Twenty-seven of these are missense mutations of 26 different residues (one residue has two reported mutations, R190H and R190L). These 27 distinct missense mutations represent 55 of 81 (68%) of the FH mutations reported in MCUL probands. 1,[5][6][7] The FH locus encodes two isoforms of fumarate hydratase, cytosolic and mitochondrial, which differ only in that the latter has an initial mitochondrial signal peptide. Fumarate hydratase catalyzes the stereospecific reversible hydration of fumarate to L-malate. The mitochondrial isoform performs this reactio...

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“…Sin embargo, se han descrito casos hereditarios 9 , y casos asociados a otros tumores como leiomiomatosis hereditaria 10 , carcinoma papilar de tiroides hereditario 11 , y sín-drome de Birt-Hogg-Dubé 12 . Además, se han descrito casos de carcinoma renal de morfología papilar en la edad pediátrica asociados a la translocación Xp11.2 13 .Estudios recientes indican que tanto el carcinoma renal tubular, mucinoso, y fusocelular [14][15][16][17][18][19][20] como el carcinoma renal túbulo-quístico [21][22][23][24] comparten las mismas alteraciones cromosómicas que el CCRP, lo cual los convierte, según varios autores 18,20 en nuevas variantes de CCRP.…”

Section: A Clasificación De La Oms Publicada En 2004unclassified

“…El síndrome de leiomiomatosis hereditaria y carcinoma renal asocia leiomiomas cutáneos y uterinos junto a carcinoma renal papilar de tipo 2, y fue descrito en tres familias en 2001 10,46 . Aproximadamente el 30% de los pacientes con este síndrome desarrollan un único carcinoma renal de alto grado de malignidad histológicamente superponible al tipo 2 de carcinoma papilar renal 47 , aunque se han descrito casos morfológicamente superponibles al carcinoma de ductos colectores y oncocitomas.…”

Section: Carcinoma Renal Papilar Asociado a Leiomiomatosis Hereditariaunclassified

El espectro del carcinoma renal papilar

Ugalde

López²

2008

Actas Urológicas Españolas

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Objetivos: Los últimos años están asistiendo a la gran expansión conceptual del cáncer renal. La conjunción entre los hallazgos histológicos y los datos moleculares ha sido un punto clave en este fenómeno, y resultado de ello ha sido la clasificación de los tumores renales del adulto de la OMS de 2004. En ella se han unido viejos y nuevos tumores renales. Lejos de estar cerrada, esta clasificación se actualiza gracias a nuevos puntos de vista surgidos a la luz de los nuevos hallazgos que se obtienen fundamentalmente en el campo de la genética.Material y Métodos: El carcinoma papilar renal en el sentido más amplio del término es el objeto de revisión en este trabajo. Este fenotipo histológico en el cáncer renal es un buen ejemplo de evolución incesante de la anatomía patológica como disciplina clínica, con un crecimiento importante en los últimos tiempos.Resultados: El conjunto de neoplasias renales que muestran una histología papilar o túbulo-papilar, o que tienen su sustrato genético, algunas de las cuales son entidades muy recientes y están aún hoy en día en discusión, es amplio y variado: carcinoma papilar esporádico convencional, carcinomas papilares ligados a síndromes genéticos (carcinoma papilar hereditario, carcinoma papilar asociado a leiomiomatosis hereditaria, carcinoma papilar asociado a carcinoma papilar hereditario de tiroides, síndrome de Birt-Hogg-Dubé) o a alteraciones genéticas específicas (carcinomas papilares con translocación Xp11.2), carcinomas papilares con morfología peculiar (carcinoma micropapilar, carcinoma papilar invertido, carcinoma papilar con células fusiformes y túbulos angulados) y carcinomas renales de nuevo cuño englobados dentro del grupo del carcinoma papilar (carcinoma tubulo-quístico y carcinoma mucinoso, tubular y fusocelular).Conclusión: Además de las variedades clásicamente reconocidas, nuevas entidades, algunas no bien definidas aún, están engrosando de forma progresiva el grupo de carcinomas renales con morfología papilar. Lejos de agotarse, este crecimiento continuará en los próximos años a la luz de los nuevos hallazgos, y en éstos los patólogos tendrán mucho que decir.Palabras clave: Tumor renal. Clasificación de la OMS. Carcinoma papilar. Alteración genética. Histología. Diagnóstico diferencial. ABSTRACTPAPILLARY RENAL CELL CARCINOMA SPECTRUM Objectives: Significant conceptual expansion of renal cancer continues to increase. The key point to this phenomenon is based on the combination of morphology and molecular data. The result is the new 2004 WHO classification of renal tumors in adults. The apparently never ending advance in molecular genetics is constantly pushing to update recently proposed listings.Material and Methods: Papillary renal cell carcinoma, considered the term in the broader sense, is the subject of this study. This histological phenotype in renal cancer, with an accelerated growth in the last times, is a good example of the never ending evolution of pathology as a clinical discipline.Results: The genetic background and the phenotype of all renal ...

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Inherited susceptibility to uterine leiomyomas and renal cell cancer

Cited by 596 publications

References 18 publications

Familial risk of cancer by site and histopathology

Familial risk of cancer by site and histopathology

Missense Mutations in Fumarate Hydratase in Multiple Cutaneous and Uterine Leiomyomatosis and Renal Cell Cancer

El espectro del carcinoma renal papilar

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