A Locus Linked to p16 Modifies Melanoma Risk in Dutch Familial Atypical Multiple Mole Melanoma (FAMMM) Syndrome Families

The CDKN2A gene that encodes the cell cycle inhibitor p16 shows mutations in many but not all 9p21-linked melanoma families. Most Dutch melanoma families segregate for a unique founder mutation (p16-Leiden), encoding a truncated nonfunctional p16 protein. The highly variable risk for p16-Leiden carriers to develop melanoma suggests a role for other genetic and/or environmental factors. We hypothesized that a 9p21 gene other than CDKN2A may be relevant in the remaining 9p21-linked melanoma families without p16 mutations but may also act as a risk modifier in p16-Leiden carriers. Haplotype analysis for 9p21 was performed using microsatellite markers in six p16-Leiden families originating from a founder population. p16-Leiden carriers in two families shared an unexpectedly large founder haplotype ( approximately 20-cM) around CDKN2A, mostly in proximal direction. Melanoma-positive p16-Leiden carriers from these families showed this extensive proximal haplotype compared with melanoma-negative p16-Leiden carriers from the same families. Additional p16-Leiden families less heavily affected with melanoma showed shorter haplotypes sharing, excluding the region proximally of CDKN2A. The presence of a gene involved in melanoma susceptibility proximal of CDKN2A is corroborated by somatic deletions of 9p in tumors, which frequently do not include CDKN2A but a more proximal chromosomal area instead. Our results provide a candidate region for further gene mapping in p16-negative 9p21-linked melanoma families and guide the search for risk modifiers in melanoma development.     

The distinctive profile of risk factors of nasopharyngeal carcinoma in comparison with other head and neck cancer types

Background

Nasopharyngeal carcinoma (NPC) and other head and neck cancer (HNCA) types show a great epidemiological variation in different regions of the world. NPC has multifactorial etiology and many interacting risk factors are involved in NPC development mainly Epstein Barr virus (EBV). There is a need to scrutinize the complicated network of risk factors affecting NPC and how far they are different from that of other HNCA types.

Methods

122 HNCA patients and 100 control subjects were studied in the region of the Middle East. Three types of HNCA were involved in our study, NPC, carcinoma of larynx (CL), and hypopharyngeal carcinoma (HPC). The risk factors studied were the level of EBV serum IgG and IgA antibodies measured by ELISA, age, sex, smoking, alcohol intake, histology, and family history of the disease.

Results

EBV serum level of IgG and IgA antibodies was higher in NPC than CL, HPC, and control groups (p < 0.01). NPC was associated with lymphoepithelioma (LE) tumors, males, regular alcohol intake, and regular smoking while CL and HPC were not (p < 0.05). CL and HPC were associated with SCC tumors (p < 0.05). Furthermore, NPC, unlike CL and HPC groups, was not affected by the positive family history of HNCA (p > 0.05). The serum levels of EBV IgG and IgA antibodies were higher in LE tumors, regular smokers, younger patients, and negative family history groups of NPC patients than SCC tumors, non-regular smokers, older patients and positive family history groups respectively (p < 0.05) while this was not found in the regular alcoholics (p > 0.05).

Conclusion

It was concluded that risk factors of NPC deviate much from that of other HNCA. EBV, smoking, alcohol intake, LE tumors, male patient, and age > 54 years were hot risk factors of NPC while SCC and positive family history of the disease were not. Earlier incidence, smoking, LE tumors, and negative family history of the disease in NPC patients were associated much clearly with EBV. It is proposed that determining the correct risk factors of NPC is vital in assigning the correct risk groups of NPC which helps the early detection and screening of NPC.     

Severe episodic neurological deficits and permanent mental retardation in a child with a novel FHM2 ATP1A2 mutation

OBJECTIVE: Attacks of familial hemiplegic migraine (FHM) are usually associated with transient, completely reversible symptoms. Here, we studied the ATP1A2 FHM2 gene in a young girl with episodes of both very severe and transient neurological symptoms that were triggered by mild head trauma as well as permanent mental retardation. Her family members suffered from hemiplegic and confusional migraine attacks. METHODS: Mutation analysis of the ATP1A2 gene was performed by direct sequencing of all exons and flanking intronic regions, using genomic DNA of the proband. Functional consequences of the mutation were analyzed by cellular survival assays. RESULTS: We identified a novel G615R ATP1A2 mutation in the proband and several of her family members. Functional analysis of mutant Na,K-ATPase in cellular survival assays showed a complete loss-of-function effect. INTERPRETATION: Permanent mental retardation in children may be caused by ATP1A2 mutations.     

A new heparin fragment decreases liver ischemia-reperfusion injury

<正>To the Editor:Ischemia-reperfusion injury following surgery and transplantation can lead to irreversible multiorgan failure.Intracellular calcium overload is associated to cellular death during ischemiareperfusion.A recently discovered heparin fragment (HF),trisulfated disaccharide (TD),that acts on sodium-calcium exchanger(NCX) decreasing intracellular Ca²⁺,showed effectiveness on protecting hepatocytes from ischemia-reperfusion injury [1],