Note: The contents of the AMP Newsletter and Website (www.ampweb.org) may not be reproduced for distribution of any kind without the express, specific, written permission of the AMP. Thank you for your cooperation. Contact AMP at 301.571.1880 or amp@pathol.faseb.org with any questions.

Now in our fourth year, the Association for Molecular Pathology is taking on new challenges. Since its inception, AMP has been supported by its parent organization UAREP (Universities Associated for Research and Education in Pathology), and we have been very fortunate to benefit from their administrative support. UAREP supported the first Molecular Diagnostic Workshops in the early 1990s that led to the formation of AMP. Recently, AMP has incorporated and has separated from UAREP, although we will continue to share administrative office space. UAREP and AMP also share, along with the American Society for Investigative Pathology (ASIP) and the Association of Pathology Chairs (APC), the excellent services of Dr. Frances Pitlick as Executive Officer. (And of course, AMP specifically benefits from the services of Maricel Herrera in the AMP office.) The coordinated pathology administrative office, located on the FASEB campus in Bethesda, provides consolidated services with minimal duplication to save costs and to keep all of the pathology organizations informed about common issues. The office of The American Journal of Pathology (AJP) is also located within the combined office, as will be the editorial office of our new journal, The Journal of Molecular Diagnostics, which we are jointly publishing with ASIP.

Speaking of our new journal, we are anticipating the selection of a Senior Editor by the end of May. Cheryl Willman, Dan Farkas, Peggy Gulley and Wayne Grody have been representing AMP’s interests on the selection committee. The AJP office is already receiving submissions for the new journal, and we still anticipate that the first issue will be published in November, in time for publication of abstracts to the AMP Annual Meeting.

Speaking of which, see this Newsletter for a summary of the Annual Meeting schedule. You should have already received the meeting brochure in the mail. Spearheaded by the initiatives of Jeff Kant and the Training & Education Committee, we have put together a package of special offers for students, residents, and fellows at the meeting, including reductions in registration fees. See inside this Newsletter as well as the meeting brochure for details. We want to encourage our "trainees" to submit abstracts to the meeting, so note that there is an additional registration reduction if an abstract is submitted by a trainee as first author. Clearly specified this year is the requirement that all abstracts have to be sponsored by a Regular Member of AMP. We hope that all mentors will encourage their fellows, residents, and students to take advantage of our special initiatives and that they will sponsor the abstracts of non-members as well as Associate Members. Posters presented at the meeting by trainees will be eligible for meritorious recognition, including cash awards supported by our Academic Sponsors. A highlight of the meeting this year will be the presentation of the AMP Award of Excellence (supported by a generous grant from Visible Genetics, Inc) to the originator of Southern blots, Dr. Edwin Southern. Dr. Southern has continued to make major contributions to molecular biology since his blotting technique was first described, and he will offer us new insights during this award lecture. Thanks to Debra Leonard for organizing the award lecture this year. Karl Voelkerding and the Program Committee have been working hard to bring us an excellent scientific meeting and the opportunity to communicate and network with each other.

Speaking of which (I am wondering how far I can take this convention as I write this), Dan Farkas, our Secretary-Treasurer, Chair of the Publications Committee, and Editor of the Newsletter, announces the new AMP homepage at www.ampweb.org. We all owe a big debt to Tony Killeen, who initiated and has maintained the AMP homepage until now. You should have already received an e-mail with your personal user name and password. Although we tested different types of computers and browsers, we know we can't imagine all the configurations. If you have any problems, please contact us; we are working with our Webmaster to iron out any glitches. See the next section for a special set of instructions on how to access and search the membership directory on the homepage. We hope to have information about the annual meeting available on the homepage shortly. We are working with the Chairs of the Subdivisions to enhance the Subdivision homepages and are in search of volunteers who would like to become webmasters of the Subdivision homepages. Please contact your Subdivision Chair

ID: Karen Kaul: k-kaul@nwu.edu;

ST: Marc Ladanyi: ladanyim@mskcc.org;

GEN: Mark Lovell: mal3u@virginia.edu)

if you are interested in helping out. We also hope to provide electronic voting on the homepage this year.

Speaking of which, see inside this Newsletter and the homepage for the Call for Nominations for this year’s elections and a description of leadership positions in AMP. Contact members of the Nominating Committee if you are interested in self-nominating or nominating a colleague. Your input is essential to keep AMP a vibrant organization.

Speaking of which, we are proud to announce that AMP’s first published paper, "Recommendations for in-house development and operation of molecular diagnostic tests," was published in April in American Journal of Clinical Pathology (vol 111, pp 449-463). The authors of the paper were members of the 1996 Clinical Practice Committee, chaired by Debra Leonard, and also include Mike Whittaker (thanks especially to you, Mike!), Dan Farkas, Karen Kaul, and Tony Shrimpton.

On behalf of the AMP Council, I wish everyone a great summer. Enjoy, but remember to take the time to submit your abstract to the annual meeting by the end of July!

Mark E. Sobel, MD, PhD, AMP President

Email: mesobel@pathol.faseb.org

We have installed an interactive Membership Directory on the new AMP homepage. Since this is available for AMP members only, you will need to use a User Name and a Password to log in. You should have received by e-mail a user name and a password for this purpose. Please note that the letters in the user name and password are NOT case-sensitive (i.e., MSobel and msobel are both valid). Once you click on "LOGIN" the search page will appear. If you choose to change your user name or password, go to the bottom of the search page, and click on "Edit Your Login Info".

Searches of the Membership Directory are possible by last name, institution, department, degree, subdivision, city, state, or country. Here again, the search is NOT case-sensitive. Note that periods are generally removed, so instead of Ph.D., use "PHD" or "phd". There are potential problems when searching by institution, since the directory presents the address provided by the member, and there are many possible ways that members from the same institution have listed their affiliation; e.g., UNM, U New Mexico, and University of New Mexico. The search will look for exactly what you ask for. If you search for University of New Mexico, it will not find UNM or U New Mexico. It may be easier for you to use the city search engine when you think you are looking for an institution which can be described or listed in various ways. Also note that the search criteria are inclusive ("anded"). For example, if you want to select members from Miami and from Pennsylvania, the search will be unsuccessful because it will look for members who have both "Miami" and "Pennsylvania" in their record.

Once you have logged in, you can access other proprietary areas of the AMP homepage (such as the Newsletter) without having to login again. However, after a certain period of inactivity has elapsed, you will be asked to login again. Good luck with using the new homepage. Contact the office if you have any problems.

Mark Sobel, MD, PhD, AMP President

The AMP T&E Committee, working with Council, has made the AMP Annual Meeting even more affordable and appealing for trainees to attend this year. Early registration (by Oct. 15) has been reduced ($150) and is a mere C note for trainees registering AND submitting an abstract by July 30. Registration for procrastinating trainees (after Oct. 15) will still be only $200, so no excuse not being there. The abstract deadline is July 30, so members, remind trainees at your institution to register early and get after those projects that need to be completed to be submitted by the abstract deadline.

Plain talk on Trainee Registration Fees:

* and a supporting letter from your Training Program Director (see abstract and registration instructions)

Trainee submissions will be judged competitively at the meeting and 3 awards of meritorious recognition conferred at the business meeting. In the context of current reimbursement in health care and AMP’s attained age of 4 years, this year awards will be lavish but not excessive, i.e. $200.

Preliminary Program

8 am-10 pm Corporate Sponsored Workshops

5-8 pm Registration

7:30-9 pm Clinical Practice Committee Meeting

9-10:30 pm Nominating Committee Meeting

7-7:50 am Registration & Continental Breakfast

8-9:45 am PLENARY SESSION I - GENETICS

9:45-10:15 am Break/Visit Posters/Exhibits

Noon-1 pm Lunch/Visit Posters/Exhibits

2:30-4 pm WORKSHOPS - SESSION A

4-5:30 pm Visit Attended Posters & Exhibits

6:30-7:30 pm Welcome Reception

7-7:55 am Continental Breakfast

9:45-10:15 am Visit Posters/Exhibits

Noon-1 pm Lunch/Visit Posters/Exhibits

1-2:30 pm WORKSHOPS - SESSION B

2:30-3:30 pm Visit Posters/Exhibits

3:30-5 pm WORKSHOPS - SESSION C

5-5:30 pm Break

5:30-6:30 pm AMP Business Meeting

7-7:55 am Continental Breakfast

10:30-Noon WORSHOPS - SESSION D

Noon Conference Adjourns

To encourage active participation of trainees during the meeting, the AMP Council is offering reduced registration to all trainees. In addition, trainees who register by the October 15 deadline will receive a further reduction in the registration fee if an abstract is submitted with their name as first author. (Please note instructions below for sponsorship of abstracts.) Trainees include Associate Members of AMP, non-members of the society who are students, residents, or fellows, as well as Regular AMP Members who fall into the student, resident, or fellow category. Abstracts submitted by trainees will be designated as trainee abstracts during the poster sessions and will be eligible for meritorious recognition at the discretion of the Training & Education Committee. All trainees must also submit a letter from their Program Director, or other appropriate official, on official letterhead, verifying their status in-training to qualify for trainee registration and for meritorious recognition.

Please Note: Trainees must submit registration by mail or fax with letter from Program Director; on-line registration is not available for this group.

All participants are invited to submit abstracts of work related to molecular pathology and diagnostics. Original abstract forms must be mailed in time to be RECEIVED by 5:00 pm EDT on Friday, July 30. FAXED ABSTRACTS ARE NOT ACCEPTABLE FOR PUBLICATION (see below). Accepted abstracts will be published with the meeting program. Abstract authors should be prepared to present posters summarizing their results.

Only Regular Members are eligible to submit abstracts. Associate Members and Non-members must have a Regular Member sign the abstract as a sponsor. Abstracts of work that has not been published as an abstract or as part of a published paper, or that is not currently under consideration as an abstract for another meeting, also will be published in the first issue of The Journal of Molecular Diagnostics. Authors must indicate on the abstract form whether this work has been presented before or is currently under consideration for publication. This will not affect presentation of the abstract at the meeting.

The Association for Molecular Pathology Nominating Committee is entertaining suggestions for nominees for the open positions listed below. The positions and descriptions of the position responsibilities are also available on the new AMP web page at www.ampweb.org. Please e-mail or call (for those without e-mail access) suggestions for nominees for Council-level positions to Debra Leonard. Please e-mail or call (for those without email access) suggestions for the Subdivision positions to relevant members of the Nominating Committee. Contact information for the Nominating Committee members is provided below.

Self-nominations are welcomed. We encourage your active participation in the governance of AMP, and hope that individuals who have not had an opportunity to serve in an elected position will be included in this year’s ballot. We also welcome incumbents who can lend an experienced hand!

On behalf of the Nominating Committee, I thank each of you in advance for your thoughtful consideration and your nomination suggestions.

COUNCIL POSITIONS

• President-elect (will become President in 2001 & Past President in 2002)
• Secretary-Treasurer (2 year term of office)
• Chair, Training and Education Committee (2 year term of office)
• Chair-elect, Program Committee (will become Chair of Program Committee in 2001)

GENETICS SUBDIVISION

• Chair-elect (will become Chair in 2001)
• Nominating Committee Representative
• Training and Education Committee Representative

HEMATOPATHOLOGY SUBDIVISION

• Chair-elect (will become Chair in 2001)
• Nominating Committee Representative
• Clinical Practice Committee Representative

INFECTIOUS DISEASES SUBDIVISION

• Chair-elect (will become Chair in 2001)
• Nominating Committee Representative
• Training and Education Committee Representative

SOLID TUMORS SUBDIVISION

• Chair-elect (will become Chair in 2001)
• Nominating Committee Representative
• Clinical Practice Committee Representative

President-elect: 1. President-elect automatically becomes the President and Past President in the subsequent two

years.

2. The primary responsibility as President-elect is to Chair the Nominating Committee, working with representatives from the subdivisions to organize and administrate the nomination and election process. The Nominating Committee is also responsible for nominating awardees of the AMP Award for Excellence in Molecular Pathology.

3. As a member of Council, the President-elect participates in the monthly Council calls and e-mail discussions, and may choose to work on specific projects of AMP.

4. The President is Chair of Council and works with members of Council to facilitate projects and other efforts. The President sets the goals and agenda for AMP, in collaboration with Council and the AMP membership. The President is the elected representative of AMP.

5. The primary responsibility of the Past President is to work with representatives from industry with interests in supporting AMP or participating in the annual meeting as a vendor. The Past President works with the AMP office to coordinate the workshops before the annual meeting and the exhibits during the meeting.

Secretary-Treasurer: 1. The Secretary-Treasurer is elected to a 2-year term of office.

2. Take and distribute minutes of AMP Council conference calls and Council meetings at the AMP annual meeting.

3. Chair the Publications Committee, and administer AMP publication rules for official AMP documents.

4. Oversight of the AMP web page, including updating information on the site, working with Subdivision Chairs to keep subdivision pages current, and working with Nominating Committee on electronic voting.

5. Nomination of Publications Committee members for Council approval as committee members rotate off the committee, including AMP Newsletter Editor, who is an ad hoc member of this committee.

6. Contribute a report for the AMP Newsletter three times per year.

Chair, Training and Education Committee: 1. The Chair of the Training and Education Committee is elected to a 2-year term of office.

2. The Chair of the Training and Education Committee is a member of Council and participates in the monthly Council calls and e-mail discussions.

3. The primary responsibility of the Chair is to work with the representatives of the subdivisions to establish and implement projects related to training and education in Molecular Pathology at all levels. The Committee has conference calls 3 times a year and a meeting in person at the annual meeting.

4. The Chair submits an article to the AMP Newsletter three times a year providing the membership with an update of the Committee's activities.

Chair-elect, Program Committee: 1. The Chair-elect auto-matically becomes Chair of the Program Committee in the following year.

2. The Program Chair-elect is a member of the program committee and provides input into the planning of the annual meeting. As a program committee member, the Program Chair-elect gains experience and insight that facilitates his/her transition to program chair in the subsequent year.

3. The Chair-elect is responsible for oversight of the portion of the annual meeting devoted to abstract and poster presentations.

4. The Program Chair is responsible for overall planning and organization of the AMP annual meeting. The Program Chair meets with the program committee through monthly conference calls which serve as a forum for updates, discussion and planning for the annual meeting.

5. The Program Chair works in conjunction with the program committee members to identify topics and speakers for plenary sessions and workshops. Subdivision chairs and chairs-elect recruit speakers and organize workshops for their respective subdivisions.

6. The Program Chair serves as the direct link to the AMP central office which administers the annual meeting. The Program Chair is responsible for providing the AMP Council with monthly updates on meeting planning.

Chair-elect of a Subdivision: 1. The Chair-elect automat-ically becomes Subdivision Chair in the 2^nd year.

2. Since the Program Committee is comprised of the Chairs and Chairs-elect of the Subdivisions, a primary responsibility of this job is to represent the Subdivision's interests in programming speakers and workshops at the Annual Meeting for the next two years. As a Program Committee member, there will be monthly conference calls to discuss progress on planning plenary and workshop sessions. Program Committee members assist the Program Chair in contacting speakers and writing confirmation letters.

3. The Chair-elect and Chair work together to assure good communication with the members of the Subdivision so that issues under discussion by the Society leadership receive appropriate input from each Subdivision.

4. The Chair-elect and Chair serve as primary points of communication with Council to assure that Subdivision activities and concerns are addressed by the Society.

5. The Chair (or Chair-elect in the Chair's absence) will participate in monthly Council conference calls.

6. The Chair and Chair-elect assist the Nominating Comm. in developing a slate of candidates for the next election.

7. The Chair submits an article to the AMP newsletter three times a year providing membership with an update of Subdivision activities or the relevant topic of choice.

8. At the Annual Meeting, chair the annual business meeting of the Subdivision.

Representative to the Clinical Practice Committee: 1. The term of office will be two years. The Chair of the Committee is a Council member.

2. The Clinical Practice Committee meets monthly by conference call and in person at the annual meeting to address issues pertaining to the clinical practice of molecular pathology. There are also frequent communications by e-mail.

3. Issues of the last 3 years included:

1. Regulatory affairs : genetic privacy, gene patenting, validation, certification, FDA initiatives, quality control and assurance, legislative and legal issues.
2. Test utilization issues include medical utility, reimbursement, availability, costs and charges, as well as development of collaborative schemes for utilization of new diagnostic modalities.
3. Test availability issues including updates of the AMP Test Directory that lists the tests available in AMP member laboratories as well as contacts with companies that might restrict access to new tests due to patenting and licensing rights.
4. Practice guidelines for molecular pathology tests

Representative to the Training and Education Committee:

1. The term of office will be two years. Associate as well as Regular members are eligible to hold this office. The Chair of the Committee is a Council member.

2. The representative is expected to interact with members of the Subdivision but also serves all AMP members.

3. Representatives are responsible for bringing member concerns on T&E issues to the Committee for discussion.

4. Members will work with the Chair and Chair-elect of the Subdivision to provide feedback to Subdivision members and to help coordinate T&E projects.

5. In past years, the T&E Committee has addressed important issues including training guidelines, compilation of curricular materials, suggestions for new workshops and outreach programs, surveys of educational offerings in molecular pathology, and communication with the American Board of Pathology.

6. The Committee meets approximately 3 times a year by conference call, once in person at the annual meeting, and there is frequent e-mail communication.

Representative to the Nominating Committee: 1. The term of office is two years. The President-elect chairs the Committee.

2. Members of the Committee work with the Chair and Chair-elect of the Subdivision to develop a slate of candidates for the next election. This includes Subdivision representatives as well as suggestions for Council-level positions.

3. The Committee meets by conference call at least once a month from Apr.-Sept. to develop the ballot. In addition, the Committee meets in person at the Annual Meeting.

4. Members of the Committee assist the President-elect in contacting potential nominees and evaluating candidates for nomination.

5. The Nominating Committee also is responsible for nominating awardees of the AMP Award for Excellence in Molecular Pathology.

Contributed by: Debra GB Leonard, MD, PhD, President-elect. P 215.662.6550; F 215.662.7529

e-mail: debraleo@mail.med.upenn.edu

The big news in 1999 Molecular Pathology Training and Education is the March approval by the American Board of Medical Specialties (ABMS) of the subspecialty board training program application for certification in Molecular Genetic Pathology (MGP), sponsored jointly by the American Board of Pathology (ABP) and the American Board of Medical Genetics (ABMG). Special thanks to the ABP and particularly Executive Vice President, William Hartmann, as well as all the ABP Trustees and Directors of the ABMG.

The first meeting of the joint Residency Review Committee (RRC) which will oversee establishment of guidelines and the accreditation of fellowship programs in MGP took place in April. To assist the RRC in its role, the T&E Committee has prepared an overview of AMP views on important elements for training and evaluating fellows in MGP, and will be working on an outline of fellowship training guidelines to accompany the Resident Guidelines prepared by the 1996-97 Committees and recently submitted as an official AMP publication.

Certification will be available to M.D.s who have completed a qualifying one year training program in MGP and who hold a primary certificate (Anatomic and/or Clinical Pathology or Genetics) from the ABP or ABMG (perhaps also other Boards but I could not verify this). Physicians who have previously obtained equivalent training in formal programs and ‘by experience’ will be ‘grandfathered’ for at least the first examination. Thus, it would be wise for current, recently graduated or former trainees in molecular pathology to begin to compile now a logbook of several hundred cases of diverse types you worked or are working on unless you anticipate the ability to easily do this when the examination is announced. The information currently required by the ABMG for Clinical Molecular Genetics (date, ID#, disease category, primary testing issue, methods used, interpretation, role of applicant and supervisor) will probably suffice.

Submission to the proposed educational resource archive of literature citations or other training resources members find useful in training residents, fellows and others in molecular pathology have been light. The Committee will continue to welcome on an ongoing basis additional citations from any regular or associate members. Email to Subsection T&E representatives (Crisan, Dumler, Payne, Tsongalis) or me. T&E will be starting on the process of categorizing these and assembling them in electronic form, hopefully for eventual posting to the AMP web page in a searchable format.

T&E has also worked with Council to reduce trainee registration rates for the Annual Meeting to new lows (see accompanying article) and continue the presentation of meritorious awards for trainee presentations at this year’s meeting in St. Louis. Y’all meet us there.

Contributed by Jeff Kant, MD, PhD,

kantja@MSX.UPMC.EDU

The Hematopathology subdivision plans are finalized for the upcoming 1999 AMP meeting. For the Plenary Session on November 5, 1999, Janet Rowley, from the University of Chicago, will speak on "Chromosomal translocations in acute leukemias." Tim McDonnell, from the University of Texas M.D. Anderson Cancer Center, will speak on "Cell death regulation and the pathogenesis of hematolymphoid malignancies." We are very pleased that both speakers accepted our invitation and we are looking forward to their presentations.

The workshops for the upcoming meeting are also scheduled. The first workshop entitled "Quantitative determination of bone marrow transplant engraftment" will be directed by Steven Schichman at the University of Arkansas for the Medical Sciences. This workshop will focus on the various techniques for bone marrow transplant testing, including the types of DNA identity markers and the kits commercially available, and will also include practical examples. The second workshop will be based on the ongoing sample exchange program for testing of IgH, bcl-2/JH, and TCR that is being coordinated by Rita Braziel. As the program committee is currently discussing various details of these workshops, now is a good time for any suggestions or comments (see e-mail address below).

The new AMP homepage has been activated and the push is on to update the Hematopathology Subdivision homepage (which it clearly needs). We hope to make significant progress in this effort in the next few weeks. However, as you know keeping a homepage updated on a regular basis (weekly would be ideal) is much work. If there is a person who would like the responsibility of keeping the Hematopathology subdivision homepage updated regularly and would like to volunteer for this task please let me know (see e-mail address below).

Contributed by: Jeff Medeiros, MD, Subdivision Chair

University of Texas M.D. Anderson Cancer Center

The program is set for the 1999 annual meeting, as you can see in this newsletter. The two workshops for our subdivision will require your participation both before and after the meeting. During the next few weeks, you will receive (via CHAMP and mail) a questionnaire addressing a variety of laboratory procedures and practices. Many of these questions are focussed on difficulties and controversial topics. We hope to use the results of this survey to guide discussion during the workshop. We hope that this will give us all great insight into various approaches used in labs for controls, contamination elimination, troubleshooting, validation of new assays, etc. Being the vociferous and opinionated group that we are, I think that discussion should be lively and the workshop very worthwhile. At any rate, do respond when you get your questionnaires! (Otherwise you will have to listen to Angela Caliendo and me, the moderators, talk for 90 minutes!) Additionally, if you have any burning issues that you want to make sure we have included in this session, let me know ASAP to get it included in the questionnaire.

The second workshop, moderated by Steve Day, will address various approaches to sample preparation. Again, the goal is discussion, so please be prepared to participate and make the most of these valuable and interactive sessions!

Contributed by Karen Kaul, MD, PhD, Subdivision Chair

Obesity seems to have the prerequisites for the type of testing that a molecular genetics lab will be performing in the not too distant future. Its genetic (multifactorial), common (up to one third of all Americans are overweight), medically important (obesity is a predisposing factor for several common chronic diseases including NIDDM and coronary heart disease) and there is an enormous demand ($30 billion per year industry). What we are waiting for is the identification of the predisposing genetic variants. They are likely to be subtle rather than major effects since even a 5% difference in activity over a long enough time period can significantly alter body fat stores and body weight. Obesity is another example of a disease associated with the modern Western lifestyle, a very different environment from that of early human evolution in which there would have been significant selection pressure to favor the genes that efficiently lead to the storage of chemical energy in a compact form. Weight regulation is turning out to be complicated, but the hope is that as the pathways are revealed and our understanding increases, rational therapies can be developed.

To date five obesity genes identified in the mouse have been cloned in the human. These are the Leptin gene (LEP on 7q), its receptor (LEPR on 1p) and some of the downstream pathway genes (TUB on 11p, CPE on 4q, and AGRP on 20q) that enable the brain to regulate body weight. In the obese, the body appears to be returning fat stores to an unhealthy set-point, and there is great interest in knowing how a body-weight set point is created. Another approach has bee through family studies to map obesity-susceptibility genes; to 2p21, 11q21-q22 and possibly 3p24.2-p22.

Unfortunately only two very rare disease-causing mutations have been identified so far, so while we may not yet know which genetic variants at which genes will be worthwhile testing, this is the time to be thinking about the ethical aspects of genetic testing for obesity. Under what circumstances (medical, cosmetic), should testing, including prenatal diagnosis be performed? Once identified, who will be providing the genetic testing, i.e., will the genetic risk factors be patented?

References:

• Comuzzie AG et al. A major quantitative trait locus determining serum leptin levels and fat mass is located on human chromosome 2.. Nat. Genet. 1997. 15: 273-275.
• Hirsch J, Leibel RL. The genetics of obesity. Hospital Practice. 1998. Mar. 15, 55-77.
• Norman RA et al. Genomewide search for genes influencing percent body fat in Pima Indians: suggestive linkage at chromosome 11q21-q22. Am J. Hum Genet. 1997. 60:166-173.
• Strobel A, et al. A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet. 1998. 18:213-215.

Contributed by:

Antony E. Shrimpton, PhD, Genetics, Chair-elect

Several recent papers have characterized the various risks of thrombophilic mutations in pregnancy. This review focuses on data regarding factor V Leiden (FVL). Some controversy exists regarding how pregnancy alters resistance to activated protein C; some authors report values are still within the normal range while others report a significant decrease in the second and third trimesters (1,2). Obviously, testing the underlying genetic lesion circumvents this issue. In terms of risk to the mother, the incidence of deep venous thrombosis in gravid women heterozygous for FVL is 28% versus <1% of controls (3). This is significant given the risk of maternal death due to pulmonary embolism. Significant associations with complications during pregnancy resulting from placental insults have been reported. A threefold increased (20% vs. 6%) incidence of FVL was found in women with complications of pregnancy associated with intervillous or spiral artery thrombosis such as severe preeclampsia, abruption, fetal growth retardation and stillbirth (4). The incidence of FVL was 29.6% in women with placental abruption (5). Women with severe preeclampsia had a 8.9% incidence of FVL compared to with control rate of 4.2% (6). In women with thrombotic lesions of the placenta and adverse pregnancy outcome, 7/13 (53.8%) were heterozygotes for FVL (7). In women with three or more pregnancy losses and no successful pregnancies the prevalence of FVL was 9.0% versus a 3.7% in the control group without a history of pregnancy loss (8). In summary, major obstetrical complications including fetal loss are associated with a two to threefold increased incidence of FVL. Due to the risk of warfarin embryopathy, heparin is the recommended thromboprophylaxis in affected women who are or wish to become pregnant (9).

References:

1. Peek MJ et al. Activated protein C resistance in normal pregnancy. Br J Obstet Gynecol 1997;104:1084-6.

2. Walker MC et al. Changes in activated protein C resistance during normal pregnancy. Am J Obstet Gynecol 1997;177:162-9.

3. Dizon-Townson DS et al. The incidence of the factor V Leiden mutation in an obstetric population and its relationship to deep vein thrombosis. Am J Obstet Gynecol 1997;176:883-6.

4. Kupferminc MJ et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999;340:9-13.

5. Wiener-Megnagi Z et al. Resistance to activated protein C and the Leiden mutation: high prevalence in patients with abruptio placentae. Am J Obstet Gynecol 1998: 179:1565-7.

6. Dizon-Townson DS et al. The factor V Leiden mutation may predispose women to severe preeclampsia. Am J Obstet Gynecol 1996; 75:902-5.

7. Arias F et al. Thrombophilia: a mechanism of disease in women with adverse pregnancy outcome and thrombotic lesions in the placenta. J Mat Fetal Med 1998; 7:277-86.

8. Ridker PM et al. Factor V Leiden as a risk factor for recurrent pregnancy loss. Ann Int Med 1998;128:1000-3.

9. Bonner J et al. Inherited thrombophilia and pregnancy: the obstetric perspective. Sem Thromb Hemostasis 1998;24 Suppl 1:49-53.

Additional mutations in factor V have been identified by sequencing DNA from patients with APC resistance who do not have the R506Q mutation. While mutations involving codon 306, which is also a protein C cleavage site, the frequency of the two mutations identified is low and unassociated with increased incidence of thrombosis.

• Franco RF et al. Factor V Arg 306® Thr (factor V Cambridge) and factor V Arg306® Gly mutations in venous thrombotic disease. Br J Haematol 1998;103:888-90.
• Williamson D et al. Factor V Cambridge: a new mutation (Arg306® Thr) associated with resistance to activated protein C. Blood 1998;91:1140-4.

Contributed by: Mark Lovell, MD

The frequency of chromosomal translocations leading to the formation of fusion proteins in leukemias and sarcomas contrasts sharply with the relative rarity of such genetic alterations in carcinomas. With rare exceptions, these fusion proteins are either chimeric transcription factors or chimeric tyrosine kinases. Various authors have postulated that these reflect some similarities in the processes of hematopoiesis and mesenchymal differentiation, which makes them susceptible to subversion by the formation of oncogenic aberrant transcription factors (1,2). The specificity of each individual translocation has been postulated to reflect a requirement for a specific cell type at a specific differentiation stage, which in turn probably reflects the presence of a suitable set of interacting proteins that may cooperate functionally with the oncogenic aberrant transcription factor to mediate transformation. An analogous hypothesis can be generated for translocations which produce chimeric tyrosine kinases, which may require a set of interacting signaling molecules particular to a given cell type or developmental stage.

Interestingly, certain genes can be rearranged in specific types of both hematologic tumors and solid tumors. Examples have been known for some time. For instance, TLS (a.k.a. FUS) is fused to the CHOP gene in about 95% of myxoid liposarcomas, and to the ERG gene in a subtype of acute myeloid leukemias. The ERG gene in turn can fuse with EWS in approximately 5% of Ewing’s sarcomas. TPM3 fuses with the NTRK1 gene in some papillary thyroid carcinomas to form a chimeric constitutively activated tyrosine kinase. Very recently, TPM3 has also been found to the fused to the ALK gene in rare cases of anaplastic large cell lymphoma (most cases show NPM-ALK) where it will presumably be shown to similarly result in inappropriate expression and activation of the ALK tyrosine kinase domain (3). Finally, a most remarkable report has recently appeared in Blood. The ETV6-NTRK3 fusion resulting from a t(12;15) translocation is found in apparently all cases of congenital fibrosarcoma (4) and the related cellular mesoblastic nephroma; the identical translocation, both cytogenetically and at the molecular level has now been demonstrated in a single case of acute myeloid leukemia in a 59-year-old woman (5). This is the first example of an identical gene fusion associated with completely different tumor phenotypes, presumably reflecting the occurrence of the same translocation in different cellular lineages, i.e. hematopoietic or mesenchymal, at different stages in life. It will be interesting to see if additional examples of this type of phenomenon will be identified, further illuminating the parallels in hematopoietic and mesenchymal differentiation.

1. Barr FG: Translocations, cancer and the puzzle of specificity. Nat Genet 19:121-124, 1998
2. Rabbitts TH: Chromosomal translocations can affect genes controlling gene expression and differentiation - why are these functions targeted ? J Pathol 187:39-42, 1999
3. Lamant L, Dastugue N, Pulford K, et al: A New Fusion Gene TPM3-ALK in Anaplastic Large Cell Lymphoma Created by a (1;2)(q25;p23) Translocation. Blood 93:3088-3095, 1999
4. Knezevich SR, McFadden DE, Tao W, et al: A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma. Nat Genet 18:184-187, 1998.
5. Eguchi M, Eguchi-Ishimae M, Tojo A, et al: Fusion of ETV6 to Neurotrophin-3 Receptor TRKC in Acute Myeloid Leukemia With t(12;15)(p13;q25). Blood 93:1355-1363, 1999

THE AMP ACROSS THE ATLANTIC
THE 1^st ISALA CONFERENCE ON APPLIED DNA DIAGNOSTICS IN ZWOLLE

In the first year of its existence, the Isala klinieken, a merger of two hospitals in Zwolle, The Netherlands (De Weezenlanden and Sophia) organized, in collaboration with the AMP and the Nederlandse Vereniging voor Klinische Chemie Regio Oost, the first Isala conference on applied DNA diagnostics. The conference took place in Zwolle on April 19-20 just when the tulips are blooming.The CEO of the Isala klinieken, Dr. J. Sindram opened the conference and gave a short overview of the Isala klinieken. After an introductory talk on the field of molecular diagnostics by conference co-organizer Dan Farkas (Pasadena,CA) Huib Storm from Leeuwarden, The Netherlands, discussed the opportunities and regulations in DNA testing in The Netherlands. RT-PCR was the principle technique discussed in the presentation of Karen Kaul (Evanston, USA), about circulating tumor cells in prostate and breast cancer, as well as in the presentation of Ellen van der Schoot, Amsterdam (The Netherlands) about rhesus genotyping of fetal cells in the maternal circulation. The Monday morning sessions was completed by another AMP member, Winand Dinjens from Rotterdam, the Netherlands, who described the clonal analysis of (solid) tumors usng p53 gene mutations and loss of heterozygosity as markers.

During the genetic disease session on Monday afternoon Karl Voelkerding addressed the issue of genomic imprinting in the diagnosis of the Prader Willi syndrome and the Angelman syndrome. Homozygous deletions of exon 7 of the SMNt gene confirms the diagnosis of Spinal Muscular Atrophy in approximatey 95% of all cases. Debra Leonard (Philadelphia,USA) not only discussed the molecular testing but also the dilemmas, pitfalls and benefits in genetic counseling in a family with SMA. Henk Engel (Zwolle, The Netherlands) showed that testing for rare genetic diseases can easily be done in well-equipped, non-university hospitals as he described the elucidation of a new mutation leading to neurohypophyseal diabetes insipidus. The difficulties in mitochondral DNA testing, like mitochondrial segregation and mtDNA heteroplasmy and the diagnosis of deafness associated diabetes was addressed by Jody van den Ouweland (Leiden. The Netherlands). Conference co-organizer and AMP member, Bert Dikkeschei showed that exon deletion analysis by capillary electrophoresis after PCR, could be used in the diagnoses of the genetic skin disease, X-linked ichtyosis and in screening for heterozygotes. In the final lecture of the day Ellen van der Schoot (Amsterdam, The Netherlands) demonstrated some applications of molecular diagnostics in the hematological malignancies.On Tuesday morning the second presentation of Karl Voelkerding was a clinical and diagnostic update on hereditary hemochromatosis. Karen Kaul made a comparison between coventional lboratory tests and TB PCR in the diagnosis of Tuberculosis and came to the conclusion that the potential saving on hospital costs per patient is about $1000. In virology, (CMV, HCV, EBV & HIV testing) the breakthrough of quantitative PCR was been discussed by Bert Niesters. Pharmocogenetics, of great general potential medically, has several drawbacks when used in psychiatric patients, and Jan van der Weide showed us why! In his second presentation Dan Farkas introduced new standards in Power Point presentations when he demonstrated chip-based, electronic DNA detection in a short movie. Hans Vos (Leiden, The Netherlands) from Bertina’s lab, gave an overview of the role of the Factor V Leiden mutation and the G20210A mutation in the prothrombin gene in the diagnosis and treatment of certain types of thrombofilia. Jules Meijerink described a t(14:18) mutation detection based upon Taqman chemistry that was shown to have several advantages in monitoring disease activities in NHL.

After two exciting days of cutting edge DNA applications in clinical laboratories, Debra Leonard concluded the conference program by using the crystal ball and Dr McCoy of Star Trek fame to give us a view into the (near?) future. The scientific program, the roundtables on risk assessment by multi gene screens, pharmacogenetics and legislation and the exhibits---everything contributed to fruitful exchange of knowledge, skills and techniques among colleagues from different clinical laboratories. Looking back on a successful first conference on DNA testing, the challenge for the second (year 2000) meeting is already occupying our minds.

Bert Dikkeschei
Clinical Laboratories Isala klinieken
Weezenlanden Groot Weezenland
208011 JW Zwolle, The Netherlands
L.D.Dikkeschei@isala.nl
Fax + 31 38 4242676
Tel + 31 38 4242688

THE BUSINESS OF BIOTECH – PART 1

Once upon a time, there was a simple model for building a business. An entrepreneur offered a product or service and succeeded or failed based on their ability to generate a profit, pay their debts and expand into new markets. To paraphrase the old Smith Barney ad, "Money was made the old fashioned way – it was earned." Mostly through hard work and the willingness to risk all in the hopes of success. This model generally served the country well from the Industrial Revolution through the Apollo program. The lessons of time resulted in some modification of the model, but it wouldn’t change dramatically until spurred by the dual revolutions of high technology electronics and biotech, and all they have grown to represent.

These new industries presented new problems. This article will focus on biotech, but until very recently the two industries have had similar dynamics. The issue facing biotech was that new ideas required long periods of time and relatively enormous amounts of capital before one could know its economic potential. The odds were long, the costs high – but the potential payoff could be tremendous. Investors believed that the new science built on an understanding of the genetic mysteries of the cell was finally the equal of the age-old scourges of disease. The pharmaceutical powerhouses seemed too set in their ways to pursue the new science. New companies, founded by scientists on the forefront of this revolution could cut through the old ways and harness this tremendous advance for the good of mankind and the profit of their investors.As luck would have it, some of the first attempts were successful. Genentech’s lymphoma drug Rituxan and Amgen’s Epogen made instant millions for investors and raised expectations to a fever pitch. Biotech couldn’t lose and investors bought in. But lightning didn’t strike twice as companies struggled with disappointments. Reality dawned; biotech companies could come up empty. The new science wasn’t a guarantee for success. And, even worse, there was no way for investors to know if a company was going to be a winner or loser until considerable time and money were irretrievably committed.Most of us are relatively unsophisticated as investors. We invest for our retirement in 401(k) or IRA type plans and most of this is in rather ordinary stocks or mutual funds. If the market goes up, we make money; if it goes down we lose. Over the last decade, without too much effort or risk, we have been able to handily beat inflation and triple the yield of traditionally safe investments like T-bills or CDs. For those with more capital, or maybe a freer spirit; there are other investment vehicles which allow you to win whether the market goes up or down. The trick is that you have to guess what the market is going to do before it actually happens. This was applied to biotech (and high tech electronics) and became the new approach to venture capital financing.

The model was fairly simple. A venture capitalist (known as the VC) collects money from investors who are willing to bet (and bet it is) that the fund managers can beat the odds and find them the big winners. By forming a fund, they spread their risk and ultimately enhance their odds of finding a winner big enough to offset the inevitable losers. The fund managers look for entrepreneurs with a winning idea who are willing to sell their soul, or at least put up all their worldly goods, for a shot at the brass ring. The VC invests enough money to get things started, provides infrastructure and professional management and a new biotech company is formed. Traditionally, the investors would have to wait until the company created a product and earned profits to make a return. The beauty of the new model is that it doesn’t really matter if the company is ever successful in the traditional sense. If other investors believe it will be successful, the VCs can sell their stake for a profit and move onto the next opportunity. Success is in the eyes of the buyers who may be another round of venture capitalists, a pharma looking to acquire technology or ordinary people looking for someplace to park their monthly 401(k) contribution. Sooner or later, the biotech will need a real product to succeed, but by that time the start-up VC has long ago cashed in their chips and moved on to the next table.

This is not to say that there is anything shady about VCs or that today’s new biotechs are any less viable then their predecessors. In fact, it can be argued that our current biotech market could not exist without the contributions of the VCs. The market is a human creation and this model is simply a way for investors to make a profit without waiting the years required to know if a new biopharmaceutical or diagnostic will ultimately succeed.

Next issue we’ll look at the concepts of market capitalization, valuation, the financial health of biotech and why this has led to the gene patents, which are so problematic to the growth of molecular pathology.

Richard S. Schifreen, Ph.D., DABCC
Business Unit Leader, Molecular Diagnostics
Promega Corporation
Rschifre@promega.com