Management of patients with germline predisposition to haematological malignancies considered for allogeneic blood and marrow transplantation: Best practice consensus guidelines from the UK Cancer Genetics Group (UKCGG), CanGene-CanVar, NHS England Genomic Laboratory Hub (GLH) Haematological Malignancies Working Group and the British Society of Blood and Marrow Transplantation and cellular therapy (BSBMTCT).

Germline predisposition to haematological cancers is increasingly being recognised. Widespread adoption of high-throughput and whole genome sequencing is identifying large numbers of causative germline mutations. Constitutional pathogenic variants in six genes (DEAD-box helicase 41 [DDX41], ETS variant transcription factor 6 [ETV6], CCAAT enhancer binding protein alpha [CEBPA], RUNX family transcription factor 1 [RUNX1], ankyrin repeat domain containing 26 [ANKRD26] and GATA binding protein 2 [GATA2]) are particularly significant in increasing the risk of haematological cancers, with variants in some of these genes also associated with non-malignant syndromic features.

Germline predisposition to haematological malignancies: Best practice consensus guidelines from the UK Cancer Genetics Group (UKCGG), CanGene-CanVar and the NHS England Haematological Oncology Working Group.

The implementation of whole genome sequencing and large somatic gene panels in haematological malignancies is identifying an increasing number of individuals with either potential or confirmed germline predisposition to haematological malignancy. There are currently no national or international best practice guidelines with respect to management of carriers of such variants or of their at-risk relatives. To address this gap, the UK Cancer Genetics Group (UKCGG), CanGene-CanVar and the NHS England Haematological Oncology Working Group held a workshop over two days on 28-29th April 2022, with the aim of establishing consensus guidelines on relevant clinical and laboratory pathways.

Genetics in myeloma: genetic technologies and their application to screening approaches in myeloma.

Background: Despite advances in the treatment of multiple myeloma (MM), it remains an incurable malignant disease. Myeloma genetics is intrinsically complex, but it offers an opportunity to categorize the disease and apply a personalized medicine approach.

Areas Of Agreement: Research into the genetics of myeloma is moving at a fast pace and is highlighting areas and patient cohorts likely to benefit from specific treatment.

Constitutional and somatic rearrangement of chromosome 21 in acute lymphoblastic leukaemia.

Changes in gene dosage are a major driver of cancer, known to be caused by a finite, but increasingly well annotated, repertoire of mutational mechanisms. This can potentially generate correlated copy-number alterations across hundreds of linked genes, as exemplified by the 2% of childhood acute lymphoblastic leukaemia (ALL) with recurrent amplification of megabase regions of chromosome 21 (iAMP21). We used genomic, cytogenetic and transcriptional analysis, coupled with novel bioinformatic approaches, to reconstruct the evolution of iAMP21 ALL.

Fluorescence in situ hybridisation (FISH) in histologically challenging conjunctival melanocytic lesions.

Background: Even in experienced hands, the classification of some melanocytic lesions of the conjunctiva remains challenging. In skin pathology, the recent application of fluorescence in situ hybridisation (FISH) has been demonstrated to be of use for the analysis and diagnosis of ambiguous melanocytic neoplasms of the skin. This study set out to evaluate this method on seven prospective conjunctival cases that were histologically equivocal.

Five members of the CEBP transcription factor family are targeted by recurrent IGH translocations in B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

CCAAT enhancer-binding protein (CEBP) transcription factors play pivotal roles in proliferation and differentiation, including suppression of myeloid leukemogenesis. Mutations of CEBPA are found in a subset of acute myeloid leukemia (AML) and in some cases of familial AML. Here, using cytogenetics, fluorescence in situ hybridization (FISH), and molecular cloning, we show that 5 CEBP gene family members are targeted by recurrent IGH chromosomal translocations in BCP-ALL.

Translocation (6;17)(q23;q11.2): a novel cytogenetic abnormality in congenital acute myeloid leukemia?

Congenital leukemia occurring within 4 weeks of birth is extremely rare and, excluding transient neonatal myeloproliferation associated with Down syndrome, makes up approximately 1% of childhood leukemias. It is usually seen as acute myeloid leukemia (AML), most frequently French-American-British (FAB) types M4 and M5. Recurrent cytogenetic abnormalities have been reported in this group, and in approximately one third of cases the MLL gene at 11q23 is involved.

Folate-sensitive fragile site FRA10A is due to an expansion of a CGG repeat in a novel gene, FRA10AC1, encoding a nuclear protein.

Fragile sites appear visually as nonstaining gaps on chromosomes that are inducible by specific cell culture conditions. Expansion of CGG/CCG repeats has been shown to be the molecular basis of all five folate-sensitive fragile sites characterized molecularly so far, i.e.

Reprogramming in inter-species embryonal carcinoma-somatic cell hybrids induces expression of pluripotency and differentiation markers.

Somatic cell reprogramming holds great promise for the development of novel cellular therapeutics. A number of sources of reprogramming potential have been identified, including oocytes, embryonic germ (EG) cells and embryonic stem (ES) cells. However, each of these sources of reprogramming factors is problematic, since they are either not freely available or have special growth requirements.

Detection of cryptic MLL insertions using a commercial dual-color fluorescence in situ hybridization probe.

Involvement of the MLL gene located at chromosome region 11q23 is a frequent occurrence in both acute myelocytic leukemia and acute lymphoblastic leukemia. More than 30 loci have now been associated with MLL, usually by reciprocal translocation. Deletions, insertions, and more complex rearrangements of MLL are rarely seen.