# Handbook of Genetic Counseling/Renal Cell Carcinoma

Renal Cell Carcinoma

## Introduction

* Renal (comprising most kidney) cancer is usually sporadic or randomly occurring
* Some individuals with renal cancer have a genetic predisposition to developing cancer and we call these hereditary cancers
* There are a couple of things that sometimes make us wonder if a cancer is due to an inherited genetic predisposition. One of these is early age of onset of cancer.
* ______ was diagnosed at a young age (most individuals with renal carcinoma are diagnosed in their 40's-60's)
* Two most common types of renal carcinomas
* Most common is clear cell renal carcinomas (comprise 80% of sporadic cases and are the type seen in Von Hippel Lindau, which rules this genetic cancer syndrome out)
* Second most common is papillary renal cell carcinomas (PRCCs) I WON'T GO INTO ALL OF THE FOLLOWING DETAILS ONLY THOSE STARRED
** generally accepted that it has a better prognosis than other types of renal cancer
** appears to be sporadic in majority of cases
** accounts for about 5-10% of sporadic renal cell carcinoma and is seen in Hereditary Papillary Renal Carcinomas (HPRC)
** estimated that male to female ratio for PRCC is between 5:1 and 8:1 (however when 9 families were studied they found 28:12 (2.33:1 ratio)
** Sporadic PRCC are usually solitary tumors (but multiple papillary adenomas were described in surrounding renal parenchyma in some cases)
** In one study all 29 patients from the 6 families with HPRC studied had multiple bilateral tumors
** Suggestion to subdivide PRCC into type 1 and type 2 tumors
** Those with family history and those with met mutation share features of type 1, but not all individuals with tumors characteristic of type 1 had an identified met mutation
** Trisomy 7 characteristic of sporadic and hereditary papillary renal carcinomas (shown in 95% of PRCCs)
** Also characterized by trisomy or tetrasomy 17, and trisomy 16, 20, and 12 and loss of Y in males
** Suggested that those with tri or tetrasomy 7 and 17 correspond to papillary adenomas and more complex karyotypic changes are papillary carcinomas

## Review genes and chromosomes

* In order to understand the difference between hereditary and sporadic cancer it can be helpful to review some genetic information because it is not something most people think about all the time.
* Some genes help control when cells divide and how fast they divide.
* Essentially there are genes that act like the breaks of a car and there are genes that function like the gas pedal to accelerate cell growth and division.
* If these genes are changed it can sometimes cause a cell to keep dividing and dividing and develop into cancer.

## HPRC

* Recently described form of hereditary cancer
* Genetic predisposition to develop multiple tumors in both kidneys (bilateral, multifocal)
* Median age of onset is 45, but ranges from 18-79 with most between 35 and 55 years old
* Explain AD inheritance with reduced penetrance
* Associated with (germline) mutation of a gene present in all of the cells of affected family members
* gene is called MET and is found at 7q31
* the gene is involved with regulating cell division
* this gene is called a proto-oncogene which just means that when it has a change or a mutation in the gene, it can cause cell division to become accelerated (it is kind of like pressing down harder on the gas pedal and not releasing the it so the car can stop)
* met mutations have also been found in 13% of tumors of PRC patients without a family history but all but one had bilateral disease and may be ascertainment bias
* half had somatic mutation and half were shown to have germline mutation so rate of met mutation in true sporadic mutations may be 7% or even lower due to bias
* In those with germline mutation it is possible that these are de novo mutations or may be possible that family members are not picked up because in known families, tumors not always detected until intense radiologic screening is done
* Germline mutation screening for met does not appear to be clinically indicated in patients with PRCC without additional evidence for genetic predisposition, which includes positive family history, unusual age at onset, bilateral disease (Mary Liebert 2001 found in Genetic Testing)
* Tumors are predominantly PRCs in HPRC but also breast, pancreas, lung, skin and stomach have been described in some of these families

## Management in those with HPRC

* Use of partial nephrectomy due to risk of tumor in other kidney
* Those at high risk might benefit from earlier and aggressive site-specific surveillance

## Differential Causes

* 1;X translocations
** may have prominent papillary architecture
** may seem to be widely metastatic and poor prognosis
** TFE3 gene identified at breakpoint
* Hereditary leiomyomatosis and renal cell cancer (HLRCC)
** Described in large Finnish family
** Along with PRCs, uterine leiomyomas, skin leiomyomas, breast cancers, and bladder cancers also found
** Mapped to 1q42-q44

## Facts about renal cell carcinoma

* accounts for about 3% of adult malignancies and 90-95% of neoplasms in the kidney
* more common in individuals of Northern European descent but incidence increasing most rapidly in African Americans
* twice as common in men
* lack of early warning signs
* 25-30% are asymptomatic

## Symptoms and presentation

* hematuria (40%)
* flank pain (40%)
* palpable mass in the flank or abdomen (25%)
* weight loss (33%)
* fever (20%)
* hypertension (20%)
* hypercalcemia (5%)
* night sweats
* malaise
* variocele, usually left sided, due to obstruction of the testicular vein (2% of males)
* cytokine release by tumor frequently causes paraneoplastic conditions

## metastasis

* lung 75%
* soft tissues 36%
* bone 20%
* liver 18%
* cutaneous sites 8%
* CNS 8%

## Risk factors

* Smoking doubles risk and contributes to as many as 1/3 of cases
* Obesity also seems to increase risk especially in women
* Risk increased also with
** Abuse of phenacetin-containing analgesics
** Acquired cystic kidney disease
** Renal dialysis
** Renal transplantation

## MET function

* proto-oncogene that encodes met receptor (receptor for hepatocyte growth factor/scatter factor)
* triggers autophosphorylation of critical tyrosines in the intracellular tyrosine kinase domain of MET, activating a signal cascade

## Notes

The information in this outline was last updated in 2002.