Beyond the Scope: Extra Colonic Cancer Risks in HNPCC and Screening VHL Family Alliance Joy Larsen Haidle, MS, CGC Genetic Counselor Humphrey Cancer Clinics

Colorectal Cancer Nat Med 2:169-74, 1996 © 2001 Myriad Genetic Laboratories Sporadic (~60%) Familial (~30%) HNPCC (3-5%) Colorectal Cancer FAP (<1%) Rare syndromes (~4%) Colorectal Cancer 130,000 cases annually in the US

Familial Adenomatous Polyposis In the classic form, the phenotype is not subtle! It will declare itself. –100s to 1000s of adenomatous polyps –Early onset CRC Almost 100% by 40y if untreated Attenuated FAP can mimic HNPCC –Smaller number of adenomatous polyps –CRC risk rises sharply after 40y and >50% –MSI stable

FAP: Associated Cancers Duodenal cancers (seen ~20 years after onset of CRC) Thyroid cancer Childhood hepatoblastomas Gastric carcinomas Medulloblastomas

FAP: Associated Findings Sebaceous or epidermoid cysts Lipomas Congenital hypertrophy of the retinal pigment epithelium (CHRPE) Desmoid tumors Mandibular ostoemas Supernumerary teeth

HNPCC Fast Facts Also known as Lynch syndrome Incidence thought to be 1/740-1/1000 people HNPCC acct for 2-7% of annual worldwide incidence of colorectal cancer (18,900-63,130 cases/yr) Autosomal Dominant inheritance 40-60% of patients who meet Amsterdam criteria test positive for mutation Extra colonic cancer risks gender specific –CRC risk higher in males than in females

HNPCC Fast Facts High (80%) risk of colorectal cancer –Mucinous (30-40%) –Poorly differentiated (23-39%) Mean age of colorectal cancer diagnosis is 44y 2/3 Colon tumors right-sided Associated with microsatellite instability (MSI) Associated with improved survival rate (65% 5-yr in MLH1 vs 44% 5-yr in sporadic CRC) 25% of individuals will develop more than one tumor

Review of Related Genes MLH1: (40% of cases) –Also makes protein complex with PMS2 to excise mispaired DNA and resynthesize –Mutation results in complete loss of function –Mean age at CRC dx 42.8 yrs MSH2: (>40% of cases) –Deletions very common; up to 30% of all disease causing mutations are deletions –Cancer rates higher than MLH1 carriers (90% to age 80y vs 85%) –Mean age at CRC dx 43.9

Review of Related Genes MSH6: (10% of cases) partial mismatch repair gene –Associated with atypical HNPCC families –Only few of families with MSH6 meet Amsterdam criteria –Associated with later onset CRC (avg age 61 yrs) –No proximal predominance for CRC –Tumor tend to be MSI-L; MSI-H and MSI-S tumors reported with MSH6 germline mutations –Makes heterodimer with MSH2: role to repair base- base mismatches AND insertion-deletion loops –Loss of MSH2 protein may occur in process of cancer progression

Review of Related Genes MSH3: partial mismatch repair gene –Redundant function with MSH6 –MSH2 and MSH3 create heterodimer responsible for correcting insertion-deletion loops; not effective in correcting base-base mismatches PMS2 (5% of cases) –Brain cancers reported in PMS2 families ?PMS1 (one family reported) This family was recently found to have a deleterious MLH1 mutation

Candidates for Testing Families that meet Amsterdam I or Amsterdam II criteria Families that meet Bethesda criteria Families that meet the Revised Bethesda guidelines Early onset (<50y) of a cancer is important “flag” to remember Anyone with polyposis (defined loosely as >10 colonic polyps over a lifetime) or family history of polyposis

Amsterdam Criteria I dx 49 dx 39 dx 42 dx 69 colca dx 49 dx 50

Amsterdam II Family At least 3 relatives with HNPCC related cancer (CRC, endometrial, ovarian, small bowel, ureter, renal pelvis) 1 case should be a first degree relative of the other two At least two successive generations should be affected At least 1 cancer should be dx before 50 yrs FAP should be excluded Tumors should be verified by pathological examination

AGA Guidelines Amsterdam I criteria Individuals with 2 HNPCC cancers (synchronous/metachronous CRC) Individuals with CRC and FDR with CRC and/or HNPCC extra colonic cancer and/or colorectal adenoma (cancer <50y, adenoma <40y) CRC or endometrial cancer <50y Right sided CRC with undifferentiated pattern on histology <50y Signet cell type CRC <50y Colorectal adenoma <40y

Revised Bethesda Guidelines CRC dx less than 50y Presence of synchronous or metachronous CRC or other HNPCC related tumor regardless of age CRC with MSI-H histology diagnosed in patient <60y –infiltrating lymphocytes, Crohns-like lymphocytic reaction, mucinous/signet ring differentiation, medullary growth pattern CRC dx in 1 or more first-degree relatives with an HNPCC related tumor, with one of the cancers dx <50y CRC diagnosed in 2 or more first or second-degree relatives with HNPCC-related tumor regardless of age

Extra Colonic HNPCC Cancers Endometrial Ovarian Pancreas Stomach Urologic Tract Cancer Small Bowel Hepatobiliary Brain Breast Skin

Endometrial Cancer CRC dx 60 Endom ca dx 66 Endom ca dx 40 CRC dx 60 Endom ca dx 55 Endometrial cancer d. ? MSH2

Endometrial Cancer Most common extra colonic cancer in HNPCC –Female MSH2 (35-40%) and MSH6 (>50%) mutation carriers highest risk –MSH6 may be associated with later onset (mean age 55yrs) Lifetime risk for females 25-60%; general pop 1.5-3% Peak ages 40s-50s; mean age 47 yrs –Almost all cases occur before 65 yrs –Median age of dx in the general population is 63 yrs –Peak age in HNPCC 15 yrs earlier than gen pop –~25% women will be premenopausal

Endometrial Cancer MSI: 9-28% of tumors show MSI –Most sporadic tumors associated with somatic MLH1 promoter methylation –MSH6 tumors may be MSI-H, MSI-L or MSI-S –Endometrial cancer dx <45 should be screen by MSI regardless of family history

Cumulative Cancer Incidence among Young High- Risk Women compared with Women of Victoria as of 1996 Cancer TypeBy age 25 (n=701)By age 30 (n=620)By age 35 (n=583)By age 40 (n=544) Ovary high risk gen pop RR % % 0.08% % 0.10% 5 0.7% 0.14% 5 Endometrial high risk gen pop RR % % 0.01% % 0.01% % 0.03% 30 Gynecologic high risk gen pop RR % % 0.09% % 0.11% % 0.17% 10 Colorectal high risk gen pop RR 0.9% 0.01% % 0.01% % 0.03% % 0.09% 110

Endometrial Cancer Screening High risk provides basis for screening Most women present with dysfunctional uterine bleeding Transvaginal ultrasound (annual) –Begin screening at yrs –One study demonstrated 23 cancers in women before age 35 yrs Endometrial sampling –No data to suggest yet if endometrial bx is better than curettage or aspiration –Value of surveillance unknown

Extra Colonic HNPCC Cancers Endometrial Ovarian Pancreas Stomach Urologic Tract Cancer Small Bowel Hepatobiliary Brain Breast Skin

84 Endomet ca dx 81 Brca dx 82 Transitional cell ureter dx 83 Ovarian cancer Multiple primary Ovca dx 41 Col polyps dx 55 Ovca dx 42 d.42 d. 56 OTC 54 m+ 58 m- 52 m+ Ovarian Cancer Family MSH6

Ovarian Cancer 85% of ovarian cancer occur less than 50 yrs –Mean age 42.7 yrs –1/3 of cases diagnosed less than 40 yrs –½ occur between age yrs –16 years earlier than age in general population –Very likely to be epithelial ovca of any histologic type Excess of endometrioid cancers –? More favorable outcome Unlikely to be poorly differentiated Unlikely to be advanced stage at diagnosis Likely to have synchronous endometrial cancer 10-12% lifetime risk

Ovarian Cancer Screening Pelvic examination –q 6-12 months beginning yrs Transvaginal US –color flow Doppler and morphologic index –q 6-12 months beginning yrs Serum CA125 –q 6-12 months beginning yrs ? Use of proteomics Consider prophylactic oophorectomy when childbearing complete or age 35-40yrs

Extra Colonic HNPCC Cancers Endometrial Ovarian Pancreas Stomach Urologic Tract Cancer Small Bowel Hepatobiliary Brain Breast Skin

Pancreatic Cancer DNA mismatch repair mutations may account for up to 4% of pancreatic cancers Lifetime risk <5% In some countries, pancreatic cancer associated with an MLH1 mutation Environmental factors not appear to be responsible for higher incidence in some populations (Korean vs Dutch) In one study, avg age onset 44.7y –Small number of people (33 Amsterdam families; 4 cases of panca)

Pancreatic Cancer Screening Annual endoscopic ultrasound Annual CA-19-9 and CEA Annual MRCP If suspicious findings then ERCP No consensus on age to begin screening, frequency, or benefit conferred by screening –Some begin screening at 50y or 10 years younger than the earliest case of pancreatic cancer –Reserved for families with history of this cancer Screening is not without risks

Extra Colonic HNPCC Cancers Endometrial Ovarian Pancreas Stomach Urologic Tract Cancer Small Bowel Hepatobiliary Brain Breast Skin

CRC CRC 37 Sto 56 Adenoma 56 CRC 51 CRC 61 CNS LEU CNS 60 LEU 44 Stomach Cancer MSH6

Stomach Cancer 19% lifetime risk with median age of 54y Risk higher in MSH2 mutation carriers –4.3% cumulative risk by 60 yrs in MSH2 vs 2.1% in MLH1 Seen at higher rates in Asian families than Western countries

Stomach Cancer Screening Upper gastrointestinal endoscopy –Every 1-2 yrs –Beginning 30-35y or 5 yrs less than the earliest gastric cancer –Some studies state begin at age 50y as this is when the greatest increase in risk occurs –Continue surveillance until 75 yrs or until causative mutation is excluded No consensus on screening –Reserved for families with history of gastric cancer –Little evidence to suggest that screening confer benefit

Extra Colonic HNPCC Cancers Endometrial Ovarian Pancreas Stomach Urologic Tract Cancer Small Bowel Hepatobiliary Brain Breast Skin

HNPCC Family with Predominance of Urothelial Cancers Uroepithelial CRC Gynecologic Rec dx 56 Kid dx 66 Col dx 51 Kid dx 65 Col dx 71 Rec dx 34 Ut cx dx 52 Rec dx 41 Kid dx 65 MTS dx 71/72 Sm Bo dx 73 Ce dx 77 Ov dx 41 Kid dx 52 Ut cx dx 27 En dx37 Ov, Cx, Ut dx 34 Col dx 40 Col dx 42 MTS dx 44 Col dx 51 Rec dx 67 Bl dx 69 Ureter dx 69 Bl dx 73 Ce dx 76 MSH2

Urologic Tract Cancer Estimated proportion caused by HNPCC is 7-15% Increased risk of urothelial cancers of the renal pelvis and ureter One study indicates the risk cumulative risk (up to age 70 yrs) was 7.3% MSH2 families may have a greater risk –One study cumulative risk to age 70 yrs 12% in MSH2 vs 1.3% in MLH1

Urologic Tract Screening Urinalysis with cytology begin age 30-35y at 1-2 year intervals Renal ultrasound begin yrs at 1-2 year intervals Sensitivity and specificity yet to be determined

Extra Colonic HNPCC Cancers Endometrial Ovarian Pancreas Stomach Urologic Tract Cancer Small Bowel Hepatobiliary Brain Breast Skin

Small Bowel Cancer: General Population Stats Account for less than 2% of all gastrointestinal malignancies –Small intestine account for 75% of length of GI tract –Incidence 2/100,000 –Average age dx 69 yrs –Adenocarcinoma is most common histologic type (40-50% in the duodenum) Carcinoid second most common type (80-90% arise in ileum)

Small Bowel Cancer in HNPCC Risk of cancer fold increased risk compared general population –Corresponds to 1-4% lifetime risk in HNPCC Younger age of onset <60 yrs –Median age 49yrs in one study 8-50% of small bowel cancers caused by HNPCC Higher male to female ratio High incidence of metachronous and synchronous tumors Different site distribution within small bowel –HNPCC =even distribution –Sporadic = predilection for duodenum

Small Bowel Screening Annual hemoglobin Small Bowel X-ray every 2 years No consensus on age to begin screening or modality

Extra Colonic HNPCC Cancers Endometrial Ovarian Pancreas Stomach Urologic Tract Cancer Small Bowel Hepatobiliary Brain Breast Skin

luca dx 69 CNS dx 68 2 colca dx 41 bili dx 61 ? dx >50 Colon cancer Hepatobiliary CNS Unknown Hepatobiliary MSH6

Hepatobiliary Tract Cancer Two studies list lifetime risk of 18% with a median age of onset of 54y Cumulative risk to age 70 yrs 2.0% One study, avg age of dx 33.2y –33 Amsterdam families; 3 cases (South Korea) –MLH1 mutations reported in these cases Listed as common extra colonic malignancy in several studies, but very few risk estimates

Hepatobiliary Tract Screening Reserved for families who have this cancer history –Transabdominal ultrasound of biliary tree –Liver function tests –No consensus on age to start or frequency –Little evidence to suggest screening confers a benefit

Extra Colonic HNPCC Cancers Endometrial Ovarian Pancreas Stomach Urologic Tract Cancer Small Bowel Hepatobiliary Brain Breast Skin

d. 68 glioblastoma polyps dx 44 d. ? d. colca d. 80 utca dx 60 d. 20 colca d. 65 MI d. 44 colca d. 65 colca colca dx 22 ovca dx 42 colca dx m+ 43 m- colca uterine ca ovca glioblastoma polyps Glioblastoma and HNPCC MSH2

Brain Tumors Lifetime risk of brain tumor is 3.35% Tumors reported –Astrocytoma* –Oligodendroglioma –Ependymoma –Glioblastoma* –Medulloblastoma Early onset (one study mean age at dx was 16.5y) –Adult onset reported, mostly children Risk CNS tumor higher in MSH2 mutation carriers –I case with PMS2 mutation reported

Brain Tumor Screening Vasen et. al. do not recommend screening for brain tumors –Low lifetime risk of this cancer –Uncertain if an improvement of overall prognosis can be achieved with early detection and intervention

Extra Colonic HNPCC Cancers Endometrial Ovarian Pancreas Stomach Urologic Tract Cancer Small Bowel Hepatobiliary Brain Breast Skin

d. leukemia Brca dx 49 d. ? Ovca dx 49 Colca dx 55 Endo ca dx 57 Uret dx 65, 77 Skin dx 75 Colca x2 dx 77 d. ? Breast cancer Ovarian cancer Leukemia Colon cancer Endometrial cancer Ureter cancer Skin Breast Cancer MSH6

Breast Cancer Unclear if part of the tumor spectrum –Thought to be a risk in MLH1 Reported but not confirmed in follow-up paper No difference is risks when MLH1 compared to MSH2 –In one series, brca usually presented at an early age –Possibly role of mismatch repair system in brca Perhaps in tumor progression MLH1 promoter methylation may play a role MSI-H infrequent in brca; MSI-L reported Additional data needed!!!

Extra Colonic HNPCC Cancers Endometrial Ovarian Pancreas Stomach Urologic Tract Cancer Small Bowel Hepatobiliary Brain Breast Skin

sebaceous adenoma brca 43 atypical mole colca 46 ulcerative colitis kidney ca colca dx 54 ovca stoca ovca colca Sebaceous adenoma Ovarian cancer Colon cancer Kidney cancer Skin MSH6

Skin Part of Muir-Torre variant (MTS) –Sebaceous adenomas –Epitheliomas –Carcinomas –Keratoacanthomas –Squamous cell carcinoma Number of skin tumors range from 1 to >10 Excess of MSH2 mutations In 40% of cases, skin lesion precedes visceral malignancy MSI/IHC reliable predictors of germline mutation even in benign MTS skin lesions

Skin Cancer Surveillance Self skin examinations Annual dermatologic examination Lower threshold to evaluate changes in skin lesions

A Striking Story colca ovca colca dx 34 ovca dx 49 colca dx 41 colca dx 52 colca dx 47

Is the History Suggestive of Hereditary Cancer? What cancers present in family? Assess family pedigree pattern Explore possible non-genetic etiology ie thyroid cancer: hx radiation tx for acne Understand risks, benefits, and limitations of genetic testing ASCO 1998 slide

Psychological Issues in Cancer Genetic Testing Decision making related to testing –How would you use this information? Psychological impact of testing Family disclosure of mutation status Impact on compliance with screening

Benefits of Genetic Testing Help to define the risk of developing cancer Enhance early detection and prevention of cancer Help to determine if relatives are at increased risk to develop cancer Help to define which relatives require increased surveillance

Social/Legal Issues of Cancer Genetic Testing Practitioner knowledge and use of testing Insurance discrimination Medicolegal implications

Key Points to Remember Hereditary risk can come from your mother or your father. Young age of onset, bilateral/multifocal or multiple primary cancers are important to note. Not everyone with hereditary risk will develop cancer. Increased surveillance and surgical options can make a difference in these families. Not all families with multiple cases of cancer represent single gene inheritance.

Original Referral brca 49 ovca 43 brca 38 brca 52 ovca brca

Two Sides to Every Family dx 45 dx 48 4 dx 60 dx 59 dx 49dx 43 dx 38 dx 51 dx 52 ovca colca brca

Key Points to Remember Hereditary risk can come from your mother or your father. Young age of onset, bilateral/multifocal or multiple primary cancers are important to note. Not everyone with hereditary risk will develop cancer. Increased surveillance and surgical options can make a difference in these families. Not all families with multiple cases of cancer represent single gene inheritance.

Age May be Key dx 20 dx 69dx 40 livca colca brca

Key Points to Remember Hereditary risk can come from your mother or your father. Young age of onset, bilateral/multifocal or multiple primary cancers are important to note. Not everyone with hereditary risk will develop cancer. Increased surveillance and surgical options can make a difference in these families. Not all families with multiple cases of cancer represent single gene inheritance.

Key Points to Remember Hereditary risk can come from your mother or your father. Young age of onset, bilateral/multifocal or multiple primary cancers are important to note. Not everyone with hereditary risk will develop cancer. Increased surveillance and surgical options can make a difference in these families. Not all families with multiple cases of cancer represent single gene inheritance.

Key Points to Remember Hereditary risk can come from your mother or your father. Young age of onset, bilateral/multifocal or multiple primary cancers are important to note. Not everyone with hereditary risk will develop cancer. Increased surveillance and surgical options can make a difference in these families. Not all families with multiple cases of cancer represent single gene inheritance.

All My Family Gets Cancer dx 62 dx 68 dx 22 dx 69 dx 81dx 80 dx 89 Hogkins brca livca lungca proca

Referral to Cancer Genetic Program Most insurance plans cover the cost of the consultation Anyone can make a referral Patients can request an appointment Contact: