Familial papillary renal cell carcinoma 1

Actionability Adult Summary Report

Secondary Findings in Adult Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Gene: MET (HGNC:7029)
• Mode(s) of Inheritance: Autosomal Dominant
• Literature Search: 06/02/2021
• Curation Status: Released (1.2.2)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
MET	papillary renal cell carcinoma (0017884)	605074	Assertion Pending

Actionability Assertion Rationale

• This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Morbidity/mortality associated with papillary renal cell carcinoma / Periodic surveillance via renal CT imaging	2	3C	3N	2	10CN

Severity of Outcome

Prevalence of the Genetic Condition

The incidence of familial papillary renal cell carcinoma (FPRCC) is unknown. However, the annual incidence of all familial renal cell carcinoma (RCC) syndromes is less than 1 in 1,500,000.

Clinical Features (Signs / symptoms)

FPRCC is characterized by a predisposition for developing multiple bilateral papillary RCCs. Patients may develop 1100-3400 microscopic tumors in a single kidney. The types of papillary tumors range from microscopic lesions to clinically symptomatic carcinomas. However, tumors are always type 1 papillary RCC with low nuclear grade. However, some tumors do metastasize.

Natural History (Important subgroups & survival / recovery)

FPRCC has late onset, typically between ages 50 and 70 years. A study of 10 families with FPRCC reported that the average age of diagnosis of affected individuals in these families was 45, with an estimated mean survival of 7 years following diagnosis. Although 5-year survival rates for patients with RCC have improved in recent years, the outcome for patients with advanced stage disease remains poor.

Likelihood of Outcome

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

Unknown

Penetrance (Includes any high-risk racial or ethnic subgroups)

>= 40 %

FPRCC is associated with high penetrance with a 90% likelihood of developing RCC by age 80.

Tier 3

Intervention Effectiveness

Patient Management

Treatment aims at controlling the risk of advanced disease, including metastasis, while at the same time preserving renal function due to the high likelihood of future de novo RCC. Sporadic and certain types of hereditary RCC usually acquire metastatic potential when their size reaches >3-7 cm. For some forms of hereditary RCC (such as FPRCC, von Hippel-Lindau syndrome, and Birt-Hogg Dube syndrome), the standard recommendation is the removal of all lesions in the same kidney once a single solid lesion or the largest solid is >3cm (the “3cm rule”), while other hereditary forms (such as hereditary leiomyomatosis and renal cell cancer and SDH-associated tumors) require more aggressive surgery due to a more aggressive nature with metastatic potential at smaller tumor size.

Tier 5

Partial nephrectomy (PN), also known as nephron-sparing surgery is now the standard method of hereditary RCC treatment. Bilateral nephrectomy eliminates the risk of metastasis from RCC but requires renal replacement therapy, including dialysis and kidney transplantation. However, the significant morbidity, mortality, and effects on quality of life, associated with dialysis makes this form of renal replacement therapy a last resort. In addition, options for kidney transplantation in hereditary patients may be limited due to the presence of RCC or other co-morbidities. Evidence for effectiveness of PN compared to bilateral nephrectomy among patients with FPRCC specifically was not available. However, available evidence suggest promising overall survival outcome for the PN intervention in hereditary RCC cases. One study assessed a cohort of 58 patients with hereditary RCC treated with PN for solid tumors greater than 4cm. The cohort which included 41 (71%) patients with von Hippel-Lindau, 10 (17%) patients with Birt-Hogg-Dube, and 7 (11%) with FPRCC. The mean age was 43.7 (range 18–63) and the mean largest tumor size was 5.3 cm (range 4–13). The mean number of resected kidney tumors was 6.4 (range 1–44). Overall survival of the cohort was 93% and metastasis-free survival was 96.5% at the median follow up of 45 months (range 2–163), rates similar to those reported in the literature series for patients undergoing PN for tumors in the sporadic population.

Tier 3

Surveillance

Imaging is often difficult due to the small size of lesions and their hypovascularity. In this context, CT is the imaging modality of choice for FPRCC patient screening. Surveillance should be started at age 30-35 and/or 10 years before the earlier age or onset of an RCC in the family. The frequency of surveillance can range from every 3-6 months to every 2-3 years depending on the size of the lesions.

Tier 3

Nature of Intervention

Nature of Intervention

Interventions identified in this report include surveillance with CT scans and treatment with nephron-sparing surgery. Surgical mortality of partial nephrectomy is less than 1% at experienced centers. A study of 50 patients with hereditary RCC who underwent 65 partial nephrectomies indicated the most common complications were pneumothorax (4.2%), renal atrophy (4.6%), prolonged urinal drainage (4.6%), and perinephric abscess (1.5%).

Context: Adult

Chance to Escape Clinical Detection

In a study of 10 families with FPRCC reported that RCC was often detected incidentally in asymptomatic individuals or during screening of asymptomatic members of RCC families.

Context: Adult

Tier 3

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			MET			605074	0017884	0003789

References List

Betti M, Corgna E. Renal Cancer. (2016) URL: http://www.startoncology.net/professional%ADarea/renal%ADcancer/?lang=en

Hereditary papillary renal cell carcinoma. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=47044

Herring JC, Enquist EG, Chernoff A, Linehan WM, Choyke PL, Walther MM. (2001) Parenchymal sparing surgery in patients with hereditary renal cell carcinoma: 10-year experience. The Journal of urology. 165(3):777-81.

Metwalli AR, Linehan WM. (2014) Nephron-sparing surgery for multifocal and hereditary renal tumors. Current opinion in urology. 24(5):466-73.

RENAL CELL CARCINOMA, PAPILLARY, 1; RCCP1. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 605074, (2016) World Wide Web URL: http://omim.org/

Verine J, Pluvinage A, Bousquet G, Lehmann-Che J, de Bazelaire C, Soufir N, Mongiat-Artus P. (2010) Hereditary renal cancer syndromes: an update of a systematic review. European urology. 58(5):701-10.