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CANCER GENETICS:

Much of the future of cancer care is in our genes. More than 1 million

people in the United States are born with an underlying genetic

mutation in all of their normal cells that predisposes them to cancer.

Identifying these high-risk individuals is paramount to cancer prevention.

For all patients, understanding the molecular mutations that lead to

cancer will enable clinicians to improve cancer care. UT Southwestern

has one of the premier Clinical Cancer Genetics programs in the

country and the largest in North Texas. It is the only program in Dallas

that offers a clinical service that is linked to a strong academic

research program. The Harold C. Simmons Comprehensive Cancer Center

genetics team is working to help our patients and clinicians put together

hereditary pieces of the cancer puzzle.

S o u rce : G e n eTe s t s d at a b a s e

T H E R A P I D PAC E O F G E N E T I C S C I E N C E

Number of diseases caused by specific gene mutations

93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11 12 13 14 15

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CO N T E N T S

02 – Program Overview

– Genetic Counseling

05 – Risk Assessment

– Population-Based Screening Programs

06 – The GI Genetics Clinic and Population-Based Screening for Lynch Syndrome

09 – Gynecology/Oncology

10 – Reaching Rural Communities

– The Power of Cascade Testing

– Molecular Genetics Tumor Board

13 – Pediatric Cancer Genetics Program with Children’s Medical Center

14 – Helping Different Patients Make Difficult Cancer Genetic Decisions

– Patient Experience in the Cancer Genetics Clinic and Beyond

18 – The Future of Genetic Testing

20 – Selected Publications

By the end of 2015, we had seen 18,600 patients for cancer genetic analysis; approximately 2,430 individuals were identified as carriers of a genetic mutation.

Linda Robinson—M.S. , CGC, A ssistant D irec tor, Cancer Genetics

P R O G R A M O V E R V I E W

All cancer is genetic, but not all cancer is inherited. Cancer is caused by genetic changes, but 5–10 percent of cancers are hereditary due to germ-line alterations. Some of the most significant advances toward understanding cancer biology have been made by studying rare inherited syndromes such as retinoblastoma and familial adenomatous polyposis.

The UT Southwestern Cancer Genetics program was started in 1992 by pediatric oncolo-gist Dr. Gail Tomlinson as a research program enrolling large numbers of families in a hereditary cancer registry. The goal was to look for genes responsible for heredi-tary cancer syndromes. This UT Southwestern program was foreshadowed 20 years previously when Drs. Michael S. Brown and Joseph L. Goldstein, also at UT South-western, started their search for the genetic cause of familial hypercholesterolemia. Their successful quest led not only to a Nobel Prize (1985) but also to a UTSW culture where future patients were as important as current patients and where discovery of disease causes and cures was the endgame.

Our program is also com-munity-based, with multiple offices throughout the Metro-plex, including Moncrief Cancer Institute in Fort Worth, as well as our outreach efforts through telemedicine.

G E N E T I C CO U N S E L I N G

Understanding the complexity of genetic and genomic testing can be daunting for patients. UT Southwestern has a large team of board-certified cancer genetic counselors who help patients through the various stages of testing and medical action. Genetic counselors have master’s-level postgraduate training in human genetics and patient education. They work with patients to determine if genetic testing is right for them and what genes should be analyzed.

Prior to their appointment, patients at UT Southwestern are given access to an online program called CancerGene Connect (developed at UT Southwestern) to complete their medical and family history of cancer. This program allows patients to reach out to family members for information about their family’s cancer history and submit that data before the appointment to our genetic counselors, who then use various risk assessment models to quantitate the patient’s chance of having

Since Dr. Tomlinson started the program, more than 18,600 patients have been seen at UT Southwestern for a cancer genetic analysis, and more than 2,430 individuals have been identified as carriers of a genetic mutation. Today, the Cancer Genetics program is led by Dr. Theodora Ross, an adult oncologist, cancer geneticist, and basic scientist. Because ours is a research-based program, our patients continue to not only benefit from the latest advances in clinical testing but also have the opportunity to participate in the future of medicine through the efforts of current UTSW researchers. For exam-ple, the program’s analysis of panel tests or whole genome sequences from patients with hereditary cancer has led to the discovery of new cancer predisposition gene mutations and helped us to understand the interaction of multiple genes. For some hereditary cancer families, whole genome sequencing has solved the mystery of what was causing cancer in their families.

The Cancer Genetics team works with all cancer specialty groups at UT Southwestern to identify cancer patients and their family members at high risk for a genetic syndrome. Hereditary cancer is a family matter, so our team also works with family members at Children’s Medical Center of Dallas and Parkland Hospital.

C A N C E R G E N E T I C S02

a genetic predisposition to cancer. Risk assessment helps determine if genetic testing is warranted, as well as if other medical interventions or sur-veillance tests, such as breast MRI scans, are needed.

Genetic testing has become more complex in just the past two years with the advent of next-generation sequencing (NGS) panel testing. With more than 100 commercially available germline gene tests, deciding which test is best for a patient requires the expertise of a genetic specialist. In some cases, it’s appropriate to look for a single, specific gene, but in other cases a select NGS panel is needed to target all the known genes that fit the patient’s family history. Our genetics team uses national guidelines and clinical expertise to determine which genes should be tested. The entire team of counselors and the program’s director hold a weekly case conference to review all cases in depth as well as emerging data on new developments in cancer genetics. For example, the Cancer Genetics team contin-uously evaluates the various commercial genetic testing laboratories to determine the quality of their tests.

R I S K A S S E S S M E N T

As part of the cancer risk assess-ment process, various risk models are calculated based on a patient’s family and medical history. CancerGene Connect software allows this to be done with ease.

HBOC affects 1 in 500 individuals, and 1 in 40 of Ashkenazi Jewish descent. Because of its Tier 1 classification and the U.S. Preventative Services Task Force’s recommendation that all women over age 18 be screened for HBOC by obtain-ing a family history of cancer, screening for HBOC should be done on a population basis and not individually.

As such, the UT Southwestern Cancer Genetics program is implementing popula-tion-based screening for family histories of cancer in its insured and under-served populations. To date, we have screened 117,759 mammogram patients in the underserved populations alone. These data serve as a baseline measure for us and others to use to improve screening as well as final outcomes. Of the unaffected women who underwent genetic testing through pop-ulation screening for a family history of cancer, 4.5 percent were found to have a muta-tion. It is unlikely that these women would have been identified without this pop-ulation-screening program. We’ve also learned that our underserved patients exhibit lower compliance with man-agement recommendations

The software is based on the Cancer Gene program developed in 1998 by breast surgeon Dr. David Euhus while at UT Southwestern. Thanks to his work, health care professionals could access risk assessment models using one easy-to-navigate, free-access, online program. The latest version of CancerGene Connect has been expanded from a desktop application to a virtual genetic counseling environment. In 2015, this product was commercialized and is available to providers at cagene.com. This soft-ware maintains a database to facilitate research at UT Southwestern and at outside universities.

P O P U L AT I O N - B A S E D

S C R E E N I N G P R O G R A M S

Screening family histories to identify patients with Heredi-tary Breast and Ovarian Cancer syndrome (HBOC) has recently been classified as a Tier 1 health application by the Centers for Disease Control (CDC). Tier 1 genomic applications are defined as those having a positive impact on public health based on available evidence. There are currently only three Tier 1 genomic screen-ing activities: HBOC, Lynch syndrome, and familial hypercholesterolemia. The last of these resulted from the pioneering work of Drs. Brown and Goldstein at UT South-western in defining the disease at the genetic level.

05

CANCER TYPE FREQUENCY (%)

Bladder 1

Breast (female) 5-10

Breast (male) 10-20

Colon and rectal 5-6

Endometrial/uterine 3-5

Gastric 3

Kidney/renal 1-2

Leukemia (all types) 1

Lung Rare

Melanoma 10

Lymphoma Rare

Ovarian 10-24

Paraganglioma 24-41

Pancreatic 5-10

Prostate 5-10

Thyroid (medullary) 25

Thyroid (not medullary) 5

How often is cancer hereditary?

When to refer for genetic counseling?

– Early age of cancer onset (≤50 years)

– Multiple family members with the same cancer

– Bilateral cancers

– Cancers in the family that are part of a known cancer predisposition syndrome

Once a mutation is confirmed, a personalized management program is developed for the patient based on national guidelines.

Ezra Burstein, M.D. — A ssociate Professor, D epar tment of Internal Medicine and leader of the GI Genetics Cl inic

compared to published data as well as compared to our smaller insured population. By improving compliance, we will increase the impact of cancer prevention in both populations.

Even though the CDC has given population screening for HBOC a Tier 1 classification, until now little has been known about the effect of screening on cancer incidence in underserved populations. UT South-western is one of the first programs in the country to report on the effect of popu-lation screening with analysis from the program’s first 20 months of screening. We used a simple software model to calculate the long-term effect (30 years) of screen-ing on breast and ovarian cancer incidence in patients with HBOC by assessing how often they chose to undergo surgical prevention measures. Using these data, we mod-eled the effect of compliance with prevention guidelines on cancer incidence over 30 years and predicted a 54 percent reduction in breast cancer and a 72 percent reduction in ovarian cancer in the insured population. However, only an 8.8 percent reduction in both breast and ovarian cancer was predicted for the underserved patients.

Our data indicate that under-served patients diagnosed with HBOC exhibit lower adherence to standard guide-lines for cancer prevention

(MLH1, MSH2, MSH6, PMS2, and EPCAM), which are related to an increased risk for colon, uterine, ovarian, stomach, and other cancers. The CDC has, as with HBOC, classified Lynch syndrome screening as a Tier 1 public health condition. Screening colon and uterine tumors for Lynch syndrome is now done routinely in the United States to identify individuals with this condition. Patients with the syndrome have a 15 percent risk of developing a second primary tumor. Treatment approaches for Lynch syndrome patients with colon cancer are altered based on the molecular diagnosis of the condition.

UT Southwestern, in partnership with Parkland Hospital, was one of the first medical cen-ters in the country to institute a tumor-based Lynch syn-drome immunohistochemical (IHC) screening test in a safety-net hospital. Identify-ing patients with tumors that are characteristic of Lynch syndrome is just the first step. The Cancer Genetics group partners with GI pathologists to ensure that all patients and their physicians are

compared to insured popu-lations. However, even the insured population has much room to improve. Population screening for HBOC will be effective for cancer preven-tion only if more work can be done to remove barriers for underserved patients who have a genetic predisposition to cancer. We are working to increase education of both patients and their physicians to improve access to life-saving surgeries and other prevention measures. These data provide the prototypical baseline for quantitative evaluation of efforts to improve adherence to National Com-prehensive Cancer Network (NCCN) guidelines for cancer prevention. They will be used at UT Southwestern and at other cancer centers across the country.

T H E G I G E N E T I C S

C L I N I C A N D

P O P U L AT I O N -

B A S E D S C R E E N I N G

F O R LYN C H

S YN D R O M E

The UT Southwestern Cancer Genetics program, in partner-ship with the Gastroenterology Division, has had a specialized high-risk GI Genetics Clinic at Parkland for the past six years. Led by Dr. Ezra Burstein, the clinic treats patients with hereditary colon cancer predisposition syndromes and coordinates all aspects of their follow-up care.

Among the patients the GI Genetics Clinic follows are those with Lynch syndrome, one of the most common hereditary cancer syndromes, affect-ing 1 in 300 individuals. The syndrome includes mutations in the mismatch repair genes

06 C A N C E R G E N E T I C S

contacted about the results and receive follow-up genetic counseling and testing. Once a mutation is confirmed, a personalized management program is developed for the patient based on national guidelines.

IHC testing is performed on all colorectal tumors in patients under age 70 and all endome-trial tumors in patients under age 50 to look for the mis-match repair (MMR) proteins implicated in Lynch syn-drome. Through this universal screening protocol at UT Southwestern, Parkland, and John Peter Smith Hospital clinics, we have identified a large number of patients who need risk assessment and screening. In our high-risk GI genetics clinic, we are able to provide continuity of care for patients through every step of the process—from initial genetic risk assessment, to genetic testing, to diagnosis of an underlying hereditary cancer predisposition syn-drome—and to undertake all aspects of follow-up surveil-lance and management indicated for that syndrome.

By providing care for cancer patients in one comprehen-sive clinic, we have observed 90 percent compliance with follow-up recommendations in these patients. Our high compliance is due in part to the use of the medical information and tools made readily available through electronic medical records. These tools allow for efficient and standardized communi-cation and coordination of the patient’s care with the entire team of providers.

the BSO) responded, provid-ing insights into their quality of life after learning about their genetic mutation.

Overall, most patients with BRCA1/BRCA2 mutations underwent risk-reducing BSO within one year of learning of their genetic mutation. However, patients were an average age of 40, and those who were Lynch syndrome carriers were an average age of 42. This is on the older end of the age recommendation for BSO and highlights the need for providers to identify these high-risk patients at younger ages to ensure appropriate care is given at the recom-mended ages. Fortunately, no occult cancers were identified in any of the patients in this cohort at the time of risk- reducing BSO.

Most patients reported that they felt well-counseled by their genetic counselors and physicians prior to surgery. However, many patients added that they turned to online message boards, support groups, and other patients for additional infor-mation. As part of our genetic counseling process, patients with identified mutations are given a list of resources that includes online and in-person support networks, ensuring that patients are not alone in their experiences of living with an increased risk for cancer.

G YN E CO LO G I C O N CO LO G Y

Women with mutations in the HBOC genes (BRCA1/BRCA2) or the Lynch syndrome genes (MLH1, MSH2, MSH6, PMS2, and EPCAM) are at an increased lifetime risk for ovarian and fallopian tube cancer (as high as 40 percent compared to the average population risk of 1.4 percent). Unfortunately, today’s screening options of CA-125 blood tests and transvaginal ultrasounds are not able to detect early- stage ovarian cancer. Thus, the NCCN recommends that women with BRCA mutations consider a bilateral salpingo-oophorectomy (BSO) between ages 35 and 40 or when childbearing is complete. However, this surgery puts premenopausal women into surgical menopause, which negatively affects the quality of life for some of these patients.

We have partnered with the Gynecologic Oncology Divi-sion here at UT Southwestern to survey this population of patients and improve their care. Under the direction of Dr. Siobhan Kehoe, 91 patients who completed a risk-reducing BSO at UT Southwestern or Parkland hospitals received surveys asking about their experi-ences pre- and post-surgery. Forty-two patients (46 percent of those who completed

Lifetime Risk for Breast Cancer

60

40

20

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General Population BRCA1/2 Mutation Carriers

12%

57%

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Elise Watson— Cer ti f ied Genetic Counselor, Cancer Genetics

UT Southwestern was the first group in Texas to use telemedicine. We now offer cancer genetic services to patients in 21 rural counties west of Fort Worth.

The biggest discovery from this group of patients was that, as expected, many patients’ quality of life was impacted by menopausal symptoms, including the hot flashes, vaginal dryness, and lack of sex drive that accompany a BSO. However, few of these patients were treated with hormone replacement therapy, vaginal estrogen, or other medications to aid in relieving these symptoms. These types of responses will now be used to guide us in managing the care of our patients and to suggest appropriate avenues for them to explore to alleviate their symptoms.

From this work, we now have a baseline of how our women with HBOC and Lynch syn-drome mutations feel before and after undergoing risk-reducing surgery. This information gives their providers a better idea of the issues to address to improve their care long-term. As the world of genetics expands and more genes are identified that increase ovarian and fallopian tube cancer risks, these data will serve as a baseline to standardize and treat menopausal symptoms. From this work, we will also work with the Gynecologic Oncology Division on future studies to continuously improve our understanding of the unique needs of this patient population.

are passed down at a rate of 50 percent. Having a genetic mutation does not mean the individual will definitely develop cancer. It simply indi-cates an increased risk. Many of the gene mutations we find in our patients raise their risk for cancer to greater than 50 percent in their lifetime. All patients with a genetic mutation are given a person-alized letter with information for their family members.

M O L E C U L A R G E N E T I C S

T U M O R B O A R D

The tumor board provides a multidisciplinary review of somatic (tumor) testing for the purposes of clarifying the potential implications of a patient’s results. This includes but is not limited to: progno-sis, additional therapeutics, available clinical trials, and possible incidence of underlying hereditary cancer predisposition syndromes. The American College of Medical Genetics (ACMG), American Society of Clinical

R E AC H I N G R U R A L

CO M M U N I T I E S

In addition to seeing patients in-person in the cancer center, UT Southwestern is seeking ways to expand beyond the boundaries of the cancer center to offer genetic coun-seling services to much of North Texas. UT Southwestern was the first group in the state of Texas to use tele-medicine to serve patients in rural counties. Today, through telemedicine, we now offer cancer genetics services to patients in 21 rural coun-ties west of Fort Worth, with telemedicine sites located in Weatherford, Burleson, and Lake Granbury. In addition, through telemedicine avail-able on the Moncrief Mobile Survivorship Truck that travels to 21 counties, we provide counseling to even more pre-viously unreachable patients. Prior to 2011, genetic services were not available in these counties; since then, we’ve seen more than 400 patients through this technology.

T H E P O W E R O F

C A S C A D E T E S T I N G

The power of genetic testing to aid in cancer prevention is amplified with cascade testing. Once an individual is identified as having hereditary cancer, our genetic counselors work with the patient and his or her family to identify other family mem-bers with the same genetic mutation. Most, but not all, of the genetic mutations related to hereditary cancer

C A N C E R G E N E T I C S10

Jason Park, M.D., Ph.D., FCAP—D irec tor of the Advanced D iagnostics Lab and A ssistant Professor at UT S outhwestern

The UT Southwestern team is continually collaborating, both internally and externally, to find the missing pieces in the cancer genetic story.

Oncology (ASCO), and Associ-ation for Molecular Pathology (AMP) all recommend multi-disciplinary review of somatic genetic testing to bridge the inevitable gap in knowl-edge between those closely involved with genomic data, such as molecular patholo-gists and genetics providers, and health care providers, such as surgeons and medical oncologists. Providers would otherwise be hard-pressed to keep up with new devel-opments, but they need to integrate this information into their medical practice for optimal care of their patients.

With genome testing by next-generation sequencing technologies, perceived and real potential risks are magnified compared with genetic testing that targets only one gene at time. There are also unique challenges to somatic genetic testing compared to the “traditional” germline genetic tests with which providers are gener-ally more familiar. Reporting pipelines for these tests are very different from those to which providers are accus-tomed. In addition, while the testing is performed primarily for reasons such as prognosis and treatment, it must be understood that there is a very real possibility of uncovering an underlying hereditary cancer predisposi-tion syndrome that would

regularly attended by treat-ing oncologists, molecular pathologists, and genetic counselors, provides a means for providers to review and discuss somatic test reports with other treating clinicians and specialists to ensure that the most accurate interpretation and clinical implementation of the test reports take place.

P E D I AT R I C C A N C E R

G E N E T I C S P R O G R A M

W I T H C H I L D R E N ’S

M E D I C A L C E N T E R

The Cancer Genetics program works closely with pediatric oncologists at Children’s Health to provide cancer genetics services to pediatric patients in Dallas. We have a monthly clinic to provide genetic risk assessment consultations, testing, and follow-up care to pediatric patients with hereditary can-cer syndromes. Since 2010, we have tested more than 180 pediatric patients. The majority of these patients are the children of adult patients from our Simmons and Park-land clinics. Providing both pediatric and adult cancer genetics services allows us to deliver continuity of care

have other health implica-tions for both the patient and his or her family members.

A recent study by UC San Diego researchers reported that 66 percent of patients whose tumors were tested with NGS had at least one sequence variant in a gene associated with a hereditary cancer predisposition syndrome and 24 percent of patients undergoing somatic tumor testing would be considered appropriate for referral for germline genetic testing. When a variant is reported in a gene that is associated with an underlying heredi-tary cancer predisposition syndrome on a somatic tumor test, steps should be taken to consider whether follow-up germline genetic testing needs to be performed. This may include assessing the patient’s clinical and fam-ily history and the potential pathogenicity of the variant.

It should never be assumed that a patient is negative for a germline mutation simply because a variant is not reported in a hereditary cancer predisposition gene on a somatic test result, especially when the patient’s history is consistent with a syndrome. True deleterious mutations in hereditary predisposition genes may be absent from the report because the reporting pipeline is designed to deliver only potentially actionable somatic results. The molecular tumor board,

13

for patients transitioning out of the pediatric clinics to adult centers, and to ensure optimal management with no gaps in surveillance and follow-up.

In addition to our clinical endeav-ors at Children’s, we are also involved in various initiatives to use molecularly based targeted therapies to improve outcomes for pediatric cancer patients. For example, Dr. Ted Laetsch, a pediatric oncolo-gist at Children’s, is working with the GAIN (Genomic Assessment Informs Novel Therapy) Consortium as a somatic tumor sequencing curation team member. The GAIN Consortium is a large multicenter effort to conduct genomics studies on pediatric cancer samples. New studies will build upon the experi-ence from this consortium, which will assess the impact of tumor sequencing on clinical outcomes. Dr. Laetsch participates regularly in our molecular tumor board, shar-ing his experiences using this relatively new diagnostic tool.

both in-person counseling and accurate written infor-mation about hereditary cancer are needed for optimal patient care.

PAT I E N T E X P E R I E N C E

I N T H E C A N C E R G E N E T I C S

C L I N I C A N D B E YO N D

An important piece of our pro-gram is the involvement of the Cancer Genetics team with the cancer support com-munity and general patient education. In Fort Worth and Dallas communities, we are intimately involved with FORCE (Facing Our Risk of Cancer Empowered), a national hereditary breast and ovarian cancer support network with smaller chap-ters in metropolitan areas like ours. Genetic counselors attend meetings to serve as additional support for our patients and others in the community who are affected by hereditary breast and ovarian cancer.

H E L P I N G D I F F E R E N T

PAT I E N T S M A K E

D I F F I C U LT C A N C E R

G E N E T I C D E C I S I O N S

In 2013 and 2015, Angelina Jolie informed the world through two New York Times opinion articles that she had her breasts and ovaries removed after learning she had a BRCA1 mutation. She empha-sized that her decision to have genetic testing and sub-sequent surgeries was highly personal and based on her own family history. Genetic counselors help patients work through their own family history and family dynamics. Each patient has a unique perspective about cancer and what he or she would do if informed of a mutation. The decision is complex, whether or not the patient has cancer. There are frequent questions, such as: How should I tell my family? Will I get another cancer? How will this impact my children? Will this affect my treatment? Genetics counsel-ors are there throughout to help patients work through these questions.

Another source for answering such questions is the book A Cancer in the Family, which Dr. Ross wrote specifi cally to help patients and their doctors alike who wonder whether the patient has a genetic predisposition to cancer and, if so, what to do about it. Using case histo-ries, the book describes the challenges and choices that come with hereditary cancer. With an estimated 1.3 million Americans affected by hereditary cancers,

Theodora Ross, M.D., Ph.D.—Professor of Internal Medicine and D irec tor of the Cancer Genetics Program

An important piece of our program is the involvement of the Cancer Genetics team with the cancer support community and general patient education. C A N C E R G E N E T I C S14

Members of our staff in Fort Worth have become Bright Pink Education Ambassadors, another national heredi-tary breast cancer support network whose members are asked to speak in the com-munity regarding hereditary breast cancer education under the umbrella of the support network. Upon fol-low-up consultation with our mutation-positive patients, we provide a comprehensive list of support networks and resources. Some of these are specific to hereditary cancer needs, but we also work to provide information regard-ing general cancer support groups and other entities from which our patient popu-lation may benefit.

UT Southwestern Cancer Genet-ics team members are also part of the larger Dallas-Fort Worth (DFW) Cancer Genetics Association, whose provid-ers perform cancer genetic risk assessment throughout the area and host an annual hereditary cancer patient education conference. Any patient affected by a heredi-tary cancer syndrome in DFW is eligible to participate—along with his or her family members. This free confer-ence is supported by various genetic testing laboratories, which provide the meals for attendees; other institutions offer support by providing the conference meeting space free of charge. Patients and their relatives are able to spend a half-day each fall learning about updates on a variety of hereditary cancer conditions from the top

for distribution to at-risk relatives. The letter contained basic mutation/gene infor-mation and the implications of this knowledge for family members.

This particular patient has two daughters, two sons, several brothers and sisters, and an extended family that lives in Fort Worth and surround-ing areas. The patient took action after meeting with her UT Southwestern genetic counselor and distributed the letter to her adult children and siblings, many of whom underwent genetic testing through UTSW and other genetics clinics. Those who tested positive started screen-ing colonoscopies every one to two years, and two siblings (ages 30 and 25) were found to have precancerous colon polyps that were removed during their first colonosco-pies. This is the promise of genetic testing realized—the true prevention of cancer and the extension of a cancer-free lifespan. This is just one of many stories from patients where genetic testing has altered the futures and lives of many families in our community.

experts in the community, including physicians, genet-ics counselors, and other allied health professionals. The venue is one of the ways in which we are able to rou-tinely update patients on the latest-breaking research and information on hereditary cancer syndromes.

Our group has historically been the leader in community patient outreach within the Simmons Cancer Center. Annually, our genetics counselors perform 50–100 educational outreach activities via presentations, newsletter articles, partici-pation in local Komen and National Ovarian Cancer Coalition races, and similar opportunities throughout the Metroplex.

For families, having knowledge that a cancer-causing hereditary mutation exists and receiving guidance from a genetic counselor can prevent the mutation from affecting future generations. An example of this is one of our patients who was diag-nosed with colon cancer prior to age 50. She was found to have Lynch syndrome via IHC analysis of her tumor and subsequent genetic testing, which identified the mutation. Colon cancer risks associated with Lynch syndrome range from 40 percent to 80 percent by age 70, and endometrial cancer risks range from 25 percent to 60 percent by age 70. Once the mutation was discovered, a family letter was provided

17

Cancer Risk Modifiers

Highest Risk

Lifestyle Genetics

Higher Risk

Higher Risk

Higher Risk

Environment

Sayoni Lahiri Certified Genetic Counselor

Dr. Theo Ross Cancer Genetics

Program Director

Sara Pirzadeh-Miller Manager

Certified Genetic Counselor

Elise Watson Certified Genetic Counselor

Brian Reys Certified Genetic Counselor

Nichole Brown Certified Genetic Counselor

Linda Robinson Assistant Director,

Cancer Genetics

Certified Genetic Counselor

Jacqueline Mersch Certified Genetic Counselor

Jillian Huang Certified Genetic Counselor

Caitlin Mauer Certified Genetic Counselor

T H E C A N C E R G E N E T I C S T E A M

T H E F U T U R E O F

G E N E T I C T E S T I N G

Until recently, cancer genetic testing was based on inspection of a few genes, but labora-tories are now able to look at a patient’s entire genome, which includes approxi-mately 20,000 genes and the intervening sequences. This is the future of genetic testing and the next revolution in cancer care.

Many families have a history of cancer in which the disease looks hereditary but the genetic etiology is unknown. Recently, members of Dr. Ross’s lab worked with the Cancer Genetics clinic and used germline whole-genome sequencing (WGS) to study 278 cancer patients who had family histories of cancer. The researchers performed whole-genome testing on two cohorts of patients, those with BRCA1/BRCA2 mutations (n=176) and those without (n=82). Using WGS, researchers were able to identify potentially pathogenic mutations in 21 percent of the latter patient population.

individuals and completion of cancer prevention activities, the Cancer Genetics team was able to work with Dr. Xian-Jin Xie from the Department of Clinical Sciences to create a computer model for quantify-ing cancer prevention. This model can now be used for future screening programs—not only to identify those at high genetic risk but also to make the results beneficial for large populations. For more information, see Robinson et al., 2015 EBioMedicine.

Even as the cancer genetics community moves to next-generation sequencing of multiple genes in the genet-ics clinics, UT Southwestern was one of the first groups to publish its experience with multi-gene panel testing and the implications of clinical care (Mauer et al., 2013 Genetics in Medicine; Yorczyk et al., 2014 Clinical Genetics). After confirming with data that different testing labora-tories were interpreting the same genetic changes differently, the Cancer Genet-ics team made its proposal to the FDA that data sharing should be part of genetic testing (Ross, 2014 New York Times; Ross, 2015 Cold Spring Harb Mol Case Stud).

The UT Southwestern team is continually collaborating, both internally and externally, to find the missing pieces in the cancer genetic story.

This study illustrates how WGS can be used to improve our ability to discover patients’ cancer genetic risks. Also with this study population, the research group demonstrated how known deleterious BRCA1/BRCA2 missense muta-tions are hidden behind large numbers of new, private variations observed in BRCA1/BRCA2 genes. This illustrates how big data can hide key data.

Not only did researchers discover loss-of-function mutations in novel genes, which could explain the family histories of cancer, they have used these data to advocate for an FDA mandate in which sharing of clinical sequence data by testing laboratories becomes a standard of clinical care. In fact, the study’s organiz-ers have deposited all of the clinical and sequence data from this WGS study into the National Institutes of Health’s repository of research sequences for researchers around the country to use, and the group will continue to make such deposits in future studies of patients’ genomes. For more informa-tion, see Foley et al., 2015 EBioMedicine.

Genetic counselors at UT South-western collaborate with other disease-oriented teams within the Simmons Com-prehensive Cancer Center to use data from these clinical services to expand the field of cancer genetics. For example, the Cancer Genetics team’s partnership with the UT Southwestern Breast Imag-ing Department and Breast Center has resulted in the analysis of 96,055 individuals at screening mammography for a family history of cancer to identify BRCA mutation carriers who have a genetic predisposition to breast and ovarian cancer. This is the largest study to date on this topic. As a result of this screening program’s suc-cess in identifying high-risk

C A N C E R G E N E T I C S18

S E L E C T E D P U B L I C AT I O N S

1. Prediction of Cancer Preven-tion: From Mammogram Screening to Identifica-tion of BRCA1/2 Mutation Carriers in Underserved Populations—Robinson L, Hendrix A, Xie X, Yan J, Pirzadeh-Miller S, Pritzlaff M, Read P, Pass S, Euhus D, Ross T. EBiomed. PMID: 26870808

2. Democratization of Genetic Data: Connecting Govern-ment Approval of Clinical Tests with Data Sharing—Ross TS. Cold Spring Harbor Mol Case Stud, 2015

3. Decreased BECN1 mRNA Expression in Human Breast Cancer is Associated with Estrogen Receptor-Negative Subtypes and Poor Progno-sis—Tang H, Sebti S, Titone R, Zhou Y, Isidoro C, Ross TS, Hibshoosh H, Xiao G, Packer M, Xie Y, Levine B. EBioMedi-cine 2015 Mar;2(3) 255-263 PMID 25825707

4. The Current State of Cancer Genetic Counseling Access and Availability—Knapke S, Haidle JL, Nagy R, Pirzadeh-Miller S. Genet. Med 2015 Aug (Epub ahead of print) PMID: 26248009

9. Hereditary Lung Cancer Syndrome Targets Never Smokers With Germline EGFR Gene T790M Muta-tions—Gazdar A, Robinson L, Oliver D, Xing C, Travis W, Soh J, Toyooka S, Watumull L, Xie Y, Kernstine K, Schiller J. J Thorac Oncol. 2014, 9: 456 PMID: 24736066

10. An Internal Performance Assessment of CancerGene Connect: An Electronic Tool to Streamline, Measure, and Improve the Entire Genetic Counseling Process—Prit-zlaff M, Yorcyk A, Robinson LS, Pirzadeh-Miller S, Lin T, Euhus D and Ross TS. J Genet. Couns 2014, 23:1034 PMID: 24916850

11. Use of Panel Tests in Place of Single Gene Tests in the Cancer Genetics Clinic—Yor-czyk A, Robinson LS, Ross TS. Clin Genet 2014 doi:10.1111/cge.12488. PMID: 25318351.

12. Cancers Associated With BRCA1 and BRCA2 Mutation Other than Breast and Ovar-ian—Mersch J, Jackson MA, Park M, Negben D, Peterson SK, Singletary C, Arun BK, Lit-ton JK. Cancer 2015, 121: 269 PMID: 25224030

13. The Integration of Next-Generation Sequencing Panels in the Clinical Cancer Genetics Practice: An Insti-tutional Experience—Mauer C, Pirzadeh-Miller S, Robinson L, Euhus D. Genetics in Medi-cine October 10, 2013 PMID: 24113346

5. Exploration of Male Atti-tudes on Partnerships and Sexuality with Female BRCA1/2 Mutation Carri-ers—Mauer C, Spencer S, Dungan J, Hurley K. 2015 J Genet Couns. doi:10.1007/s10897-015-9870-4 PMID: 26250348

6. Use of Whole-Genome Sequencing for Diagnosis and Discovery in the Cancer Genetics Clinic—Foley SB, Rios JJ, Mgbemena VE, Robin-son S, Hampel HL, Toland AE, Durham L, Ross TS. EBio-Medicine 2014, 2:75-81 PMID: 26023681

7. Re-evaluating the Role of

BCR/ABL in Chronic Myelog-enous Leukemia—Ross TS, and Mgbemena VE. Molecular & Cellular Oncology 2014, 1 (3), e963450

8. American Society of Clinical Oncology Expert State-ment: Collection and Use of a Cancer Family History for Oncology Providers— Lu KH, Wood ME, Daniels M, Burke C, Ford J, Kauff ND, Kohlmann W, Lindor NM, Mulvey TM, Robinson L, Rubinstein WS, Stoffel EM, Snyder C, Syngal S, Merrill JK, Wollins DS, Hughes KS, ASCO. J Clin Oncol. 2014 32: 833 PMID: 24493721

14. Huntingtin-Interacting Pro-tein 1 Phosphorylation by Receptor Tyrosine Kinases—Ames HM, Wang AA, Coughran A, Evaul K, Huang S, Graves CW, Soyombo AA and Ross TS. Mol Cell Biol 2013; 33(18): 3580-3593. PMID: 23836884

15. Toward a Therapeutic Reduction of Imatinib Refractory Myeloproliferative Neoplasm-initiating Cells Philips ST, Hildenbrand ZL, Oravecz-Wilson KI, Mgbe-mena VE, and Ross TS. Oncogene 2013, advance online publication 18 Novem-ber. PMID: 24240679

16. Implementation of Univer-sal Routine Screening for Lynch Syndrome in Univer-sity and Safety-Net Health System Settings: Successes and Challenges—Marquez E, Geng Z, Pass S, Summerour P, Robinson L, Sarode V, Gupta S. 2013 Genetics in Medicine. 15 (12). PMID: 23598716

17. A Novel Germline Mutation in BAP1 Mutation Predis-poses to Familial Clear-Cell Renal Cell Carcinoma—Far-ley MN, Schmidt L, Mester J, Pena-Llopis S, Pavia-Jimenez A, Christie A, Ricketts C, Peterson J, Middleton L, Vocke C, Kinch L, Grishin N, Merino M, Metwalli A, Xie X, Dahia P, Eng C, Linehan M, Bruga-rolas J. Mol Cancer Res. 11.0 (2013): 1061-71. Print. PMID: 23709298

22. Successful Strategies for Increasing African Ameri-can Participation in Cancer Genetic Studies: Hopeful Signs for Equalizing the Benefits of Genetic Medi-cine—Patterson AR, Davis H, Shelby K, McCoy J, Robinson LD, Rao SK, Banerji P, Tomlin-son GE. Community Genet. 2008;11(4):208-14. Epub 2008 Apr 14. PMID: 18417968

23. Custodianship of Genetic Information: Clinical Chal-lenges and Professional Responsibility—Patterson A, Robinson L, Naftalis E, Haley B, Tomlinson G. J Clin Oncol Vol 23 Number 9 3/20/05 2100-2104. PMID: 15774800

24. Pretest Prediction of BRCA1 or BRCA2 Mutation by Risk Counselors and the Computer Model BRCAPRO Euhus D, Smith K, Robinson L. J Natl Cancer Inst. 2002;94(11):844-51. PMID: 12048272

18. Expression of BCR/ABL p210 from a Knockin Allele Enhances Bone Marrow Engraftment Without Induc-ing Neoplasia—Foley SB, Hildenbrand ZL, Soyombo AA, Magee JA, Wu Y, Oravecz-Wilson KI, Ross TS. Cell Rep 2013 Oct 17;5(1):51-60. PMID: 24095735

19. Analysis of Induced Plu-ripotent Stem Cells from a BRCA1 Mutant Family—Soyombo AA, Wu Y, Kolski L, Rios JJ, Rakheja D, Chen A, Kehler J, Hampel H, Coughran A, Ross TS. Stem Cell Reports 2013 Oct 3;1(4): 336-49. PMID: 24319668

20. Direct-to-Consumer Genetic Testing: Helpful, Harmful, or Pure Entertainment?— Pirzadeh-Miller S, Bellcross C, Robinson L, Matloff E. Vol 8 Number 6 June 2011 Commu-nity Oncology

21. Huntingtin-Interacting Protein 1: A Merkel Cell Carcinoma Marker that Interacts With c-Kit—Ames HM, Bichakjian CK, Liu GY, Oravecz-Wilson KI, Fullen DR, Verhaegen M, Johnson TM, Dlugosz, AA and Ross TS. J Invest Dermatol 2011. 131(10): 2113-2120. PMID: 21697888

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