Preserving the Precious Gift of Sight

Louise C. Strong, MD

HUMBLE RESEARCH PROJECT

Department of Molecular Genetics

University of Texas MD Anderson Cancer Center

Houston, TX

 

Dr. Strong’s Research Project

Genetic Etiology of Retinoblastoma
 

Current Research Interests

This proposal will build on the resources developed during previous years of RRF support, and will be focused on Dr. Strong’s ongoing efforts to provide a unique early cancer detection program for individuals with a hereditary cancer predisposition involving childhood and adult cancers with a range of sites and ages at risk. The focus of the program is on retinoblastoma (RB1 mutation carriers) and Li Fraumeni syndrome (TP53 mutation carriers) individuals. Both groups are at high risk of childhood cancer. These tumors are a significant health problem as the most frequent cause of death in hereditary retinoblastoma patients is a second malignant neoplasm; it is also an important biologic question, as the retinoblastoma “pathway” is considered to be critical to the development of most if not all cancers. The purpose of this project is to pilot a new program in education and screening for individuals at genetic high risk of multiple different cancer types that can occur from infancy through older age due to the presence of a germline mutation in the Rb1 tumor suppressor gene.

Progress in 2016

Dr. Strong has continued to maintain her database and sample collection of retinoblastoma kindreds, with follow-up of existing kindreds, and ascertainment of additional 5 new hereditary retinoblastoma kindreds during 2016. She now follows more than 350 retinoblastoma kindreds. Dr. Strong had proposed to pilot the education and screening program with up to 10 hereditary retinoblastoma patient who had return appointments scheduled for 2016, with focus on those over age 5 years. However few of the patients off treatment returned, emphasizing the importance of contacting patients/families directly regarding the rationale and opportunities for cancer screening. Changes in health insurance are part of the problem, but also the lack of consistent education re risk of new tumors and relevance of screening is likely part of the problem.

Plans for 2017

Specific Aims include: 1) To update and maintain Dr. Strong’s current registry of hereditary retinoblastoma patients at risk for new non-ocular tumors and determine if they are undergoing any surveillance. It has been an ongoing RRF aim to maintain the registry of retinoblastoma patients and family members with the relevant sample and history collection. To provide sufficient education and guidelines for patients and family members seeking counseling and/or screening. 2) To document response, interest, barriers to participation, and clinically significant outcomes.

Strong Group
Strong Group

Progress in 2015

During the past year, Dr. Strong has conducted a pilot project applying this novel cancer screening approach to another hereditary cancer predisposition syndrome Li Fraumeni Syndrome (LFS) that has many parallels to hereditary retinoblastoma. In each group the risk of a second malignant neoplasm continues to increase over age, with median age of 25 – 30 years for Rb1 survivors, but with a continuing increasing risk over time.

Dr. Strong proposes to update her registry of hereditary retinoblastoma patients at risk, to determine their interest and ability to participate in this program and to pilot the program in various age groups excluding those under five years of age. The overall goal is to apply a new program in education and early cancer detection to her population of hereditary retinoblastoma patients to detect any new tumors at any early stage where effective treatment is available and to reduce the overall morbidity and mortality from hereditary retinoblastoma. This year would be a pilot year for retinoblastoma survivors. Specific aims: To maintain the current registry of hereditary retinoblastoma patients at risk for new non-ocular tumors; to pilot the proposed education and screening program with up to 10 hereditary retinoblastoma patients who have return appointments scheduled for 2015, focusing on those over age five years. Issues of interest will be feasibility for patient and family, satisfaction with experience, willingness to return the following year, incidental findings requiring follow-up, and findings of clinical significance.

 

Progress to date

Dr. Strong has conducted a pilot project applying this novel cancer screening approach to another hereditary cancer predisposition syndrome Li Fraumeni Syndrome (LFS) that has many parallels to hereditary retinoblastoma. The original purpose of the project was to determine the relationship between the germline Rb1 gene mutations, retinoblastoma and other non-ocular cancers, p53, and the associated molecular genetic changes in tumorigenesis. Much of that work has been completed and confirmed the original hypothesis that germline Rb1 mutations significantly increased the risk of non-ocular cancer within and outside the areas of radiation therapy, and that the spectrum of tumors was broad.

 

Dr. Strong: New non-ocular cancers in Retinoblastoma family

(click on link to see detail of chart below)

Dr. Strong’s program to date has ascertained some 127 hereditary retinoblastoma kindreds, including 36 in which at least one family member had a second malignant non-ocular neoplasm.  Shown is a figure of a family originally ascertained in 1985 due to an unusual occurrence of retinoblastoma in 6 siblings and cousins, but without the typical direct inheritance pattern.  Some years later we were able to identify the genetic change or mutation in the Rb1 (retinoblastoma gene, “mut” in the figure) and find that there were many carriers of the mutation who had not developed retinoblastoma.  Over the years of follow-up, 6 new, non-ocular cancers have occurred in the family, all in those carrying the Rb1 mutation, some of whom had retinoblastoma as infants, others who carried the same genetic change or mutation but never developed retinoblastoma.  These data show the importance of the Rb1 gene in multiple tumor types, and the importance of following families with genetic predisposition to cancer to determine the full extent of the cancer risk.

Early Research Findings – Retinoblastoma

Early in her studies Dr. Strong reviewed medical records of retinoblastoma patients seen at M. D. Anderson Cancer Center, and the finding that was most surprising, and concerning, to her (in early 1970s) was that many of the children who were successfully treated for their retinoblastoma in infancy and early childhood went on in older age to develop new cancers.  This finding applied mostly to those with bilateral or familial retinoblastoma (the hereditable subgroup), and many of the tumors occurred in areas previously treated with radiation therapy.

It was known of course that radiation therapy increased the risk of cancer, but the number of new tumors seemed exceptionally high.  Initially these tumors were attributed to the radiation therapy, but over time Dr. Strong’s laboratory observed that new tumors also arose frequently in hereditary retinoblastoma patients in areas not exposed to radiation, and she began to realize that there was an underlying genetic risk of certain tumors types in hereditary retinoblastoma patients, and that perhaps the radiation only further increased that risk, and shortened the time to tumor.

Understanding the Factors that Contribute to Second Cancers

One of the ongoing aims of Dr. Strong’s research has been to understand the factors that contribute to the second cancers, with the hope that the information could be useful in identifying those at highest risk, and in identifying the molecular pathways involved that might suggest potential intervention or treatment targets.  Her laboratory has followed a large series of hereditary and non-hereditary retinoblastoma patients over many years now, including those treated at M. D. Anderson Cancer Center since its earlier days (1940s), and others referred to us for genetic studies.

Over these years she and others have identified a small subset of families that seemed to have a genetic change in the retinoblastoma gene that she considered to be of “low penetrance”, meaning that the risk of retinoblastoma was not as high as usual, so that there might be individuals who carried the retinoblastoma mutation but did not did develop retinoblastoma, or developed retinoblastoma in only one eye (unilateral retinoblastoma).  These individuals could still transmit that gene mutation to their children, and some of their children might develop retinoblastoma.

Follow-up of these individuals with “low penetrance” retinoblastoma genes has continued to bring unexpected findings, and to reinforce Dr. Strong’s concept that retinoblastoma patients should all have genetic testing, and that those with inherited retinoblastoma gene mutation should have active medical follow-up throughout their life.

Four Generations Studied

This is exemplified in the photograph (below) in which Dr. Strong is showing a four generation  pedigree of a family with “low penetrance” retinoblastoma – several related individuals with no signs of retinoblastoma have had children with retinoblastoma (the individuals with  red had retinoblastoma, those with blue have non-ocular cancer).  In 1997 her laboratory identified the mutation in the family, and determined that the same mutation was present in those who had retinoblastoma (6), and those who did not have retinoblastoma (7) but had children with retinoblastoma.

Dr. Strong with chart showing four generation pedigree of a family with retinoblastoma
Dr. Strong with chart showing four generation pedigree of a family with retinoblastoma

Dr. Strong’s laboratory anticipated that since they were at lower risk for retinoblastoma, perhaps they would be at lower risk for the other tumors occurring later in life and associated with the hereditary form of retinoblastoma.   Follow-up of this family suggested they were wrong – as shown in the pedigree, most of those carrying the retinoblastoma mutation, even thought they had no retinoblastoma, and no radiation therapy, by age 50 they had developed one or more cancers.  The cancers were not of random types, or those most common in the general population, but were those known to be uniquely common to hereditary retinoblastoma patients – uterine and other sarcomas, lung cancer, melanoma.

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Mission of RRF

The mission of the Retina Research Foundation is to reduce retinal blindness worldwide by funding programs in research and education. As a public charity, RRF raises funds from the private sector and the investment of its endowment funds.

RRF’s 48th Anniversary

October 1, 2017