An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers.

Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals.

Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk.

Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.

Marrow aplasia developing 13 years after HLA-identical sibling allogeneic transplantation for chronic myeloid leukaemia:successful treatment with antithymocyte globulin and peripheral blood stem cell infusion from the original donor

Secondary or late graft failure has been defined as the development of inadequate marrow function after initial engraftment has been achieved. We describe a case of profound marrow aplasia occurring 13 years after sibling allogeneic bone marrow transplantation for chronic myeloid leukaemia (CML) in first chronic phase. Although the patient remained a complete donor chimera, thereby suggesting that an unselected infusion of donor peripheral blood stem cells (PBSC) or bone marrow might be indicated, the newly acquired aplasia was thought to be immune in aetiology and some immunosuppression was therefore considered appropriate. Rapid haematological recovery was achieved after the infusion of unselected PBSC from the original donor following conditioning with anti-thymocyte globulin (ATG).

Whose sins do the Brethren confess? The problem of sin as the problem of expiation

Among Brethren fisher families in Gamrie, northeast Scotland, professional clergy and written liturgy are held to be blasphemous denials of the true workings of the Holy Spirit. God, I was told, chooses to speak through all born-again (male) persons, unrestricted by the vain repetitions of lettered clerics and their prayer books. In this context, confession of one’s own sin is a private and pointedly interior affair. In Gamrie, not only did every man seek to be his own skipper, but also his own priest. Yet, much of Brethren worship is given over to ritualised acts of confession. So whose sins do the Brethren confess, and to what end? This article argues that among the Brethren of Gamrie, such acts involve confessing not one’s own sin, but the sins of a ‘sick’ and ‘fallen’ world. More than this, by attending to the sociological (as opposed to theological) processes of confessing the sins of another, we see a collapse in the distinction between confiteor and credo that has so dogged anthropological studies of Christianity. In Brethren prayer and bible study, as well as in everyday gossip, the “I confess” of the confiteor and the “I believe” of credo co-constitute one another in and through evidences of the ‘lostness’ of ‘this present age’. But how, if at all, does this solve ‘the problem of sin’? This article suggests that, with the ritual gaze of confession turned radically outward, Brethren announcements of global wickedness enact (in a deliberate tautology) both a totalising call for repentance from sin, and a millenarian creed of the imminent apocalypse. Here, the problem of ritual can be understood as the problem of (partially failed) expiation.