CAG repeat size in Huntingtin alleles is associated with cancer prognosis

Abstract

The abnormal expansion of a ≥ 36 CAG unit tract in the Huntingtin gene (HTT) leads to Huntington's disease (HD), but has also been associated with cancer: the incidence of cancer is lower in HD patients than in age-matched controls, but HD-causing variants of HTT accelerate the progression of breast tumors and the development of metastases in mouse models of breast cancer. To investigate the relationship between HTT CAGs and cancer, data concerning 2407 women with BRCA1 or BRCA2 mutations that predispose to breast and ovarian cancers and 431 patients with breast cancer without family histories were studied; the size of the CAG expansions on both HTT alleles was determined in each subject. The proportion of individuals carrying a CAG expansion in a pathological range for HD was 10 times more frequent than previously reported in the literature. In carriers of BRCA2 mutations, the length of the HTT CAG tract was correlated with lower incidence of ovarian cancer. Among carriers of BRCA1 mutations who developed a breast cancer, its onset occurred 2.4 years earlier in individuals with intermediate HTT alleles (≥27) than in those with a CAG tract o27. Finally, in patients with sporadic HER2 breast cancer, metastasis increased by a factor of 11.10 per 10 additional CAG repeats in HTT. We concluded that whereas long CAG length could be associated with lower cancer incidence, it could also be paradoxically associated with cancer severity (age of apparition and metastasis development).

A survey of recent unusual high-resolution DNA structures provoked by mismatches, repeats and ligand binding

“…Detailed structural analysis showed that echinomycin induces deformation in the mismatched DNA duplex, allowing cooperative recognition of the T:T mismatch by a second echinomycin molecule. Sequences harboring multiple CAG/CTG repeats are prone to form intra-strand T:T mismatches and have been associated with increased cancer risk in the past ( 84 , 85 ). This recent finding may be useful in re-assessing the utility of echinomycin for detection of MMR-deficient cancers, possibly by leveraging the DNA binding-induced fluorescence quenching properties of echinomycin.…”

Cancer: From Wild-Type to Mutant Huntingtin

“…Additionally, we showed that wild-type HTT is involved in normal mammary gland development [ 12, 14, 15 ]. Moreover, we described an association between the size of CAG repeats in wild-type HTT and cancer prognosis [ 16 ], as well as decreased cancer incidence in the HD population [ 17 ]. In this review, we discuss the function of HTT during carcinogenesis, as well as the relationship between CAG repeats size and cancer incidence and prognosis.…”

Neurodegenerative diseases and cancer: sharing common mechanisms in complex interactions

“…Although smoking has been reported to be more frequent in presymptomatic HD gene carriers than in the general population, cancer incidence has been reduced in HD. Thion et al (2016) made an interesting observation, asserting that polyglutamine diseases showed a lower incidence of cancer, independently of the CAG length (even if the CAG expansion does not reach the incomplete or complete penetrance range). They found that also though the frequency of cancer may be inversely correlated to the number of CAG repeats (nCAG), a large nCAG might favor the progression and local spreading of some cancers, particularly breast tumors (Thion et al, 2016).…”

“…Thion et al (2016) made an interesting observation, asserting that polyglutamine diseases showed a lower incidence of cancer, independently of the CAG length (even if the CAG expansion does not reach the incomplete or complete penetrance range). They found that also though the frequency of cancer may be inversely correlated to the number of CAG repeats (nCAG), a large nCAG might favor the progression and local spreading of some cancers, particularly breast tumors (Thion et al, 2016). This was supported by McNulty et al (2018) in their research report from 6540 subjects participating in the REGISTRY study of the European Huntington's Disease Network, one of the most extensive studies performed comparing cancer incidence in HD patients with the general population, observing lower rates of malignancy in the former group.…”