Norifumi Tanaka

Prediction of affected MEN2A gene carriers by DNA linkage analysis for early total thyroidectomy: A progress in clinical screening program for children with hereditary cancer syndrome☆☆☆

The gene predisposing to multiple endocrine neoplasia type 2A (MEN 2A) has been assigned to chromosome 10, and affected gene carriers can be identified before the development of associated malignancy in some informative families. We applied these advances in gene mapping to clinical screening for possible pediatric surgery. A family with MEN 2A, consisting of 88 members and their spouses, was studied to test the reliability of the provocation of plasma calcitonin with pentagastrin and the possibility of DNA diagnosis of mutated gene carriers with DNA probes closely linked to the MEN2A gene including RBP3 and FNRB genes. Nineteen of the 88 were diagnosed as MEN 2A carriers. Twelve of them were treated surgically and the others died of medullay thyroid carcinoma (MTC) or pheochromocytoma. A strikingly sensitive response of calcitonin was observed in all those with MTC. The genotypes cosegregating with the abnormal allele at MEN2A in this family could be deduced from clinically established affected members. The early detection of gene carriers allows us to concentrate our screening efforts on children at high risk and to release non gene carriers from repeated unnecessary testing. MEN2A is one of the first cancer syndromes for which DNA screening permits early detection of members at high risk.

Preclinical detection of men 2A gene carrier using linked DNA markers

SummaryWe have performed preclinical risk estimation of multiple endocrine neoplasia type 2A (MEN 2A) by using the polymorphic DNA markers tightly linked to the MEN2A locus. The gene for MEN 2A has been assigned to the pericentromeric region of chromosome 10 by linkage analysis. The preclinical detection of gene carriers in MEN 2A families using tightly linked DNA markers is useful for surgical treatment at an early stage. The DNA markers, RBP3 (retinol-binding protein 3, interstitial) and FNRB (fibronectin receptor, beta polypeptide), are both tightly linked to the MEN2A locus, and are localized to opposite sides of the MEN2A locus. We have used RBP3 and FNRB as markers for preclinical diagnosis. Of 18 Japanese families with MEN 2A, 6 families are informative for both loci, and other 10 families are informative for either RBP3 or FNRB. In one informative family, a 20-year-old female is predicted to be the gene carrier (probability; about 99%). She should be carefully followed up till full penetrance age. We conclude that DNA-based prediction of MEN 2A is an effective procedure for clinical use.

Mapping of the genes around MEN2A locus using pulsed-field gel electrophoresis

SummaryThe gene for multiple endocrine neoplasia type 2A (MEN 2A) is closely linked to RBP3 (retinol-binding protein 3, interstitial, probe IRBP.H4) and the DNA marker D10S15 (probe pMCK2), which have been assigned to the proximal long arm of chromosome 10 by linkage analysis both in Caucasian and Japanese populations. We have constructed a rare-cutting restriction map around the RBP3 and D10S15 loci by pulsed-field gel electrophoresis (PFGE). The RBP3 and D10S15 loci appeared to be within a single 160 kb MluI fragment. In 5 patients with MEN 2A, gene rearrangements, such as a gross deletion, were not found in the 880 kb NruI fragment which covered the closest region to the MEN-2A locus from the RBP3 and D10S15 loci.

STUDIES ON THE PATIENTS WITH RECURRENT BREAST CANCER AFTER A LONG DISEASE-FREE INTERVAL

One hundred forty-eight patients with recurrent breast cancer were treated in our hospital during the 15 years from January 1967 to December 1981. Eighteen patients had a long disease-free interval (DFI) (more than 5 years).We compared these patients with patients having a short DFI (less than 2 years) and an intermediate DFI (2 to 5 years).The results were as follows; (1) The average age of long DFI patients was as relatively younger as 47.1 years than those in the other groups. (2) 23.5% or 55.6% of the patients was in stage I or lymphnode-negative respectively. (3) Hormone receptors assay in 5 patients revealed that all were ER (t). (4) Common sites of recurrences included soft tissue and bone. (5) Long postrelapse survival (PRS) was confirmed in the long DFI patients. (6) Surgery was the first-line treatment in five patients with soft tissue recurrences. Endocrine therapy was also the treatment of choice.Therefore, we conclude that aggressive surgical treatment and/or endocrine therapy are efficant for the recurrent breast cancer with a long DFI.