Genetics: (4) Hereditary Cancer

Familial Cancer

2 or more affected 1st or 2nd degree relatives Unclear pattern of inheritance -- chance, common environment, genetic factors? Risk could be up to 2-3 times general population

Risk Factors for Breast Cancer

>50 y/o History of combination estrogen/progesterone replacement therapy (HRT therapy) -Birth control is a risk.. But a small risk compared to pregnancy risk and also has substantial protective effect against ovarian epithelial and endometrial CA Lengthy "menstrual life" -i.e.) early menarche, late first full-term pregnancy, and late menopause Short length of maternal breastfeeding or not breastfeeding at all Central obesity, moderate alcohol intake -Alcohol has a small cardioprotective effect and must be considered on a case by case basis Radiation as CA treatment <30 y/o Genetic predisposition

CRC genetic factors

APC mutation uPolyposis coli aka Familial Adenomatous Polyposis (FAP) uGardner's and Turcot's syndrome u presence of soft tissue and bony tumors, congenital hypertrophy of the retinal pigment epithelium, mesenteric desmoid tumors, and ampullary cancers in addition to the colonic polyps, brain tumors uUsually develops spontaneously and affects individuals by age 25 u100 or more polyps can be present MSH2/MLH1 mutations uHereditary nonpolyposis colon cancer (HNPCC), aka *Lynch's syndrome* uaffects those <50 uRight sided colon ca more common in this condition uAmsterdam II Criteria: characterized by the presence of three or more relatives with histologically documented colorectal cancer, one of whom is a first-degree relative of the other two; one or more cases of colorectal cancer diagnosed before age 50 in the family; and colorectal cancer involving at least two generations

GI Hereditary Cancer Syndromes

Appropriate Referrals: uSuspicious of HNPCC (Hereditary Non-Polyposis Colon Cancer aka Lynch Syndrome): uIndividuals with a personal or family hx of colon cancer, with at least one diagnosis under age 50 uIndividuals with a personal or family hx of uterine, colon, ovarian, other GI cancers in any combination, with at LEAST one diagnosis under age 50 uSuspicious of FAP (Familial Adenomatous Polyposis) uIndividuals with multiple adenomatous polyps (multiple being anywhere from 20 to 1000s) or a 1st degree relative with polyposis

Hereditary Breast and Ovarian Cancer (HBOC)

Breast cancer is a common disease panethnically. Approximately 15% to 20% of breast cancer is thought to cluster in families while only 5% to 10% is caused by single gene defects. Ovarian cancer is far less common; approximately 10% to 25% of ovarian cancer is caused by single gene defects.

Breast CA pathology

Breast cancer is a malignant proliferation of epithelial cells lining the ducts or lobules of the breast

Cancer Genetics

Cancer is a genetic disease Most cancers arise sporadically due to genetic mutations, however some cancers occur in families that carry a germline mutation in a cancer gene 10% of cancer patients inherit a genetic defect conferring a susceptibility to cancers over their lifetimes.

Screening for CRC

Digital rectal examination Stool testing • Occult blood • Fecal DNA Imaging • Contrast barium enema • Virtual (i.e., computed tomography colonography) Endoscopy • Flexible sigmoidoscopy • Colonoscopy

Prevention of Lynch Syndrome

HNPCC (Lynch syndrome) urecommended that members of such families undergo annual or biennial colonoscopy beginning at age 25 years, with intermittent pelvic ultrasonography and endometrial biopsy for afflicted women uProphylactic colectomy (not routinely recommended however) uProphylactic total hysterectomy and salpingo-oopherectomy in women <35 or once child-bearing is complete

Screening for BRCA1/BRCA2 Carriers:

Individuals meeting the criteria established by the NCCN should be referred to counseling and possible genetic testing Female Cancer Risk uWomen who are found to have a disease-associated mutation in BRCA1 or BRCA2 should initiate breast cancer surveillance. uSelf-breast examination—though studies suggest limited efficacy uClinical breast examination beginning at age 25 and repeated at 6-month intervals uMammography beginning at age 25 and repeated annually uBreast magnetic resonance imaging (MRI) beginning at age 25 and repeated annually u*There are currently no effective ovarian cancer surveillance methods*. Male Cancer Risk •Men who are found to have a disease-associated mutation in BRCA1 or BRCA2 should initiate breast and prostate screening •Surveillance recommendations for male mutation carriers include: •Clinical breast examination repeated annually (starting at age 30) •Prostate-specific antigen testing annually (starting at age 40) •Digital rectal examination annually (starting at age 40) Counseling •BRCA1 and BRCA2 are inherited in an autosomal dominant fashion. Each child of an affected parent has a 50% risk of inheriting the condition. •Presymptomatic testing should be offered to all first-degree relatives of an affected individual.

Sporadic Cancer

Majority of cancer cases (~85%) Usually not inherited - may appear as a single occurrence of cancer in a family Age of diagnosis typically later in life (or "common" for particular cancer type) Median age at DX is 61

Multifactorial inheritance

Means that "many factors" (multifactorial) are involved in causing a birth defect. The factors are usually both genetic and environmental, where a combination of genes from both parents, in addition to unknown environmental factors, produce the trait or condition (chw.org).

Diagnostic Criteria for HBOC

National Comprehensive Cancer Network Criteria (NCCN)—at least one or more of the following: •Early-onset cancer (age <50 years), typically premenopausal breast cancer including both invasive and ductal carcinoma in situ (DCIS) breast cancers •Two primary tumors of the breast or breast and ovarian or fallopian tube or primary peritoneal cancer in a single individual •Two or more primary tumors of the breast or breast and ovarian or fallopian tube or primary peritoneal cancers in first- second- and third-degree relatives from the same side of the family •At-risk populations (eg, Ashkenazi Jewish, Icelandic) •Member of a family with a known BRCA1 or BRCA2 mutation •Any male breast CA •Ovarian or fallopian tube or primary peritoneal cancer at any age

Cancer Genetics

No single mutation results in cancer. It's an accumulation of mutations in both brakes and in the accelerators of cellular behavior. You have to dismantle many of the controlling elements in the cell in order for cancer to develop. If you just dismantle a few of them you might get a benign tumor, but you won't get a cancer. It's only when all of these pathways, or many of them, are inactivated that a cancer results. It wouldn't be correct to say that a given mutation in a given gene causes cancer, what you can say is a given mutation *contributes* to the development of cancer.

Hereditary nonpolyposis colorectal cancer (HNPCC)

People with ___ or Lynch syndrome are more at risk of developing ovarian ca women with HNPCC should undergo prophylactic hysterectomy with *salpingo-oophorectomy* before the age of 35 or when child bearing is complete

Screening for average risk of breast cancer

Screening for average risk patients should begin at age 40 annually -Some sources say after 55 y/o it can be every 2 years (cancer.org/cdc.gov) -American Cancer Society (ACS) supports the perception that screening mammography reduces breast cancer mortality by one-quarter to one-third in women aged ≥50 years Keep in mind that a screening mammogram is not the same as a diagnostic mammogram -Diagnostic mammogram would be if any findings were discovered prior to mammogram (ie. masses, symptoms reported by patient)

Abnormal mammogram

Subtle abnormalities that are first detected by screening mammography should be evaluated carefully by compression or magnified views. These abnormalities include clustered, heterogeneous, linear, and branching microcalcifications; densities (especially if spiculated); and new or enlarging architectural distortion. If a nonpalpable mammographic lesion has a low index of suspicion, mammographic follow-up in 3-6 months is reasonable.

HNPCC Screening Protocol

Uterine & Ovarian cancer uFor women, intermittent pelvic US and annual endometrial aspirate is recommended starting between the ages of 25-35. uWomen confirmed as having HNPCC can consider prophylactic TAH-BSO after childbearing is complete, or at the time of menopause.

adenomatous polyp (adenoma)

___ : a polyp with the potential to become cancerous •Mutation of tumor suppressor gene on the APC

days 5-7 of menstrual cycle

___ are the best times for breast exam during follicular stage (~3 days after your period)

APC mutation

___ loss of apc function (apc is a tumor suppressor gene that controls apc protein encoding)

Invasive ductal carcinoma (IDC)

___, sometimes called infiltrating ductal carcinoma, is the *most common type of breast cancer*. About 80% of all *breast cancers* are invasive ductal carcinomas. Invasive means that the *cancer* has "invaded" or spread to the surrounding *breast* tissues uIncreased use of mammography has led to more frequent diagnoses of *noninvasive* breast cancer. uOnly lung cancer is more deadly than breast CA in women

Screening for CRC

guidelines: uThe risk of colon cancer in an individual with a first-degree family member is two times higher than the general population. uIf an individual has a first-degree relative who was diagnosed with colon cancer or advanced adenoma before the age of 60, or two or more first-degree relatives had colorectal cancer or advanced adenomas at any age, screening with colonoscopy is recommended at age 40 or 10 years before the youngest relative's diagnosis, whichever comes first uAdditional exams should be repeated every 5 years uIndividuals who demonstrate characteristics of a familial cancer syndrome, or are first-degree relatives of one, should be referred to a genetic specialist for further evaluation, testing, and more intensive screening. uFAP uRelatives of those with polyposis coli should be tested for APC mutation and children of affected should screened by annual flexible sigmoidoscopy until age 35 uHNPCC (Lynch Syndrome) urecommended that members of such families undergo annual or biennial colonoscopy beginning at age 25 years, with intermittent pelvic ultrasonography and endometrial biopsy for afflicted women

Ovarian ca

the ovary is responsible for follicle maturation associated with egg maturation, ovulation, and cyclical sex steroid hormone production. These complex biologic functions are linked to stromal and germ cells within the ovary. These cells can be broadly grouped into stromal cells and ovarian germ cells and the enveloping epithelial cells. uEpithelial (serous) tumors are the most common in those with malignant ovarian ca uType 2 ovarian ca is more aggressive than type 1 uMost originate in the fallopian tubes uCarcinoma in situ has been identified in the tubal epithelium with early losses in TP53 and the BRCA1/BRCA2 genes characterizing early tubal intraepithelial cancers uOvarian tissue may also host metastatic tumors arising from breast, colon, gastric, and pancreatic primaries.

Immunohistochemistry staining (IHC)

uAdvantages uEasy to perform uRapid results uCan direct gene sequencing. uEx: if MSH2 protein expression is absent, this is indicative of a mutation in the MSH2 uIHC can be indicative of a gene mutation for the estimated ~10% of mutations that are MISSED in direct sequencing uDisadvantages uInterpretation by pathologists, ordering MDs. uDifficulty with MLH-1

Risk factors for crc

uAge: 90% of cases occur in people OVER the age of 50 uDiet- Western diet high in animal fats uLiving in urban areas- directly correlated with per capita consumption of calories, meat protein, and dietary fat and oil as well as elevations in the serum cholesterol concentration and mortality from coronary artery disease uanimal fats found in red meats and processed meat leads to an increased proportion of anaerobes in the gut microflora, resulting in the conversion of normal bile acids into carcinogens. uLow fiber diets have a weak correlation, however a diet low in fruits/vegs usually means a high animal fat diet uObesity: develop insulin resistance u increased circulating levels of insulin leads to higher circulating concentrations of insulin-like growth factor type I (IGF-I). This growth factor appears to stimulate proliferation of the intestinal mucosa uHereditary factors: Up to 25% of patients with colorectal cancer have a family history of the disease, suggesting a hereditary predisposition uTobacco smoking esp >35 y/o

Screening for CRC

uBoth the American Cancer Society and the National Comprehensive Cancer Network recommend either fecal occult blood testing annually coupled with flexible sigmoidoscopy every 5 years or colonoscopy every 10 years beginning at age 50 in *asymptomatic* individuals with no personal or family history of polyps or colorectal cancer. uIf pt has hx of adenomatous polyp then they should have a colonoscopy every 5-10 years depending on risk factors uColonoscopy not recommended for people over 75 y/o u

Small intestine

uClinical characteristics uvague, nonspecific abdominal pain, weight loss, obstructive symptoms, bleeding, or changes in bowel habits. uDiseases of chronic inflammation such as Crohn disease may increase the risk of adenocarcinoma uCeliac disease has been associated with a risk of enteropathic T-cell lymphoma. uIndividuals with metastatic carcinoid tumors may present with carcinoid syndrome—a constellation of symptoms typically including flushing and diarrhea, but may also include palpitations, hypotension, and bronchoconstriction.

Colorectal Cancer

uColorectal cancer remains the second leading cause of cancer deaths in the United States, with an estimated 143,000 new diagnoses u*The majority of these cancers and deaths could be prevented* uA significant number of afflicted individuals demonstrate a family history of colon cancer uCareful integration of the family and personal history, physical examination findings, and endoscopic findings play a critical role in recognition and management of these high-risk individuals.

key points: HBOC

uDiagnosis of BRCA mutations can change management decisions uPay attention to ethnicity uGenetic counseling uWhen prophylactic treatment is warranted and when it is not uWhat screening methods are required and at what age

Small intestine

uDiagnostic criteria uSmall bowel cancers include adenocarcinoma, lymphomas, carcinoids, and mesenchymal tumors (including gastrointestinal stromal tumors) uDefinitive diagnosis is often made by tissue analysis obtained via endoscopy, surgery, or interventional radiology

Screening for CRC

uEarly detection of adenomatous polyps+ earlier surgical removal= better chances of survival udigital examination should be part of any routine physical evaluation in adults aged >40 years or fecal occult blood test if bleeding uHas limitations uAbout 50% of patients with documented colorectal cancers have a negative fecal occult blood test due to carcinomas having intermittent bleeding patterns

Prevention of FAP

uFAP (Gardner's and Turcot's syndrome) uIf not treated surgically (total colectomy), almost all individuals with these syndromes will develop carcinoma by <40 y/o uAlthough NSAIDs and cyclooxygenase-2 inhibitors can temp decrease size of polyps it is not a permanent solution uRelatives of those with polyposis coli should be tested for APC mutation and children of affected should screened by annual flexible sigmoidoscopy until age 35

Prevention of Breast CA

uHealthy diet/exercise may have relatively little effect when it comes to prevention uAvoidance of combined estrogen/progestin HRT is a huge preventative strategy uBilateral prophylactic mastectomies reduce the risk of breast cancer incidence and mortality by more than 95% u Because of its obvious adverse effect on sexuality, cosmesis, and breast-feeding, this approach is not considered appropriate for a woman of *average* risk Chemoprevention in post-menopausal women with use of the selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene, as well as aromatase inhibitors are effective methods to lower breast cancer risk uOptional: uPreventive or "prophylactic" double mastectomy, has been found to reduce the risk of breast cancer in high-risk BRCA 1/ 2 carriers by >90% For BRCA1/2, a prophylactic bilateral oophorectomy and salpingo-oophorectomy reduces breast CA risk uConsider before the age of 35 after childbearing is complete Oopherectomy reduces risk of Breast cancer by 50% and Ovarian Ca by 80-90% Alternative is salpingectomy only initially

Hereditary GI Cancer Syndromes:Conclusion

uHereditary colorectal cancer syndromes make up a minority of CRC but are important to recognize. u uPatients should be selected for testing based on their family history. uReferral to a genetic counselor is essential for the proper management of these patients.

Screening for Ovarian CA

uLaboratory evaluation demonstrates a markedly elevated CA-125, a shed mucin (MUC16) associated with, *but not specific for*, ovarian cancer uScreening for ovarian cancer is currently not recommended outside of a clinical trial. uScreening studies, even in the BRCA1/BRCA2 families, suggest that any of the available screening techniques, including serial evaluation of the CA-125 tumor marker and transvaginal ultrasound, are insufficient to reliably detect early-stage ovarian cancer.

Prevention of CRC

uLower consumption of animal fats and high calorie meals ucontrary to popular belief no direct benefit of fiber from fruits/vegs in preventing the recurrence of colorectal adenomas or the development of colorectal cancer uAspirin and NSAIDs uthought to suppress cell proliferation by inhibiting prostaglandin synthesis uSmoking cessation uEstrogen therapy in women has been linked to a decrease of cases (must weight the pros and cons as we know it can > chance of breast or ovarian ca)

Ovarian ca risk factors

uNulliparity, obesity, diet, infertility treatments, and possibly hormone replacement therapy have all been linked to an increase in risk. uThe most common heritable abnormality linked to ovarian cancer is a germ-line mutation in either BRCA1 or BRCA2 uHereditary nonpolyposis colorectal cancer (HNPCC) aka lynch syndrome is associated with ovarian CA

OVARIAN CA Clincal management and PREVENTION

uProtective factors include the use of oral contraceptives, multiparity, tubal ligation, aspirin use, and breast-feeding u Women with BRCA1/2 mutations are advised to undergo prophylactic removal of fallopian tubes and ovaries after completing childbearing and ideally before age 40. Early prophylactic salpingo-oophorectomy is highly protective. Salpingo-oophorectomy also appears to protect these women from subsequent breast cancer (risk reduction 50%).

Clinical Manifestations of Breast CA

uVirtually all breast cancer is diagnosed by biopsy of a nodule detected either on a mammogram or by palpation uCharacteristics of malignant breast mass: uenigmatically, painless masses, and, more importantly, hard, irregular masses, especially if tethered or fixed to the underlying chest wall. uPain and cyst-like characteristics are less likely malignant, but should still be considered for further testing or referral as it is not a determining diagnosis (read notes) uBiopsy would be appropriate even in negative mammogram if the mass does not change through all phases of menstrual cycle or post-menopausal uIn premenopausal women, lesions that are either equivocal or nonsuspicious on physical examination should be reexamined in 2-4 weeks, during the follicular phase of the menstrual cycle. Days 5-7 of the cycle are the best time for breast examination. u A dominant mass in a postmenopausal woman or a dominant mass that persists through a menstrual cycle in a premenopausal woman should be referred to an experienced breast diagnostician for further evaluation, including biopsy if appropriate. uIt cannot be stressed too strongly that in the presence of a breast lump a negative mammogram does not rule out cancer, and if it persists or enlarges during follow-up, the patient should be referred to an experienced breast diagnostician for possible biopsy.

Biennial colonscopies starting at age 25

uWhat is an appropriate recommendation for the child of someone who is diagnosed with Lynch syndrome? uA) Fecal occult and digital rectal exam uB) Biennial colonscopies starting at age 25 uC) Prophylactic colectomy uD) salpingo-oopherectomy before 25 years old

Follow up mammogram in 3-6 months

uWhat would be an appropriate follow up recommendation for a 45-year-old woman with a nonpalpable low risk index lesion on a mammogram and negative family history? uA) US guided biopsy uB) Follow up mammogram in 3-6 months uC) Screen for BRCA1/BRCA2 uD) Resume yearly screening mammograms

CRC imaging

uXray with barium contrast u "apple core lesions" significant for adenocarcinoma uColonscopy is still the gold standard for ca screening

polyp

•A ___ is extra tissue that grows in the colon, for example