Although only about 18,000 cases of breast cancer each year are associated with an obvious hereditary predisposition, primary cancers developed in more than 200,000 breast cancer survivors in the United States as a result of a hereditary predisposition, and these survivors remain at risk for secondary cancers.20, 21 Genetic testing has emerged as one of the most important indicators of risk factors pointing to a need for intensified screening for breast cancer.²² When detected at an early stage, more than 90% of breast cancers are curable. These statistics underscore the rationale for the use of genetics in clinical oncology. We have previously reviewed in detail the management of women and men who are at hereditary risk for breast cancer,²³ and this review will be summarized and updated here.

From 1 in 150 to 1 in 800 individuals in the population carry a genetic susceptibility to breast cancer,26–26 and the prevalence is much higher in certain ethnic groups. Syndromes of breast cancer susceptibility are linked to mutations of BRCA1 and BRCA2, as well as a smaller number of cases with germline mutations of RAD51C, PTEN, p53, CHEK2, STK11, CDH1, and rarer syndromes (Table 12-3).

Recently, germline mutations in RAD51C have been identified in families with breast and ovarian cancer.27,28 Follow-up studies indicate that RAD51C is a low-frequency, moderate- to high-risk ovarian cancer susceptibility gene with the relative risk for ovarian cancer in RAD51C-mutation carriers as high as fivefold.^31–31 Cowden syndrome (CS) was initially described as a dominant inheritance of multiple hamartomatous lesions, including papillomas of the lips and mucous membranes and acral keratoses of the skin.³² This disease was ultimately linked to germline mutations of PTEN. In persons with Li-Fraumeni syndrome, early-onset breast cancer occurs with soft-tissue sarcomas, osteosarcoma, leukemia, brain tumors, adrenal cortical tumors, and other cancers. Rarely, a typical breast-ovarian kindred may be found to have a germline p53 mutation.³³ In Northern European families, specific mutations of CHEK2 are associated with familial breast cancer.³⁴ Although the common European CHEK2 mutation is rare in persons in North America,³⁵ analysis of women for CHEK2 founder mutations stratified for family history of breast cancer demonstrated that carriers with a positive family history had a greater than 25% lifetime risk for breast cancer.³⁶ Women with Peutz-Jeghers syndrome carry germline mutations in the STK11 gene and are at increased risk for breast cancer.^37,38 Both benign and malignant breast tumors occur in Muir-Torre syndrome, a variant of hereditary nonpolyposis colon cancer that is associated with germline mutations of MSH2 and MLH1. Carriers of ATM mutations have ~twofold elevated breast cancer risk.^41–41

Early linkage studies suggested that in about 50% of breast cancer kindreds, the cancer was linked to BRCA1; in 30%, it was linked to BRCA2; and in the remainder, it was linked to BRCA3 and other as yet unidentified genes.⁴² In up to two thirds of families with both male and female breast cancer, the cancers were due to BRCA2, whereas more than 80% of families with both breast and ovarian cancer harbored BRCA1 mutations.⁴³ Multiple, common, lower penetrance genes are likely to account for a significant component of currently unexplained familial breast cancer risk.⁴⁴ Two such low-penetrance breast cancer alleles that were revealed in large population studies are BRIP1 and PALB2.^47–47 A host of putative lower penetrant gene mutations have been identified through whole-genome association studies,^48,49 although the clinical relevance of these associations remains unclear. Recently, two rare variants in XRCC2 have been identified as causing breast cancer susceptibility.⁵⁰ An analysis of the tumor exomes of 507 unselected breast tumors revealed ~10% to have underlying germline mutations of genes, including ATM, BRCA1, BRCA2, BRIP1, CHEK2, NBN, PTEN, RAD51, and p53 (Fig. 12-1).⁵¹

Compared with the 10% breast cancer risk for women in the general population, estimates of the breast cancer risk that is conferred by a common susceptibility gene ranged from 67% to 69% by age 70 years based on epidemiological analyses.24,25 Genetic linkage studies of families that were selected because of early-onset breast or ovarian cancer gave risk estimates as high as 70% to 90% in families in which mutations of either of these two genes were segregated.^54–54 Ovarian cancer risks in these families varied from 10% to 80%, and risk for a second breast cancer was as high as 64% by age 70 years. More recent estimates based on population studies led to slightly lower risk estimates, with a lifetime breast cancer risk of 56% by age 70 years (confidence interval: 40% to 73%), and ovarian cancer risk estimated at 16%.⁵⁵ Penetrance estimates that were determined through clinic-based ascertainment of families revealed a 64% risk for breast or ovarian cancer by age 70 years.⁵⁶ The role of ascertainment and other possible biases in deriving these estimates, as well as risks for cancer of the prostate, colon, pancreas, and other sites in BRCA mutation carriers has been reviewed.⁵⁷ In addition to Fanconi anemia, persons with compound BRCA2 mutations may experience childhood medulloblastomas.⁵⁸

CS is an autosomal-dominant disorder characterized by multiple hamartomas with a high risk of benign and malignant tumors of the thyroid, breast, and endometrium. Consensus criteria for CS establish three diagnostic categories.¹¹⁷

Pathognomonic criteria include adult Lhermitte-Duclos disease (LDD) (defined as presence of a cerebellar dysplastic gangliocytoma)¹¹⁸ and mucocutaneous lesions, facial trichilemmomas, acral keratoses, papillomatous lesions, and mucosal lesions. Major criteria include breast cancer, thyroid cancer (especially follicular histology), macrocephaly,¹¹⁹ and endometrial carcinoma. Minor criteria include other thyroid lesions (e.g., goiter), mental retardation, hamartomatous intestinal polyps, fibrocystic breast disease, lipomas, fibromas, and genitourinary tumors (e.g., uterine fibroids and renal cell carcinoma) or genitourinary malformation. The operational diagnosis of CS is made if an individual meets any one of the following criteria: pathognomonic mucocutaneous lesions alone if there are six or more facial papules, of which three or more must be trichilemmoma, or cutaneous facial papules and oral mucosal papillomatosis; or oral mucosal papillomatosis and acral keratoses; or six or more palmoplantar keratoses. Alternatively, the individual may fulfill two major criteria, but one must have either macrocephaly or LDD. Alternatively, the individual may have one major and three minor criteria or four minor criteria.

The palmar and plantar hyperkeratotic pits usually become evident later in childhood. Subcutaneous lipomas and cutaneous hemangiomas are seen in persons with CS with low frequency.¹²⁰ An increased risk of early-onset male breast cancer has been noted in mutation carriers.¹²¹

Cumulative lifetime risks for female breast cancer are 81% to 85.2%122,123; for LDD, 32% (CI: 19% to 49%)¹²²; for thyroid cancer, 21% to 35.2%,^122,123; for endometrial cancer, 19% to 28.2%^122,123; and for renal cancer, 15% to 33.6% (CI: 6% to 32%).^{122, 123} The lifetime risks for colorectal cancer are 9% to 16%,^{122, 123} and the risk for melanoma is 6%.¹²³

Common Colon Cancer Predisposition Syndromes

Highly penetrant, dominant, susceptibility syndromes account for about 5% of colon cancer cases. The most common syndrome is Lynch syndrome with familial adenomatous polyposis constituting a rarer familial syndrome. For adults, genetic epidemiological analyses suggest a common susceptibility allele for both colon cancer and adenomatous polyps that accounts for at least 15% and possibly half of cases.130, 131

Hereditary diffuse gastric cancer (HDGC) is characterized by autosomal-dominant susceptibility to diffuse gastric cancer (DGC) and lobular breast cancer (LBC). Penetrance for small foci of in situ or invasive cancer is virtually complete; however, the lifetime risk of clinically significant gastric cancer is estimated to be 80%.²²⁸ The ages of diagnosis of DGC in CDH1 mutation carriers ranges from 14 to 85 years of age,²²⁹ with an average of 38 years.²³⁰ Unfortunately, endoscopic surveillance for DGC is inadequate, and therefore germline CDH1 mutation carriers are advised to undergo prophylactic total gastrectomies to remove their risk of DGC. Female carriers also have a 60% lifetime risk of LBC.²²⁸

Approximately 44,000 new cases of pancreatic adenocarcinoma (PAC) were diagnosed in the United States in 2012.²³⁶ Familial clustering of PAC was demonstrated in 5% to 10% of these cases, whereas 2% could be attributed to mutations in a highly penetrant Mendelian susceptibility gene.²³⁷

Carney complex (CNC) is a multiple neoplasia syndrome that is referred to by acronyms such as NAME²⁵⁵ and LAMB syndrome in the medical genetics literature.^{128, 256} As described by Carney in 1985,¹²⁸ the complex is characterized by myxomas, skin pigment abnormalities, endocrine tumors, and schwannomas. The median age at diagnosis is 20 years, with spotty skin pigmentation and heart myxomas being the most common initial clinical manifestations.²⁵⁷ The skin abnormalities involve the lips, the conjunctiva and inner or outer canthi, and the mucosa of the vagina or penis. Atrial myxomas are by far of greatest clinical concern, because they usually result in a decreased life span and account for the major causes of mortality in affected individuals; cardiac myxoma can cause stroke and death.²⁵⁸ Cardiac myxomas occur in 32% of mutation carriers.²⁵⁹ Ductal breast adenoma has been described as part of the Carney complex, as well as myxoid fibroadenomas and other findings on breast imaging.²⁶⁰ In one study of 338 persons diagnosed with CNC, 34 of 194 women (17.5%) had breast myxomas, often bilateral.²⁵⁸ Large-cell calcifying Sertoli cell tumor, seen in 41% of male mutation carriers,²⁵⁹ detected as early as 2 years of age, has been associated with infertility due to hormonal imbalance.²⁶¹

Primary pigmented nodular adrenocortical disease occurs most frequently in association with CNC in 60% to 95% of patients,259,262 and 14% have Cushing syndrome.²⁶² Thus the diagnosis of primary pigmented nodular adrenocortical disease should prompt screening for CNC. Other organs that are involved in CNC are the thyroid gland and ovaries. Thyroid gland tumors occur in 25% and include follicular hyperplasia and follicular adenoma; thyroid cancer, follicular and papillary carcinoma, occurs in 2.5%.²⁵⁹ Ultrasonography is useful for screening and diagnosis of these lesions.²⁶³ Ovarian serous cystadenomas have been described in the literature, and ovarian lesions occur in 14%,²⁵⁹ suggesting that pelvic ultrasound may be indicated as a part of the evaluation of women with CNC.²⁶⁴

Diagnostic criteria for CNC²⁵⁸ require two or more of the manifestations or one major manifestation and one of the minor criteria. Major criteria are skin pigmentary abnormalities (multiple lentigines of the face, blue nevus, or epithelioid blue nevus); myxoma (cutaneous or mucosal myxomatosis); cardiac myxoma; endocrine tumors/overactivity (primary pigmented nodular adrenocortical disease, a micronodular form of adrenal hyperplasia, growth hormone-producing pituitary adenoma, large-cell calcifying Sertoli cell tumor, or thyroid adenoma or carcinoma); psammomatous melanotic schwannoma; thyroid carcinoma or multiple thyroid nodules on ultrasound in a young patient; multiple breast ductal adenomas; and osteochondromyxoma. To make the diagnosis, an individual must have two of the components listed or one of the manifestations in addition to an affected first-degree relative or have an inactivating mutation of the PRKAR1A gene. A malignant neoplasm is a relatively uncommon finding in affected patients.

Paragangliomas are tumors of the paraganglia, which are derived from neuroectodermal and mesodermal origins in the parasympathetic and sympathetic axis, and thus can exist from the base of the skull to the pelvis. There tumors are called chemodectomas in the head and neck and are derived from nonchromaffin chemoreceptors in the carotid, aortic, jugular, or vagal bodies. These tumors are usually benign, and also can be symptomatic because of size and compression effects of surrounding local structures. Of 30 cases reviewed in one series, about half were bilateral, with a family history of chemodectoma in about one third of these cases.268, 269 Most of the familial cases presented with multiple tumors. The remarkable feature about hereditary chemodectomas is the evidence of imprinting; chemodectomas develop in children of affected fathers, but not in the children of affected mothers.²⁷⁰ Pheochromocytomas are paragangliomas that are located in the adrenal medulla and or anywhere along the parasympathetic and sympathetic tracts. Pheochromocytomas are usually benign tumors and can be active (secreting hormones) or inactive depending on their sympathetic or parasympathetic origin. The paragangliomas and pheochromocytomas can be single or multiple; the presence of multiple, bilateral, recurrent, and early (<40 years) or a family history of such tumors should prompt early referral for genetic assessment.

Genetics

In 1993, it was observed that RET gene mutations were associated with MEN2a, MEN2b, and FMCT.282, 283 Specific RET gene mutations have been associated with MEN2a, MEN2b, and FMCT.^{279, 282, 284–286} RET testing of sporadic cases of medullary carcinoma of the thyroid will yield a relatively low (5%) rate of diagnosis of MEN2a in the absence of a family history of the disease, C cell hyperplasia, or multifocality.^{283, 287} Nonetheless, RET testing is more sensitive than traditional biochemical screening. Asymptomatic children with RET mutations and normal plasma calcitonin levels had small foci of medullary carcinoma of the thyroid at time of “prophylactic” surgery.²⁸⁸ These findings were confirmed in a large study in the United States.²⁸⁹

A study of 477 MEN2a families showed an association between codon 634 mutations and pheochromocytoma and between mutations at codons 768 and 804 and FMCT, whereas codon 918 mutation is MEN2b-specific. Rare families with both MEN2 and Hirschsprung disease have MEN2-specific codon mutations.²⁹⁰ A 611 codon mutation is associated with a mild form of FMCT with slow progression. The classic M918T mutation in exon 16 is found in MEN2b, and a less common mutation in RET codon 883 has also been reported.^{291, 292}

Clinical Management

RET testing has been established as the gold standard for MEN2a screening, and prophylactic thyroidectomy has been established as the primary preventive intervention. Guidelines from the American Thyroid Association for the management of medullary thyroid cancer reflect the known genotype-phenotype correlations in relation to the ages at which they recommend childhood prophylactic surgeries.²⁹³ Heterozygotes for RET mutations in the setting of MEN2a are screened with abdominal ultrasound and CT, as well as 24-hour urine studies through the adult years, at least to age 35 years. Plasma screening for the pheochromocytomas has been suggested (see the section on VHL disease). The treatment of choice for patients with MEN2a or MEN2b with a unilateral pheochromocytoma is unilateral resection, because substantial morbidity and mortality are associated with the Addisonian state after bilateral adrenalectomy.²⁹⁴ RET kinase inhibitors have been in clinical trials to evaluate their efficacy in treatment of metastatic medullary thyroid cancer in sporadic and familial cases of medullary thyroid cancer.^295–299 Recently the U.S. Food and Drug Administration (FDA) approved the use of the RET kinase, vascular endothelial growth factor (VEGF) receptor, and epidermal growth factor receptor (EGFR) inhibitor, vandetanib, to treat adult patients with metastatic medullary thyroid cancer. This approval emerged from the results of a randomized, double-blind phase 3 trial that showed improvement in progression-free survival after once-daily administration of the oral agent in this setting.²⁹⁵

Gorlin Syndrome and Nevoid Basal Cell Carcinoma Syndrome

Basal cell carcinomas (BCCs) are the most common malignancy in humans, with three quarters of a million cases each year. In a small subset of families, BCCs occur at an early age and in great numbers. The nevoid basal cell carcinoma syndrome (NBCCS) consists of multiple BCCs, usually manifest after puberty, accompanied by odontogenic jaw cysts, congenital skeletal abnormalities, ectopic calcification of the falx cerebri, and characteristic pits in the skin of the palms and soles.300, 301

A hallmark of the syndrome is the increased susceptibility of the skin to the damaging and tumor-inducing effects of ionizing radiation.³⁰² Multiple BCCs have developed within 6 to 36 months after radiation therapy. Unlike Bloom syndrome or ataxia telangiectasia, there is no in vitro evidence of chromosome fragility.

One estimate of the prevalence of the syndrome, 1 in 57,000, comes from a study of a population of 4 million in northwest England.³⁰³ As described by Gorlin³⁰⁰ in 1987, penetrance for the syndrome is virtually 100% over a lifetime.³⁰¹ Although NBCCS diagnostic criteria are based on the presence of major and/or minor criteria (two major and one minor criteria or one major and two minor criteria),^304,305 limited information is available regarding the sensitivity and specificity of each criteria. As will be described shortly, a consensus statement from an international colloquium on basal cell nevus syndrome suggested that a suspected diagnosis should be considered based on one major criterion and molecular confirmation; two major criteria; or one major and two minor criteria.³⁰⁶ The component tumors that are included in these criteria are also a topic of debate. One study showed that in approximately 5% of patients with Gorlin syndrome, medulloblastoma develops in the first few years of life, and that 10% of patients with medulloblastoma diagnosed at age 2 years or younger have Gorlin syndrome.³⁰⁷ Another study found that the only histopathological subtype of medulloblastoma in patients with NBCCS is the desmoplastic subtype, which occurs in only 20% of sporadic medulloblastoma cases; it was suggested that the occurrence of the desmoplastic subtype in a patient younger than 2 years of age is pathognomic.³⁰⁸ The international consensus group concluded that childhood medulloblastoma (also called primitive neuroectodermal tumor) should be considered a major criterion. Thus the major criteria include: (1) BCC prior to 20 years of age or excessive numbers of BCCs out of proportion to prior sun exposure and skin type; (2) odontogenic keratocyst of the jaw before 20 years of age; (3) palmar or plantar pitting; (4) lamellar calcification of the falx cerebri; (5) medulloblastoma, typically desmoplastic; and (6) a first-degree relative with basal cell nevus syndrome. The minor criteria include: (1) rib anomalies; (2) other specific skeletal malformations and radiologic changes (i.e., vertebral anomalies, kyphoscoliosis, short fourth metacarpals, and postaxial polydactyly); (3) macrocephaly; (4) cleft/lip palate; (5) ovarian/cardiac fibroma; (6) lymphomesenteric cysts; (7) ocular abnormalities (i.e., strabismus, hypertelorism, congenital cataracts, glaucoma, and coloboma).³⁰⁶

The autosomal-dominant hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC) predisposes to benign cutaneous and uterine leiomyomas (fibroids), uterine leiomyosarcomas, and papillary type II RCC or renal collecting duct carcinoma.320–323

Cutaneous leiomyomas arise from the erector pili muscles, existing as single or multiple lesions. They can be skin-colored or light brown and are sensitive to touch and cold temperature. Cutaneous lesions may be diffuse and symmetric or present in segmental bands along the lines of Blaschko. Of 11 females, nine presented with cutaneous leiomyomas and nine had uterine leiomyomas.324,325 Leiomyomas of the uterus are multiple and symptomatic and result in hysterectomy by age 30 years in more than 44% of women with HLRCC.³²² Kidney tumors in persons with HLRCC are aggressive and often single, small lesions of high malignant potential. Within an HLRCC kindred, the age at onset of four cases of kidney cancer ranged from age 33 to 48 years, and all were diagnosed in females.^320,326 A Finnish series of 98 HLRCC cases found a standardized increased risk of 71-fold for uterine leiomyosarcoma and 6.5-fold for RCC.³²⁷ In a separate series of patients with HLRCC, renal cancer occurred in 62% of 21 patients, 76% had cutaneous leiomyomas, and uterine leiomyomas occurred in 90% to 100% of the women.³²⁸ Adrenal gland adenoma and kidney cysts, as well as breast and bladder carcinoma, have also been reported.³²⁷ However, a study of 85 patients with breast cancer with a family history of HLRCC found no increased risk for breast cancer, although a considerably larger sample size could be more informative.³²⁹

VHL disease is characterized by hemangioblastomas of the retina, brain, and spinal cord, pheochromocytomas, renal cysts, and clear cell renal cell carcinoma, pancreatic endocrine tumor, and endolymphatic sac tumors.340,341 Diagnosis depends on the presence of a VHL-associated tumor and a family history consistent with VHL or alternatively the presence of at least two VHL-associated tumors.³⁴¹

Birt-Hogg-Dubé (BHD) cancer predisposition syndrome was first described in 1977.³⁴⁶ This rare genodermatosis comprises an unusual triad of findings: fibrofolliculomas that appear as white or skin-colored papules on the face and upper torso, spontaneous pneumothorax, and kidney tumors.³²³ The cutaneous lesions usually appear in the region of the head, neck, and upper part of the trunk in the third or fourth decade of life, and renal tumors develop in about 15% to 30% of patients with cutaneous BHD syndrome. A recent review of 130 solid renal tumors resected from 30 patients with BHD in 19 different families revealed that renal tumors were multiple and bilateral and were noted at an early age (mean: 50.7 years). The vast majority were hybrid oncocytic neoplasms with areas reminiscent of chromophobe renal cell carcinoma and oncocytoma, whereas a significant number were chromophobe renal cell carcinomas, and a minority were conventional clear cell renal carcinomas,^{347, 348} thus demonstrating the phenotypic heterogeneity of renal cancer that is unique to this syndrome compared with other hereditary renal cancer predispositions. Chromophobe and hybrid oncocytic tumors comprise 23% and 67% of BHD renal tumors, respectively; clear cell tumors comprise 7% and oncocytomas comprise 3%, whereas papillary renal cell carcinomas are rarely noted.³⁴⁹ Persons with BHD syndrome are at markedly increased risk of spontaneous pneumothoraces. About a third, 64 of 198 (32%), of BHD-affected individuals had a history of a spontaneous pneumothorax.³⁵⁰ The syndrome is also associated with a progressive flecked chorioretinopathy with constricted visual fields.³⁵¹ There is an association with colorectal neoplasia in some families with BHD,³⁵² as well as colorectal polyps in up to half of patients with BHD.^{352, 353} Similarities exist between BHD and tuberous sclerosis (TSC), which may be explained by the fact that both BHD and TSC genes function in the same pathway, mammalian target of rapamycin (mTOR). In this regard, angiomyolipomas were described in patients with BHD and fibrofolliculomas were described in patients with TSC in recent case reports.^{354, 355}

Tuberous Sclerosis and Gastrointestinal Stromal Tumor

Other syndromes which have shown the promise of targeted therapy include TSC³⁶¹ and inherited gastrointestinal stromal tumor (GIST).³⁶²

TSC is an autosomal-dominant syndrome caused by germline mutations in TSC1 and TSC2. Major features include facial angiofibromas or forehead plaque, nontraumatic ungual or periungual fibromas, hypomelanotic macules (three or more), shagreen patch (connective tissue nevus), multiple retinal nodular hamartomas, cortical tuber, subependymal nodule, subependymal giant cell astrocytoma (SEGA), cardiac rhabdomyoma, single or multiple, lymphangiomyomatosis, and renal angiomyolipoma. Minor features include multiple randomly distributed pits in dental enamel, hamartomatous rectal polyps, bone cysts, cerebral white matter radial migration lines, gingival fibromas, nonrenal hamartoma, retinal achromic patch, “confetti” skin lesions, and multiple renal cysts. Clinical diagnosis determining the probability of having TSC is based on a combination of major and minor features.³⁶¹

Angiomyolipomas are the dominant renal lesions in TSC, whereas RCC has been reported in 1% to 3% of patients with TSC.³⁶³ Clinical management of angiomyolipomas is by observation, removal, or embolization, depending on the size and location of the tumor and its potential for spontaneous bleeding. Recently, medical therapies targeting the mTOR pathway have been proposed as another treatment modality. In 2009, the FDA granted everolimus (Afinitor) an orphan drug designation to treat renal angiomyolipomas and subependymal giant cell astrocytomas in patients with TSC. (Orphan designations are given to drugs that have shown promise in the treatment of a disease or condition affecting fewer than 200,000 patients in the United States.) In April 2012, the FDA granted approval to specifically treat noncancerous kidney tumors (renal angiomyolipomas) not requiring immediate surgery in patients with TSC complex after the results of a phase 3 randomized controlled trial (EXIST-2) that enrolled 118 patients at least 18 years of age who had angiomyolipomas, randomized 2 : 1 to receive oral everolimus (Afinitor) at 10 mg once daily or placebo until tumor progression or unacceptable toxicity. With only half of the patients receiving less than 8 months of treatment, 42% treated with Afinitor showed a substantial reduction in tumor size lasting, on average, more than 5 months, whereas none of the patients receiving placebo showed any tumor shrinkage.³⁶⁴ As part of the FDA approval, Afinitor’s manufacturer (Novartis) will continue to monitor the patients for at least 4 years to determine the duration of the response and how it affects the need for surgery and the control of the disease.³⁶⁵

Mesenchymal stromal tumors of the gastrointestinal tract, called GISTs, are associated with germline and sporadic mutations in KIT and PDGFRA,366–369 leading to constitutive activation. Familial cases are inherited in an autosomal-dominant manner; the mean age of diagnosis is in the fifth decade, and multicentric disease generally develops in the small bowel.³⁶² Neurofibromatosis type 1, Carney-Stratakis, and Carney triad are associated with GIST, although these tumors do not tend to demonstrate mutations in c-KIT and PDGFR.³⁶² In 2002 the selective abl, c-kit, and PDGFR tyrosine kinase inhibitor, imatinib, was granted approval by the FDA for the treatment of CD117-positive unresectable or metastatic GIST. In 2006, sunitinib was granted approval by the FDA for patients whose disease progressed while taking imatinib or for those who could not tolerate imatinib. Because of an overlap between germline and sporadic mutations, it is observed that the use of imatinib stabilized the esophageal GISTs in a patient harboring a germline mutation in c-KIT, previously reported in the germline and sporadic setting mutation.³⁷⁰

A common theme relating to the pharmacologic treatment and prevention of hereditary cancers is the development of drugs targeting specific pathways. Cancer predisposition syndromes represent human models of “knockouts” or “knockins” of germline alterations in oncogenic pathways and as such may be amenable to pathway-specific approaches. Therefore ongoing advancements in the understanding of the molecular pathways and the development of targeted agents will have immediate applicability to the treatment and, ultimately, chemoprevention of hereditary cancer.