No abstract

Uterine leiomyomas are common benign tumors of the myometrium. We performed a meta-analysis of two genome-wide association studies of leiomyoma in European women (16,595 cases and 523,330 controls), uncovering 21 variants at 16 loci that associate with the disease. Five variants were previously reported to confer risk of various malignant or benign tumors (rs78378222 in TP53, rs10069690 in TERT, rs1800057 and rs1801516 in ATM, and rs7907606 at OBFC1) and four signals are located at established risk loci for hormone-related traits (endometriosis and breast cancer) at 1q36.12 (CDC42/WNT4), 2p25.1 (GREB1), 20p12.3 (MCM8), and 6q26.2 (SYNE1/ESR1). Polygenic score for leiomyoma, computed using UKB data, is significantly correlated with risk of cancer in the Icelandic population. Functional annotation suggests that the non-coding risk variants affect multiple genes, including ESR1. Our results provide insights into the genetic background of leiomyoma that are shared by other benign and malignant tumors and highlight the role of hormones in leiomyoma growth.

No abstract

The etiology of RCC is incompletely understood and the inherited genetic contribution uncertain. Although there are rare mendelian forms of RCC stemming from inherited mutations, most cases are thought to be sporadic. We sought to determine the extent of familial aggregation among Icelandic RCC patients in general. Medical and pathologic records for all patients diagnosed with RCC in Iceland between 1955 and 1999 were reviewed. This included a total of 1,078 RCC cases, 660 males and 418 females. With the use of an extensive computerized database containing genealogic information on 630,000 people in Iceland during the past 11 centuries, several analyses were conducted to determine whether the patients were more related to each other than members drawn at random from the population. Patients with RCC were significantly more related to each other than were subjects in matched groups of controls. This relatedness extended beyond the nuclear family. RRs were significantly greater than 1.0 for siblings, parents and cousins of probands. RRs were 2-3 for first-degree relatives and 1.6 for thirddegree relatives. The incidence of renal cell carcinoma (RCC) is high in Scandinavia compared to the rest of the world; and in Iceland, for unknown reasons, it is higher than in most other countries, comprising about 2% of all diagnosed cancers. [1][2][3] The etiology of RCC remains incompletely understood, with only a few environmental factors showing a strong causative relationship. The role of heredity has been suspected, and this has been supported by reports of a few families displaying mendelian inheritance. However, families with multiple cases of RCC are very rare, and earlier reports suggested that only 1-3% of RCC cases are hereditary when considering family history. 4 -6 FCRC is usually found within the context of the uncommon autosomal dominant familial multiorgan cancer syndrome VHL disease, associated with germline mutations in the VHL gene. 7 Rare families with FCRC not linked to the VHL syndrome have also been described, where cases are characterized by an early age at onset and bilateral tumors. 8 -11 However, kindreds with FCRC characterized by late onset and unilateral involvement have also been reported. 12 Germline mutations in the VHL gene have not been identified in association with non-VHL FCRC. Hereditary papillary RCC has also been described, with mutations in the MET gene identified in about 80% of families. 7,13 An international case-control study has suggested an inherited predisposition to RCC in addition to those cases that are associated with certain rare hereditary conditions. This was supported by an increased RR of 1.6 for first-degree relatives of RCC patients. 14 Excess risk of RCC related to ethnic background has additionally been reported in some case-control studies, suggesting that genetic factors are involved. 15,16 Also a population-based survey of all cancers in Sweden has indicated a significantly increased risk to siblings and offspring of probands. 17 Our goal was to investigate t...