Genetic anticipation describes the phenomenon where symptoms appear at an earlier age or are more severe, or both, in subsequent generations of families with a genetic disease. This phenomenon is commonly seen in neurodegenerative diseases (Trottier et al., 1994), and in some hereditary cancers including breast, ovarian and pancreatic cancer (Dagan and Gershoni-Baruch, 2002, Martinez-Borges et al., 2009, Schneider et al., 2011). A recent study by Wong et al. (2014) suggests that there is genetic anticipation in families with HLRCC.
Following the observation that some of the HLRCC families under their care seemed to be showing genetic anticipation with respect to kidney cancer, the authors decided to systematically investigate whether this is the case. Review of the literature and their case series identified 11 families where at least two generations of a family were affected with renal cell carcinoma (RCC), and where ages of diagnosis and/or death were available.
In all families there was evidence of genetic anticipation. Most of the families carried an FH mutation unique to that family, suggesting that genetic anticipation in HLRCC can be caused by multiple mutations, if not all FH mutations. On average, children were diagnosed with RCC 18.6 years earlier than their affected parent, and grandchildren were diagnosed 36.2 years sooner, suggesting an additive effect in each generation. There was no evidence of genetic anticipation for the uterine symptoms of HLRCC, and skin symptoms were not analysed due to the difficulty in accurately determining when this symptom first appears. In the family that most strongly showed anticipation for RCC, the proband was diagnosed with RCC at the age of 17, his two affected uncles were diagnosed at 34 and 45, and his grandmother was diagnosed at 69.
However, the proband’s father – who presumably carries an FH mutation – remains well and without RCC at the age of 54. Additionally, while all families showed a trend towards earlier onset of disease in later generations, two other families included examples where a family member was diagnosed at an older age than a relative from a previous generation. Therefore, although there is clear evidence of genetic anticipation in HLRCC, it is not a fully penetrant phenomenon.
Genetic anticipation is commonly seen in neurodegenerative disorders and greater disease severity is caused by increased expansions of triplet repeats in each generation (Trottier et al., 1994). However, the mechanism responsible for genetic anticipation outside of triplet-repeat disorders is less clear. Martinez-Delgado et al. (2011) showed that women with hereditary breast cancers had shortened telomeres due to BRCA mutations, which likely occurred during DNA transmission from parent to child.
Telomeres protect the end of chromosomes from genomic rearrangement, and shortened telomeres predispose to cancer (Willeit et al., 2010). Telomeres shortening has also been reported to be the cause of genetic anticipation in Li-Fraumeni syndrome and dyskeratosis congenita (Tabori et al., 2007, Vulliamy et al., 2004), meaning this may be the mechanism causing genetic anticipation in HLRCC. However, neither triplet repeat expansion nor telomere shortening cause genetic anticipation in Lynch syndrome (Seguí et al., 2013), meaning that there is at least one additional mechanism to be discovered.
Improved screening or better awareness of symptoms, especially if an individual is known to be at risk, could explain the genetic anticipation seen in some conditions. However, in the four families under the care of the authors of this study, most patients presented with advanced RCC and died within a few years of their diagnosis. This suggests that genetic anticipation seen in HLRCC is not caused by earlier diagnosis, but that patients in later generations really are developing symptoms at a younger age. In this case, genetic anticipation makes it difficult to design a screening programme that is appropriate for all patients. However, due to the young age of some HLRCC patients – RCC has been reported in an 11 year old child with HLRCC (Alrashdi et al., 2010) – and the aggressive nature of the disease, the authors recommend commencing kidney screening at the age of 10.
This is a small study analysing 11 HLRCC families, and cannot rule out birth cohort or environmental effects as causes of earlier symptom development in younger patients. More information is required before genetic anticipation in HLRCC is fully understood. Data collected by the Cancer in our Genes International Patient Databank will help answer this question though, and may shed light on whether some mutations cause more extreme genetic anticipation than others. Indeed, retrospective analysis of the German Familial Pancreatic Cancer patient registry showed that there is genetic anticipation in hereditary pancreatic cancer (Schneider et al., 2011). Thus, the CGIP Databank may also reveal any genetic anticipation in BHD, VHL or SDHB.
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www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.