Huma Q. Rana, MD, MPH, an assistant professor of medicine at Harvard Medical School and clinical director of Cancer Genetics and Prevention at Dana-Farber Cancer Institute, discusses the rationale for the ProGen trial, which compared the effectiveness of video education versus in-person genetic counseling for men with prostate cancer.

There are increasing indications for germline genetic testing in prostate cancer, says Rana. Through several clinical studies, the field has recognized that there is a high prevalence of inherited mutations among men with advanced prostate cancers, and this could have significant implications on treatment. Men with advanced prostate cancer, particularly those with underlying mutations in genes such as 

, are known to have poor outcomes, says Rana. Therefore, it is important to identify these men and make matched targeted therapy available to them and their oncologists.

In recognizing that prostate cancer is a very common disease and that traditional germline genetic testing would be very difficult to implement—potentially overwhelming already strained systems for genetic testing—a randomized controlled trial was conducted. In the trial, investigators compared the effectiveness of a short video that focused on the educational components of a genetic counseling visit with in-person genetic counseling for men with potentially lethal prostate cancers, concludes Rana.

Videos

Huma Q. Rana, MD, MPH, discusses the rationale for the ProGen trial, which compared the effectiveness of video education versus in-person genetic counseling for men with prostate cancer.

Dr. Rana on the Rationale for Video Genetic Counseling in Prostate Cancer

Huma Q. Rana, MD, MPH, an assistant professor of medicine at Dana-Farber Cancer Institute and the clinical director of Cancer Genetics and Prevention at Harvard Medical School, discusses the prevalence of pathogenic variants in patients with prostate cancer enrolled on the ProGen study.

The ProGen study enrolled patients with prostate cancer and a family history indicative of a pathogenic variant who were then randomized 1:3 to in-person genetic counseling or video education. The goal of the trial was to evaluate completion of the intervention, uptake of genetic testing, satisfaction, knowledge, and distress over time by randomization arm. Investigators also wanted to identify clinical factors associated with presence of pathogenic variants in cancer susceptibility genes.

The main actionable finding from the study showed that among men with advanced prostate cancer, pathogenic variants or likely pathogenic variants in genes are responsible for homologous recombination repair, explains Rana; this includes genes such as BRCA1/2, and other genes within the same homologous recombination Fanconi anemia DNA repair pathway, such as PALB2, CHEK2, and ATM.

Additionally, 13% of patients were found to have a pathogenic variant. Of those subjects, 32% were positive for a 

 pathogenic or likely pathogenic variant, concludes Rana.

Huma Q. Rana, MD, MPH, discusses the prevalence of pathogenic variants in patients with prostate cancer enrolled on the ProGen study.

Dr. Rana on the Prevalence of Pathogenic Variants in Prostate Cancer

Huma Q. Rana, MD, clinical director, Cancer Genetics and Prevention, instructor of medicine, Harvard Medical School, Dana-Farber Cancer Institute, discusses genetic testing guidelines for patients with ovarian cancer.

Every woman with a diagnosis of ovarian cancer should undergo germline genetic testing, says Rana; that includes women with a diagnosis of fallopian tube or primary peritoneal cancer. It is recommended that women with nonmucinous epithelial ovarian cancer undergo genetic testing, although any type of histology is encouraged for testing. Additionally, the test should be a comprehensive panel, inclusive of BRCA1/2, Lynch syndrome, and other related genes that are important in the homologous recombination DNA repair pathway, she says.

At Dana-Farber Cancer Institute, the standard of care with regard to genetic testing often involves Pan-Cancer panels, which offer next-generation sequencing of several cancer associated genes. Through genetic testing, family members who are at risk of developing the disease can be identified. Additionally, targeted therapies can be paired with specific mutations for patients who have been diagnosed with the disease—namely, PARP inhibitors for patients with 

Dr. Rana on Genetic Testing Guidelines for Patients With Ovarian Cancer

This article reviews two newly described cancer syndromes: DICER1 and BAP1 tumor predisposition syndrome, and four uncommon syndromes: Familial Atypical Multiple Mole Melanoma (FAMMM) syndrome, Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) syndrome, Cowden syndrome (CS), and von Hippel Lindau (VHL) disease which can be under-recognized in an oncology practice. Clinical features and indications for testing are reviewed to help oncologists identify patients appropriate for genetic evaluation. Medical management recommendations and notable counseling points, such as potential for pediatric risk are detailed to highlight the importance of testing for patients and families.

Over 200 hereditary cancer syndromes have been described, with the majority being rare or uncommon. These syndromes are almost certainly under-reported given the broad range and variable expressivity of the associated features. The advent of next generation sequencing has enabled greater access to testing and has led to the discovery that at least some of these syndromes are more common than previously thought.

The major benefit of cancer genetic testing is that it can lead to personalized treatment, screening, and risk reducing strategies for patients and their families. Oncologists are often the first-line providers in helping to recognize patients with inherited cancer syndromes and are increasingly integrating genetic test results in the care of their patients. While referrals to cancer genetics are diverse in nature, some indications include: patients with rare tumor types, patients diagnosed with cancer at younger than typical ages, patients diagnosed with multiple primary cancers, patients who do not have cancer, but do have at least one relative with a rare tumor or at least two relatives with related cancers or multiple primaries, and/or patients who have a known gene mutation in the family.

In this review, we discuss the clinical features, gene function, and medical management recommendations for six hereditary cancer syndromes. This includes two newly described syndromes: DICER1 and BAP1 tumor predisposition syndrome, and four under-recognized syndromes: Familial Atypical Multiple Mole Melanoma (FAMMM) syndrome, Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) syndrome, Cowden syndrome (CS), and von Hippel Lindau (VHL) disease.

DICER1 syndrome is an autosomal dominant hereditary cancer syndrome.

 The most common features of DICER1 syndrome are pleuropulmonary blastomas (PPB), cystic nephromas, and ovarian sex-cord stromal tumors, especially Sertoli Leydig

. Other associated tumors include embryonal rhabdomyosarcomas of the uterine cervix and other sites, nasal chondromesenchymal hamartomas, cerebral and ciliary body medulloepitheliomas, pituitary blastoma, Wilms’ tumor, bladder cancer, and thyroid cancer.

 Juvenile hamartomatous intestinal polyps, multinodular goiter, and thyroid, lung, and kidney cysts are also seen.

The cancer risk is highest in early childhood, in large part due to the PPB risk with the majority of DICER1-associated tumors occurring before age 40.

 DICER1 syndrome is newly described and information about associated cancer risks is still emerging. The DICER1-related lifetime tumor risk seems to be 50% for females and 20% for males.

 Individuals who have personal and/or family histories of PPB, cystic nephroma, ovarian sex-cord stromal tumor, nasal chondromesenchymal hamartoma, medulloepitheliomas, pituitary blastoma, and/or embryonal rhabdomyosarcoma of the uterine cervix should be offered DICER1 genetic testing.

DICER1 is a ribonuclease responsible for producing short-interfering RNA and microRNA (miRNA) that regulate post-translational gene expression.

 Aberrant DICER1 function results in oncogenic miRNA, which does not require loss of the wild-type allele or a second-hit for disease development.

Management for infants and children with DICER1 syndrome includes complete physical exams, chest CT scans, chest x-rays, and renal ultrasound exams. Older children and adults with DICER1 syndrome should have clinical thyroid exams and possibly thyroid ultrasound scans.

BAP1 (BRCA1 associated protein-1) tumor predisposition syndrome is an autosomal dominant inherited cancer syndrome. Germline BAP1 mutations are associated with an increased risk for atypical melanocytic tumors, cutaneous and uveal melanoma, mesothelioma, and renal cell carcinomas,

. The atypical melanocytic lesions resemble Spitz nevi and have been characterized as “atypical Spitz tumors” (ASTs), although they have a unique histology and exhibit both BRAF and BAP1 mutations.

One study found 8% of patients with metastatic uveal melanoma to carry a germline BAP1 mutation.

 The exact spectrum of BAP1 associated malignancies and the extent of risk to develop these malignancies continues to evolve. A referral to genetics should be considered for individuals with a personal or family history of: metastatic uveal melanoma; non-metastatic uveal melanoma and cutaneous melanoma; cutaneous melanoma and mesothelioma; >1 mesothelioma diagnoses.

BAP1 is a deubiquitinating enzyme associated with the BRCA1 protein complex and it is involved in many cellular processes including regulation of the cell cycle and signaling pathways. Somatic BAP1 mutations have been seen frequently in malignant melanomas, uveal melanomas, and renal cell carcinomas. One study found inactivating BAP1 mutations in 47% of uveal melanomas.

Patients with a germline BAP1 mutation can be followed with annual eye exams and frequent skin checks.

 Low-dose computed tomography (CT) scan, magnetic resonance imaging (MRI), and ultrasound have been proposed as possible screening measures for lung and renal carcinomas however no consensus guidelines have been established.

Familial Atypical Multiple Mole Melanoma Syndrome

Familial Atypical Multiple Mole Melanoma (FAMMM) is a dominant condition thought to account for 40% of familial melanoma,

 1% of single primary melanomas, and 3% of multiple primary melanomas (MPM).

 Features of FAMMM include numerous (usually > 50) atypical nevi and familial melanoma often at early ages of onset.

 The risk for melanoma varies based on geography and exposure to the sun with estimates ranging from 50% to over 90%.

 The lifetime risk for pancreatic cancer in individuals with FAMMM is increased,

 but can vary tremendously from 10% to over 60%.

 Individuals with numerous dysplastic nevi, MPM, or melanoma in the context of family history of melanoma and/or pancreatic cancer should be referred for testing. 

FAMMM is caused by mutations in the CDKN2A gene, which disrupts the function of the p16 (INK4) isoform of the protein.

 This can lead to unregulated cell cycle progression from G1 to S phase and subsequent genomic instability that is critical in the pathogenesis of melanoma and pancreatic cancer.

Management of individuals with FAMMM has historically focused on patient education

 to limit sun exposure, quarterly dermatological exams often with digital dermoscopy, and vitamin D supplementation. Although pancreatic cancer screening has not demonstrated efficacy, surveillance options are available through both research studies and cancer centers that employ a combination of imaging and endoscopic ultrasound.

 The risk for pediatric melanoma and the opportunity to reduce risk by stringent sun protection should prompt assessment and testing of children in affected families.

Hereditary Leiomyomatosis and Renal Cell Cancer

Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is an autosomal dominant syndrome caused by mutations in the FH (fumarate hydratase) gene. HLRCC is characterized by cutaneous and uterine leiomyomas and renal tumors.

 Most individuals with HLRCC have >1 cutaneous leiomyoma, typically on their trunk and/or extremities. Uterine leiomyomas (fibroids) are present in virtually all women with HLRCC.

While many women have uterine fibroids, HLRCC-associated leiomyomas are numerous, large, and on pathology show prominent nuclei or large orangeophilic nucleoli surrounded by a perinucleolar halo.

 HLRCC confers approximately a 15% lifetime risk of renal carcinoma, typically aggressive Type 2 papillary renal cell carcinomas, which often present as unilateral and solitary tumors.

 Cutaneous and uterine leiomyosarcoma have been reported but this risk is low. Individuals with multiple cutaneous leiomyomas (one histologically confirmed), individuals with Type 2 papillary renal cell carcinoma, and individuals with a single cutaneous leiomyoma with a family history of kidney cancers and/or uterine leiomyomas should be referred to genetics.

FH is a mitochondrial tumor suppressor gene that produces fumarase, the enzyme responsible for converting fumarate into malate in the citric acid cycle. Build up of fumarate impairs the degradation of hypoxia inducible factor HIF-1a resulting in a pseudo-hypoxic state that contributes to tumor development.

Individuals found to carry a mutation can be followed with frequent dermatologic examinations as well as annual abdominal MRIs in children and adults. Women are followed with annual gynecological exams and may need myomectomy or hysterectomy for symptom management.

 Individuals with HLRCC are at risk to have a child with Fumarate Hydratase Deficiency (FHD) if their partner also carries an FH mutation. FHD is a severe autosomal recessive inborn error of metabolism.

Cowden Syndrome (CS) is an autosomal dominant hereditary cancer syndrome that predisposes to multi-organ hamartomas and cancers.

 The most common cancers to develop in CS are hormone receptor positive breast cancers, follicular thyroid cancer, and endometrial cancers. Other CS-associated cancers are renal cell carcinomas and colorectal cancers.

 Benign features such as macrocephaly, biopsy proven tricholemmomas, gastrointestinal harmartomas/ganglioneuromas, and neurodevelopment issues are also features of CS.

 Testing for CS is indicated when individuals meet a number of criteria which entail a combination of benign, often pathognomonic features, and/or have component tumors of the disease.

PTEN gene mutations only account for 25% of individuals who meet CS clinical criteria.

 The PTEN protein functions both in the nucleus and cytoplasm to downregulate MAPK and PI3K/Akt.

CS cases without an identifiable PTEN mutation may be explained by methylation of KLLN, 

The National Comprehensive Cancer Network Comprehensive (NCCN) has published recommendations for management of CS including: annual thyroid ultrasounds, breast MRIs and mammograms, as well as early and frequent colonoscopies.

Dermatological follow-up is often indicated and renal imaging has been proposed. Patients should be counseled regarding reproductive risks, which include risk for pediatric cancers in offspring as well as developmental delay and autism.

von Hippel Lindau (VHL) disease is an autosomal dominant hereditary cancer syndrome that is associated with a variety of tumors and cysts. The most common features of VHL syndrome are retinal angiomas, central nervous system (CNS) hemangioblastomas, and clear cell renal cell carcinomas (RCC).

 The lifetime risk of a CNS hemangioblastoma is 60% to 80% and the risk of RCC is 70%.

 Other features include pheochromocytomas and paragangliomas, pancreatic islet cells, endolymphatic sac tumors, epididymal cystadenomas, polycythemia (erythrocytosis), and cystadenomas of the broad ligaments of the uterus.

 Cysts, adenomas, and angiomas can also occur in the kidney, liver, pancreas, spleen and adrenal gland.

Individuals who have a personal and/or family history of clear cell kidney cancer, pheochromocytoma and/or paraganglioma, cerebellar hemangioblastoma, or retinal angioma should be offered VHL genetic testing.

 About 90% of individuals with VHL syndrome develop at least one manifestation; however, there is wide variable expressivity.

 The tumors can occur in childhood or adulthood.Â 

VHL is a multifunctional gene with a strong gatekeeper role, especially in the kidney. When the VHL gene is mutated, the absence of HIF degradation results in abnormal accumulation of VEGF and other hypoxia-inducible mRNA leading to tumor and cyst development.

Management for children and adults with VHL disease includes: annual physical exam, dilated eye exam, kidney evaluation with ultrasound, MRI exams of the brain, spine, and abdomen, including thin-slice MRI with contrast of the internal auditory canal, biochemical screening for pheochromocytomas, and annual audiology testing.46,48,49 Pregnant women with VHL need to be monitored closely due to the potential rapid growth of vascular tumors.

DICER1 syndrome, BAP1 tumor predisposition syndrome, FAMMM, HLRCC, Cowden syndrome, and VHL are complex disorders with reduced penetrance and pleiotropic effects. It remains important for patients and providers to recognize the evolving nature of these syndromes and the inherent limitations in predicting age-specific risk of component cancers. As several of these syndromes are newly described and others exceedingly rare, management guidelines are often based on expert consensus rather than evidence-based outcome measures. Greater recognition of individuals with these syndromes and comprehensive, long-term follow-up studies are needed to determine the efficacy of various screening modalities and establish best practices.

The skills of a diverse set of medical providers including oncologists, pathologists, dermatologists, genetics professionals, and others are required for proper diagnosis and age appropriate risk management. Genetic counseling and testing can serve to provide an explanation for the development of cancers in a family and define risk for unaffected family members. Astute oncologists, through close collaboration with their genetics colleagues, are instrumental in identifying individuals with rare cancer syndromes to ensure that these patients–and their families–receive optimal care tailored to their specific genetic predispositions.

Affiliations: Carmelina E. Heydrich, MS, LGC, Dana-Farber Cancer Institute; Katherine A. Schneider, MPH, LGC, Dana-Farber Cancer Institute; Huma Q. Rana, MD, Clinical Director, Center for Cancer Genetics and Prevention, Dana-Farber Cancer Institute.

Huma Q. Rana, MD, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02115; phone: 617-632-6292; email: HumaQ_Rana@dfci.harvard.edu.

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Articles

Experts discuss the clinical features, gene function, and medical management recommendations for six hereditary cancer syndromes. 

Huma Q. Rana, MD

Articles

Dr. Rana on the Rationale for Video Genetic Counseling in Prostate Cancer

Dr. Rana on the Prevalence of Pathogenic Variants in Prostate Cancer

Dr. Rana on Genetic Testing Guidelines for Patients With Ovarian Cancer

When to Consider Referral to a Genetic Counselor for Lesser Known Cancer Syndromes