Allogeneic Transplantation and the Risk for Transmission of Genetic Disease: The Heritable Cancer Disorders

STEM CELLS AND DEVELOPMENT 16:191–212 (2007)© Mary Ann Liebert, Inc.DOI: 10.1089/scd.2006.0080

Issues in Development

Allogeneic Transplantation and the Risk for Transmission ofGenetic Disease: The Heritable Cancer Disorders

KENNETH D. MCMILIN1 and SUSMITA DASGUPTA1

ABSTRACT

With the development of new approaches to transplantation therapy, such as those building uponthe potential found in stem cells, it is vital to pursue a clear understanding of transplantation risks.Allogeneic transplantation presents risk for the transmission of disease of various types, includinggenetic disease. Predisposition to develop cancer is a feature of numerous genetic disorders, and itmay be transmissible by transplantation. Some genetic disorders predisposing to cancer are re-markably common, either worldwide or in specific populations, and they could pose significant risk.Hence, to reduce risk to recipients, there is reason to exclude from donation those potential donors(including embryos) harboring certain germ-line mutations. However, the frequent absence of read-ily identifiable features might confound the effort to exclude those who harbor mutation. Thus, itis also important to consider the magnitude of risk that they represent. For some disorders, life-threatening cancer is highly likely to develop in those individuals born with germ-line mutation, butwhether recipients would face the same risk from transplanted mutation is not always evident. Giventhe diversity of pathways that lead to cancer, there may be diverse factors that impact the likeli-hood for cancer to develop in the recipient, with some factors decreasing and others increasing therisk. One factor of special concern is the possibility that manipulation of donor cells, prior to trans-plantation, might introduce additional genetic or epigenetic abnormality, thereby increasing the risk.

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INTRODUCTION

THE TRANSPLANTATION OF ORGANS, TISSUES, OR CELLS

(taken from living or cadaveric donors) has becomea major factor in the modern treatment of disease, andeven more remarkable future advances are anticipated.Indeed, cells with the potential for extensive prolifera-tion and manipulation ex vivo, such as stem cells, haverecently become available, and with these novel cells itmay someday be possible to produce a wide array of trulyregenerative transplantation products (1,2). For the ben-efit of patients suffering from diverse types of disease,intense effort to develop these promising new transplan-tation therapies is essential. Nonetheless, it is also im-portant to pursue a thorough understanding of inherenttransplantation risks, so that all appropriate action can be

taken to reduce risk and prevent inadvertent harm to re-cipients.

Allogeneic transplantation presents risk for the directtransmission, from donor to recipient, of disease of var-ious types, such as cancer, genetic disease, immunologicdisease, and, of course, infectious disease (3–5). Al-though the infectious disease risk is well known, recog-nition of risk for the transmission of disease of other typesremains inadequate (6).

Potential donors may present with various undiagnosedrisks, including both predisposition to disease and asymp-tomatic disease. For example, in many individuals, in-fection such as human immunodeficiency virus (HIV) orhepatitis C virus (HCV) remains unrecognized and undi-agnosed for many years, before progressing to overtsymptomatic disease. Fortunately, routine testing of

1Alabama and Central Gulf Coast Region, American Red Cross Blood Services, Birmingham, AL 35205.

donors for HIV and HCV can detect the presence of theseviruses and thus prevent their transmission. Nonetheless,other potentially unrecognized donor infections, forwhich testing is not performed, continue to present riskto the transplantation recipient (7–9).

Similarly, early cancer may remain at an asymptomaticstage for a substantial period of time, unrecognized andundiagnosed in the potential donor, yet posing risk of life-threatening disease, if transmitted by transplantation tothe recipient (10–12).

Just as infection or cancer could be present in theasymptomatic donor, an unrecognized undiagnosed ge-netic disease could be present. Although some featuresof genetic disease might not be transmissible by trans-plantation, other features likely are. Among the poten-tially transmissible manifestations of various genetic dis-orders, predisposition to malignancy poses a particularlyinsidious threat of serious disease if transplanted to therecipient (13).

Cancer in the general population is ordinarily regardedas sporadic disease, typically arising with the accumu-lation of oncogenic mutations (and epigenetic changes)acquired during the course of life (14). Nonetheless,some individuals are born with a strong predispositionto develop cancer, as a manifestation of underlying her-itable germ-line mutation. Genetic disorders predispos-ing to the development of cancer may exhibit diverse ad-ditional characteristic features. Yet for many of thesesyndromes, an asymptomatic stage often persists formany years, prior to the development of overt clinicalmanifestations.

Thus, the transplantation of living organs, tissues, orcells, including those originating from asymptomaticdonors, may present risk of various types to the trans-plantation recipient. The risk arising from germ-line mu-tation that predisposes to the development of cancer re-quires special consideration. Even if fully malignant cellshave not yet evolved prior to transplantation, the pro-gressive and proliferative nature of cancer implies riskthat, in time, the recipient could develop life-threateningmalignancy, arising from the predisposition inherent inthe transplant (15–17). Moreover, with the diversity ofpathways that lead to cancer, there likely are diverse fac-tors that could exacerbate (or mitigate) risk for the de-velopment of cancer in the recipient.

Hence, to facilitate evaluation of the potential trans-mission risk that they represent, various genetic disordersthat predispose to cancer are presented in Table 1.

THE RISK FOR DISEASE TRANSMISSION

The risk for transmission of heritable malignant dis-ease through transplantation remains largely speculative,

but certain issues nonetheless warrant explicit consider-ation.

Prevalence and penetrance

Among the genetic disorders that predispose to the de-velopment of cancer, many are exceptionally rare, butsome are more common. For example, Lynch syndromeis considered to be relatively common, with an incidencereported to be about 1 in 400 (290). Alpha-1-antitrypsindeficiency and neurofibromatosis type 1 are also rela-tively common. Hereditary breast and ovarian cancer isa remarkably common disorder among Ashkenazi Jews,with about 2% carrying a predisposing mutation (115).And there are other disorders (such as hereditary multi-ple exostoses) that may be less common in the generalpopulation, yet have elevated incidence in certain spe-cific populations (130).

Whether a genetic disorder is or is not common de-pends not only on the prevalence of disease causing al-leles but also on their penetrance. Highly penetrant alle-les are associated with some of the more commonheritable cancer syndromes (290). Nonetheless, it is im-portant also to consider the cumulative cancer risk thatderives from low-penetrance alleles, especially those thatare more prevalent (291).

Low-penetrance alleles

The spectrum of alleles presenting risk, if transplanted,extends beyond those that cause readily identifiable syn-dromes with characteristic overt manifestations. Thereare low-penetrance alleles for which an isolated case ofcancer may be the predominant clinical expression, andthe heritable predisposition underlying this cancer canthus be difficult to discern, given the large backgroundof truly sporadic disease.

Familial breast cancer, associated with the BRCA1 andBRCA2 genes, is well known. However, there is addi-tional genetic predisposition to breast cancer (beyond thataccounted for by BRCA1 or BRCA2) and this has stimu-lated interest in the discovery of low-penetrance alleles.For example, it has been found that the 1100delC alleleof the CHEK2 gene confers increased risk for breast can-cer, elevated above the general population risk by a fac-tor of about 2 (292). Because the frequency of this alleleis roughly 1% in northern European whites, the contri-bution to breast cancer may be substantial. Moreover, itappears that the 1100delC allele presents an even higherrisk for breast cancer when it is combined with certainother low-penetrance alleles (293).

Familial adenomatous polyposis, an autosomal domi-nant disease, is associated with truncating mutations ofthe APC gene that lead to severe polyposis and high risk

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TABLE 1. SELECTED GENETIC DISORDERS ASSOCIATED WITH INCREASED RISK FOR MALIGNANT DISEASE

Disordera Selected featuresb References

Alagille syndrome Autosomal dominant; JAG1 gene mutation, frequently de novo; may (18–21)be mosaic; highly variable expression, ranging from subclinical tolife threatening; often manifest within first year of life; hepatic,cardiovascular, vertebral and ocular anomalies; chronic cholestasis;liver failure; possible increased risk for hepatocellular carcinoma

Alpha-1-antitrypsin deficiency Homozygous PiZZ deficiency may affect about 1 in 2000, with (22-24)substantial geographic variation; highly variable expression andpresentation, including cholestatic jaundice in infants and pulmonaryemphysema in adults (especially cigarette smokers); cirrhosis; portalhypertension; progression to liver failure, potentially in childhood;hepatocellular carcinoma

Ataxia telangiectasia Autosomal recessive; ATM gene mutation; progressive neuro- (25–27)degeneration; oculocutaneous telangiectasia; immunodeficiency;chromosomal instability; hypersensitivity to ionizing radiation; highincidence of cancer, especially lymphoma and leukemia

Beckwith–Wiedemann syndrome Incidence about 1 in 10,000; usually sporadic; occasional familial (28–31)occurrence; diverse genetic and epigenetic abnormalities involvinggenes in chromosomal region 11p15, including KCNQ1OT1,CDKN1C, H19, and IGF2; variable expression; prenatal andpostnatal overgrowth; abdominal wall defects; macroglossia; markedly increased incidence of childhood cancer; Wilms tumor; adrenocortical carcinoma; hepatoblastoma; rhabdomyosarcoma; neuroblastoma

Birt–Hogg–Dube syndrome Autosomal dominant; mutation of BHD gene (also known as FLCN); (32-35)manifestation in adulthood, typically with multiple cutaneousfibrofolliculomas on head, neck and upper thorax; pulmonary cysts;spontaneous pneumothorax; diverse renal tumors, including both clear cell and chromophobe renal cell carcinoma (potentially multipleand bilateral, diagnosed at average of about 50 years old)

Bloom syndrome Rare in the general population, but about 1 in 100 Ashkenazi Jews is a (36–39)mutation carrier; autosomal recessive; mutation of BLM (a memberof the RecQ gene family); genomic instability; sister chromatidexchange; variable clinical expression; growth retardation;immunodeficiency; photosensitive erythema, typically involving theface; strong predisposition to cancer, including carcinoma of manycommon types, lymphoma, leukemia, and certain rare tumors ofchildhood

Carney complex Autosomal dominant; potentially heterogeneous; PRKAR1A gene (40–43)mutation (found in about half to two-thirds of the cases); may arisede novo; variable expression, even comparing affected patients in thesame family; some diagnosed as infants, but most manifest later inlife, with median age at detection about 20 years old; spottypigmentation of skin; wide variety of mostly benign neoplasms; pituitary adenoma; thyroid adenoma and carcinoma; cardiac andcutaneous myxomas; primary pigmented nodular adrenocorticaldisease; testicular tumor; psammomatous melanotic schwannoma,which may be malignant

Costello syndrome Usually sporadic; HRAS gene mutation, frequently de novo; postnatal (44–47)growth deficiency; mental retardation; coarse facial features; redundant skin of hands and feet; hypertrophic cardiomyopathy;papillomata in nasal, perioral and perianal regions; rhabdomyosarcoma;neuroblastoma; bladder carcinoma

(continued)

Cowden syndrome Estimated incidence about 1 in 200,000; autosomal dominant, with (48–51)both familial and isolated cases; PTEN gene mutation; becomesmanifest during patients’ second and third decades; variableexpression, some patients presenting only subtle skin lesions (resulting in under diagnosis); multiple facial trichilemmomas; oral mucosal papillomatosis; multiple palmoplantar keratoses; macrocephaly; Lhermitte–Duclos disease (dysplastic gangliocytoma of the cerebellum); breast carcinoma; thyroid carcinoma (usually follicular type); likely other cancer (e.g., endometrial carcinoma)

Diaphyseal medullary stenosis with Rare; autosomal dominant; maps to 9p22–p21; skeletal dysplasia; (52–54)malignant fibrous histiocytoma diaphyseal sclerosis and cortical thickening; bone infarctions;

pathologic fractures; progressive bowing of lower extremities;bone malignant fibrous histiocytoma

Dyskeratosis congenita Rare; frequently X-linked recessive, with mutation of DKC1 gene (55–58)(also associated with a severe variant, Hoyeraal–Hreidarsson syndrome); occasionally autosomal dominant, with mutation of TERC gene; premature telomere shortening; variable age at onset; variable severity; anticipation (in families with autosomal dominant inheritance); abnormal skin pigmentation; nail dystrophy; mucosal leukoplakia; progressive bone marrow failure (frequently leading to early death); epithelial and hematologic cancer of various types

Epidermodysplasia verruciformis Rare; autosomal recessive; mutation of EVER1 gene (also known as (59–62)TMC6) or EVER2 gene (also known as TMC8); infection by certainhuman papillomaviruses, including oncogenic genotypes; usuallybecomes manifest during childhood; numerous, widespread, persistent wart-like or macular skin lesions; multiple nonmelanomaskin cancers, including invasive squamous cell carcinoma, frequentlyappearing on sun-exposed skin

Familial adenomatous polyposis Prevalence about 1 in 10,000; autosomal dominant; APC gene (63–66)(FAP) mutation; about 10–30% appear to be de novo; variable expression;

hundreds to thousands of colorectal polyps, typically beginning in second decade of life (and disease known as attenuated FAP, which has fewer colorectal polyps, also may be caused by APC mutation); duodenal polyps; gastric polyps; osteomas; desmoid tumors (which can cause substantial morbidity and mortality); treatment frequently includes prophylactic colectomy, but if untreated, high risk for colorectal carcinoma; risk for various extracolonic cancers; duodenalcarcinoma; thyroid carcinoma; hepatoblastoma

Familial chordoma Rare; possibly autosomal dominant; chordoma (a tumor characterized (67–70)as locally aggressive, potentially recurrent following resection, andsometimes metastatic)

Familial gastrointestinal stromal Rare; autosomal dominant; activating mutation of KIT gene (or, it (71–74)tumors appears, mutation of PDGFRA gene); may remain undiagnosed well

into adulthood; cutaneous hyperpigmentation; hyperplasia ofinterstitial cells of Cajal; multiple gastrointestinal stromal tumors

Familial medullary thyroid Autosomal dominant; mutation of RET proto-oncogene (also associated (75–78)carcinoma (FMTC) with multiple endocrine neoplasia types 2A, 2B); C-cell hyperplasia;

medullary thyroid carcinoma (manifesting at variable age, includingolder age)

Familial melanoma Potentially autosomal dominant; heterogeneous; in some families, (79–82)mutation of CDKN2A gene (which encodes protein p16INK4A, as wellas p14ARF in alternate reading frame); in a few families, mutation of CDK4 gene; multiple atypical nevi; malignant melanoma; in some kindreds, pancreatic carcinoma

TABLE 1. SELECTED GENETIC DISORDERS ASSOCIATED WITH INCREASED RISK FOR MALIGNANT DISEASE (CONT’D)


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Familial neuroblastoma Rare; possibly autosomal dominant with incomplete penetrance; possibly (83–86)oligogenic inheritance; likely heterogeneous; PHOX2B gene mutation;variable expression, even within individual families; neuroblastoma(potentially multiple primary tumors) in infancy or childhood, with extremes of tumor behavior (ranging from spontaneous regression to relentless lethal progression) likely confounding recognition of the contribution germ-line mutation makes to disease incidence

Familial nonmedullary thyroid Possibly autosomal dominant with incomplete penetrance; candidate (87–90)carcinoma susceptibility loci reported at 2q21 and 19p13; nonmedullary thyroid

carcinomaFamilial Paget’s disease of bone Autosomal dominant (possibly with incomplete penetrance); genetic (91–94)

heterogeneity; SQSTM1 gene mutation; often asymptomatic; focalabnormal remodeling of bone; bone pain; pathological fracture;osteosarcoma, potentially in familial as well as sporadic disease(accounting for a substantial fraction of this cancer diagnosed in adults)

Familial pancreatic cancer Possibly autosomal dominant, with anticipation; pancreatic cancer (95–97)Familial platelet disorder with Rare; autosomal dominant; mutation of RUNX1 gene (also known as (98–100)

predisposition to acute AML1 or CBFA2); platelet function defect; thrombocytopenia;myelogenous leukemia acute myelogenous leukemia

Familial Wilms tumor Heterogeneous; Wilms tumor, typically manifesting in childhood (101–103)(potentially multifocal and bilateral)

Fanconi anemia Incidence about 1 in 300,000; autosomal recessive; heterogeneous; (104–107)FANCA, FANCC, FANCD1 (BRCA2), FANCD2, FANCE, FANCF,or FANCG gene mutation; hypersensitivity to DNA crosslinkingagents; chromosomal instability; somatic mosaicism; variableclinical expression; congenital skeletal anomalies; growth retardation;progressive bone marrow failure; myelodysplastic syndrome; acutemyelogenous leukemia; head and neck squamous cell carcinoma, and other nonhematologic tumors

Glycogen storage disease type I Incidence about 1 in 100,000; autosomal recessive; genetic and clinical (108–111)heterogeneity; mutation of G6PC (gene for glucose-6-phosphatasecatalytic subunit) or G6PT1 (gene for glucose-6-phosphate transporter, also known as SLC37A4); often manifests during firstyear of life; growth retardation; hypoglycemia; hepatomegaly; renaldisease; neutropenia and recurrent infections (in type Ib); multiplehepatic adenomas; hepatocellular carcinoma

Hereditary breast and ovarian cancer Relatively common; BRCA1 or BRCA2 gene mutation; breast cancer; (112–115)ovarian cancer

Hereditary diffuse gastric cancer Autosomal dominant; mutation of CDH1, gene for E-cadherin; (116–119)multifocal occult cancer in stomachs of asymptomatic carriers ofmutation; marked variability in age at manifestation, occurring asyoung as 14 years old; diffuse gastric cancer (diagnosis ofsymptomatic disease associated with poor prognosis); potentialincreased risk for breast cancer

Hereditary hemochromatosis Autosomal recessive; genetic heterogeneity; mutation of HFE gene (120–123)(with prevalence of homozygosity for disease-associated C282Ymutation about 1 in 200 in some populations); variable expression,potentially subject to environmental and genetic modifiers; symptomsnoted at about 40–60 years old; chronic increased absorption ofdietary iron, with progressive accumulation in heart, pancreas, liver,and other organs; cardiomyopathy; arrhythmia; diabetes; cirrhosis;hepatocellular carcinoma

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Hereditary leiomyomatosis and Autosomal dominant; mutation of FH gene, which encodes fumarate (124–127)renal cell cancer hydratase; multiple cutaneous leiomyomas; uterine leiomyomas (and

possibly uterine leiomyosarcoma); renal cell carcinoma (often aggressive)Hereditary multiple exostoses Prevalence about 1 in 50,000 (but reportedly much more prevalent (128–131)

in certain isolated populations); autosomal dominant; heterogeneous;EXT1 or EXT2 gene mutation; variable clinical expression (bothinterfamilial and intrafamilial); typically manifests during childhood;limb length discrepancy; short stature; multiple osteochondromas (cartilage-capped exostoses), often at juxtaepiphyseal regions oflong bones; chondrosarcoma

Hereditary pancreatitis Autosomal dominant; mutation of PRSS1, gene for cationic trypsinogen; (132–135)variable expression; recurrent attacks of acute pancreatitis, often beginning in childhood or adolescence; frequently progresses to chronic pancreatitis; potential pancreatic exocrine and endocrine insufficiency; risk for pancreatic cancer, potentially occurring multiple decades after initial symptoms of pancreatitis

Hereditary papillary renal carcinoma Autosomal dominant; mutation of MET proto-oncogene; multiple, (136–139)bilateral papillary renal tumors; papillary renal carcinoma (potentially aggressive)

Hereditary pheochromocytoma Autosomal dominant; mutation of SDHB or SDHD genes (encoding (140–143)subunits of succinate dehydrogenase complex and associated withparagangliomas) or VHL gene (associated with von Hippel–Lindaudisease) or RET gene (associated with multiple endocrine neoplasiatype 2); pheochromocytoma, often bilateral

Hereditary prostate cancer Heterogeneous (with various genes and loci identified); prostate cancer (144–145)Hereditary retinoblastoma Incidence about 1 in 20,000 (familial and sporadic); autosomal (146–149)

dominant; RB1 gene mutation, potentially de novo; retinoblastoma,typically within first few years of life (often multifocal and bilateral);increased risk for osteosarcoma and certain additional nonocularcancers, including epithelial cancers (especially in conjunction withcarcinogenic exposure)

Hereditary tyrosinemia type 1 Incidence about 1 in 100,000 worldwide, but substantially higher in (150–153)certain geographic regions (about 1 in 2000 among French-Canadiansin part of Quebec); autosomal recessive; FAH gene mutation;deficiency of fumarylacetoacetate hydrolase; somatic mosaicism;reversion of inherited mutation, in the liver; variable expression;acute and chronic forms (both sometimes occurring in the samesibship); potential presentation in early infancy and progression todeath within first year of life; hepatomegaly; cirrhosis; liver failure;renal tubular dysfunction; porphyria-like neurologic crises; hepato-cellular carcinoma, often in childhood or adolescence

Huriez syndrome Rare; autosomal dominant; reported to map to 4q23; often manifest in (154–156)infancy or early childhood; scleroatrophy of hands; keratoderma ofpalms and soles; hypoplasia of nails; aggressive squamous cell carcinoma arising in affected skin

Hyperparathyroidism–jaw tumor Autosomal dominant; mutation of HRPT2 gene (also known as CDC73); (157–160)syndrome fibro-osseous lesions of the mandible and maxilla; renal cysts and

tumors; uterine tumors; parathyroid adenomas; parathyroid carcinomaJuvenile polyposis syndrome Prevalence estimated to be about 1 in 100,000; autosomal dominant; (161–164)

genetic heterogeneity; mutation of SMAD4 gene (also know asMADH4) or BMPR1A gene; presentation with blood per rectum,anemia or obstruction, in childhood or later; multiple juvenile polypsin gastrointestinal tract, including colon and stomach; gastrointestinalcancer, including colorectal cancer and stomach cancer

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Kindler syndrome Rare; autosomal recessive; KIND1 gene mutation; skin fragility; (165–168)blistering in early childhood; photosensitivity; progressive poikiloderma; various mucosal lesions; reported risk for skin ormucous membrane malignancy

Li–Fraumeni syndrome Autosomal dominant; TP53 gene mutation; breast cancer; soft tissue (169–172)sarcoma; brain tumor; bone cancer; adrenocortical carcinoma;increased risk for certain other cancers (including leukemia)

Lynch syndrome (hereditary Relatively common, accounting for about 1–6% of all colorectal cancers; (173–176)nonpolyposis colorectal autosomal dominant; heterogeneous (associated with various DNAcancer, HNPCC) mismatch repair genes); MLH1, MSH2, MSH6, or PMS2 gene

mutation; microsatellite instability (characterized by expansion orcontraction of genomic simple repeat sequences, in tumors); colorectal cancer (often before 50 years old); increased risk forvarious extracolonic cancers, including endometrial, ovarian, urinarytract, biliary tract, gastric, and small bowel cancer

Medulloblastoma SUFU gene mutation has been reported; childhood medulloblastoma (177–178)(desmoplastic)

Mosaic variegated aneuploidy Autosomal recessive; BUB1B gene mutation; intrauterine growth (179–182)syndrome retardation; microcephaly; mental retardation; mosaic aneuploidy

(primarily trisomy and monosomy of various chromosomes, indiverse tissue samples); childhood cancer (Wilms tumor, rhabdomyosarcoma)

Muir–Torre syndrome Autosomal dominant; MSH2 or MLH1 gene mutation; variant of (183–186)HNPCC (in many patients); multiple keratoacanthomas; sebaceous adenoma, sebaceous epithelioma, or sebaceous carcinoma; internal malignancy (often colorectal cancer)

Multiple endocrine neoplasia type 1 Prevalence perhaps 1 in 30,000 (but estimates vary); autosomal (187–190)dominant; MEN1 gene mutation, some (perhaps 10%) apparentlyarising de novo; variable expression, including age at onset (potentially recognized in second, third, fourth or fifth decade oflife); diverse benign tumors, often multicentric; cutaneousangiofibroma; collagenoma; lipoma; adrenocortical hyperplasia oradenoma; parathyroid hyperplasia or adenoma; duodenal or pancreaticgastrinoma, pancreatic insulinoma (and other pancreatic endocrinetumors); pituitary prolactinoma (and other anterior pituitary tumors);gastric carcinoid; thymic carcinoid; bronchial carcinoid; malignanttumor, often carcinoid or gastrinoma in origin

Multiple endocrine neoplasia type 2 Autosomal dominant; activating mutation of RET proto-oncogene (also (191–194)(variants MEN2A, MEN2B) associated with FMTC variant of MEN2); marfanoid habitus (in

MEN2B); mucosal neuromas and intestinal ganglioneuromatosis (inMEN2B); parathyroid hyperplasia or adenoma (in MEN2A); pheochromocytoma (often bilateral); medullary thyroid carcinoma(potentially in childhood, but also later in life) potentially multifocaland aggressive (especially in MEN2B)

Multiple familial trichoepithelioma Autosomal dominant; mutation of CYLD gene (reported in some (195–198)families); multiple trichoepitheliomas, predominantly on the face,potentially beginning in childhood; basal cell carcinoma has beenreported (as well as other malignancies in disorders associated withCYLD gene mutation)

MUTYH-associated polyposis Biallelic mutation of MUTYH gene (also known as MYH); defective (199–202)base excision repair; multiple colorectal adenomas; colorectalcarcinoma

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Neurofibromatosis type 1 Incidence about 1 in 3000; autosomal dominant; NF1 gene mutation, (203–206)about half apparently de novo; may be mosaic; variable expression;café-au-lait spots; axillary and inguinal freckling; Lisch nodules;skeletal dysplasia; multiple neurofibromas; plexiform neurofibroma; pheochromocytoma; multiple gastrointestinal stromal tumors; glioma;malignant peripheral nerve sheath tumor; leukemia (including juvenile myelomonocytic leukemia)

Neurofibromatosis type 2 Incidence about 1 in 40,000; autosomal dominant; NF2 gene mutation, (207–210)frequently de novo; may be mosaic; variable expression (severedisease potentially leading to death in early adulthood); multiplenervous system tumors, including schwannomas (especially bilateralvestibular schwannomas); meningioma; spinal tumor

Nevoid basal cell carcinoma Prevalence about 1 in 60,000; autosomal dominant; PTCH gene mutation (211–214)syndrome potentially de novo; variable expression, even within an affected

family; calcification of falx cerebri; palmar or plantar pits; ovarian fibroma; cardiac fibroma; odontogenic keratocysts (often recurrent following surgery); multiple basal cell carcinomas; medulloblastoma (with incidence peak in early childhood)

Nijmegen breakage syndrome Rare; autosomal recessive; mutation of NBS1 gene (also known as (215–218)NBN); growth retardation; microcephaly; immunodeficiency;chromosomal instability; hypersensitivity to ionizing radiation;predisposition to cancer, especially lymphoma

Noonan syndrome Incidence about 1 in 2000; autosomal dominant; often sporadic; (219–222)mutation of PTPN11 gene (or KRAS gene, recently reported); variable expression; congenital heart defects; frequent pulmonarystenosis; webbed neck; short stature; bleeding diathesis; juvenilemyelomonocytic leukemia (JMML)

Perlman syndrome Rare; thought to be autosomal recessive; early death (often neonatal); (223–226)macrosomia; hepatomegaly; nephromegaly; nephroblastomatosis;Wilms tumor

Peutz–Jeghers syndrome Autosomal dominant; mutation (often de novo) of STK11 gene (also (227–230)known as LKB1); variable expression; mucocutaneous pigmentedmacules, typically affecting lips, perioral skin and buccal mucosa(often becoming apparent in early childhood); multiple gastro-intestinal polyps (in stomach, small intestines, and colon); recurrent intussusception; increased risk for cancer of various organs, including stomach, small intestine, colon, pancreas, and breast

Porokeratosis Autosomal dominant; multiple clinical types; onset ranging from infancy (231–234)through adulthood; multiple annular cutaneous lesions with peripheralkeratotic ridge; cutaneous malignancy

Recessive dystrophic epidermolysis Autosomal recessive; mutation of COL7A1, gene for type VII collagen; (235–238)bullosa variable expression, from relatively mild to severe; potentially

manifest at or shortly after birth; chronic blistering of skin; mucousmembrane involvement; atrophic scarring; fusion of fingers; jointcontractures; esophageal strictures; cutaneous squamous cellcarcinoma (a frequent cause of death)

Rhabdoid predisposition syndrome Mutation of SMARCB1 gene (also known as hSNF5/INI1); aggressive (239–242)cancer, in infancy or early childhood; rhabdoid tumor of kidney;extrarenal rhabdoid tumor; atypical teratoid/rhabdoid tumor ofcentral nervous system

Rothmund–Thomson syndrome Rare; autosomal recessive; mutation of RECQL4 (a member of the (243–246)RecQ gene family); variable expression; skeletal abnormalities(including osteopenia and dysplasia); growth deficiency; photo-sensitivity; skin rash (arising during infancy); poikiloderma; sparsehair; juvenile cataracts; osteosarcoma



Simpson–Golabi–Behmel syndrome X-linked (with mild expression in some carrier females); mutation of (247–250)GPC3 gene (at Xq26); prenatal and postnatal overgrowth; super-numerary nipples; cardiac defects; skeletal abnormalities; renalabnormalities; Wilms tumor (and possibly other embryonal tumors)

Sotos syndrome Sporadic (typically); autosomal dominant (in some families); NSD1 (251–254)gene mutation or deletion (haploinsufficiency); prenatal and postnatal overgrowth; macrocephaly; developmental delay; advancedbone age; potential increased risk for various types of cancer

Tuberous sclerosis complex Incidence potentially greater than 1 in 10,000 (roughly 70% appearing (255–258)to be sporadic); autosomal dominant; mutation of TSC1 gene (encoding hamartin) or TSC2 gene (encoding tuberin); variableexpression; widespread organ involvement, including skin, brain,heart, lungs, and kidneys; facial angiofibromas; subependymal giantcell astrocytoma; cortical tubers; seizures (often the presenting symptom, potentially during infancy); mental retardation; cardiacrhabdomyomas; pulmonary lymphangiomyomatosis (potentiallyfatal); bilateral renal angiomyolipomas; potential for malignant renaltumors (including renal cell carcinoma)

Turcot syndrome Mutation of mismatch repair gene or of APC gene (corresponding to (259–262)distinct types of the disease); multiple colorectal polyps; colorectalcancer; primary central nervous system tumor (potentially fatal)

Tylosis with esophageal cancer Autosomal dominant; maps to 17q25; focal palmoplantar keratoderma (263–266)(typically becoming evident during childhood or adolescence); oralhyperkeratosis; esophageal squamous cell cancer

Von Hippel–Lindau disease Incidence about 1 in 40,000; autosomal dominant; VHL gene mutation (267–270)(sometimes de novo); variable expression; typically presents in second or third decade of life; retinal angiomatosis; cerebellar,brainstem and spinal cord hemangioblastomas; endolymphatic sactumor; broad ligament cystadenoma; epididymal cystadenoma; pheochromocytoma; pancreatic cysts; pancreatic neuroendocrine tumor (potentially malignant); renal cysts; renal cell carcinoma(potentially multicentric)

WAGR syndrome Rare; chromosomal region 11p13 microdeletion; contiguous gene (271–274)syndrome, involving WT1 and PAX6; aniridia; genitourinarymalformation; mental retardation; Wilms tumor (potentially bilateral)

Werner syndrome Described as rare or as uncommon (but reported to be more common in (275–278)Japan); autosomal recessive; mutation of WRN (a member of the RecQ gene family); genomic instability; typically manifests after first decade of life with certain progeroid features; premature grayingor loss of scalp hair; short stature; bilateral cataracts; scleroderma-like skin; osteoporosis; atherosclerosis; diabetes; meningioma; myeloid disorders; soft tissue sarcomas; osteosarcoma; possibly other cancers (melanoma, thyroid cancer)

Wilson’s disease Incidence about 1 in 40,000; autosomal recessive; ATP7B gene (279–282)mutation; accumulation of copper in liver, brain, and other organs; highly variable clinical presentation (including age at diagnosis and presence of hepatic, neurologic, or psychiatric manifestation); Kayser–Fleischer rings; possible increased risk for intra-abdominal malignancy (and monitoring for hepatocellular carcinoma recently recommended, although the incidence seems remarkably low)

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Xeroderma pigmentosum (XP) Described as rare, but with geographic variation (reportedly about (283–286)1 in 40,000 in Japan); autosomal recessive; heterogeneous (with complementation groups XP-A through XP-G); mutation of XPA,XPC, or XPD (ERCC2) gene (or of POLH gene, in XP variant);defect in nucleotide excision repair of damaged DNA; variableexpression; progressive neurodegenerative disease; hypersensitivity to ultraviolet light; poikiloderma; early onset skin cancers, including basal cell carcinoma, squamous cell carcinoma, and malignant melanoma; possible increased risk for certain internal cancers

aRapid ongoing progress in the study of those genetic disorders with increased risk for cancer (or comparable life-threatening ma-lignant disease) precludes comprehensive presentation at this time. Furthermore, with future knowledge (including identification ofadditional genes) refinement of the nosologic description of these disorders seems likely, with the potential that, for example, somedisorders currently regarded as distinct, may be found to overlap (195), whereas other disorders may be further subdivided. Thus, wehave focused on selected disorders exhibiting Mendelian inheritance (287), and we have excluded many of the disorders with in-creased risk for leukemia or lymphoma previously reviewed by one of us (13). Also, consideration of certain disorders for inclusionhas been complicated by incomplete current knowledge regarding etiology and pathophysiology. For example, familial nonmedullarythyroid carcinoma has sometimes been defined on the basis of two or more affected first-degree relatives, but it appears that, in “two-hit” families, a large fraction of the affected individuals are sporadic cases (288); and, although autosomal dominant inheritance insome families is plausible, polygenic inheritance has also been proposed, to account for the relative scarcity of families with largernumbers of affected relatives. Despite these concerns, we have tried to be inclusive, and we have listed certain genetic disorders thatpredispose to malignant disease even though they may not traditionally have been regarded as familial cancer syndromes.

bListed features are generally intended to describe a particular disorder; they may or may not be due to germ-line mutation ofa listed gene. Most of the listed genes are designated in accordance with the official symbol of the HUGO Gene NomenclatureCommittee (289), but some conform instead to terminology used in the pertinent literature. Numerical values cited for diseaseincidence or prevalence are of limited reliability (and are approximated using a single significant digit); some derive from restrictedpopulations, not necessarily reflecting global diversity, and others suffer from inherent difficulty in recognition and diagnosis ofthe disorder. For example, prior to association with a specific gene, Cowden syndrome was thought to be substantially less fre-quent than is currently estimated. Various other disorders, designated as rare, may differ in their incidence by more than two or-ders of magnitude, potentially occurring more frequently or less frequently than disorders for which numeric values are cited. Inaddition to the listed genes, disorders may be caused by other genes, potentially known or unknown at present. For example,there are additional genes, beyond those listed in the table, which are associated with Fanconi anemia (104). Heterogeneous dis-orders for which a specific mode of inheritance is designated might also present with an alternative mode of inheritance. For ex-ample, hereditary hemochromatosis (which typically occurs as autosomal recessive disease) is also found in pedigrees exhibit-ing autosomal dominant inheritance (121). Genes associated with cancer predisposition may have pleiotropic effects, giving riseto diverse additional manifestations. However, for some disorders, characteristic features may represent the concurrent effects ofmultiple genes, rather than pleiotropic effects of a single gene. Furthermore, the association of cancer with a disorder may be in-frequent, or infrequently described, as with, for example, the reported association of hepatocellular carcinoma with Alagille syn-drome (19, 21). Indeed, in certain instances the association of cancer with a disorder is weak and yet the disorder is listed, in aneffort to be inclusive. Nonetheless, this list of cancers that are associated with genetic disorders is necessarily incomplete, for avariety of reasons, including premature death (typical, for example, in Fanconi anemia and xeroderma pigmentosum), which couldobscure the diversity of cancer, along with the magnitude of risk, that might become manifest if patients were to survive longer(or might become manifest if mutation-bearing cells were transplanted into an unaffected recipient).

for colorectal cancer. However, presence in the germ-lineof the I1307K allele of APC has rather different impli-cations (64,294). Carriers have an increased likelihood todevelop colorectal carcinoma, but with a relative risk ofonly about 1.5 to 2. Nonetheless, because this allele isfound in roughly 6% of the Ashkenazi Jewish popula-tion, the contribution to cancer burden may be substan-tial. Furthermore, a distinct relationship to oncogenesishas been suggested. The I1307K sequence differs fromwild-type by a specific transversion from T to A, result-ing in eight contiguous adenosine residues. This ho-mopolymeric tract is thought to cause instability and fa-cilitate somatic mutation.

Heterozygous mutation carriers

For autosomal recessive disorders that predispose to can-cer, heterozygous carriers of germ-line mutation are typi-cally regarded as unaffected, but some may in fact have anelevated risk for cancer. They also may be rather prevalent,either worldwide or in specific populations. For example,there is speculation, and some evidence, that increased riskfor cancer may affect heterozygous carriers of Fanconi ane-mia, Nijmegen breakage syndrome, and Werner syndrome(215,277,295,296). Moreover, for each of these disorders,the estimated frequency of heterozygotes approximatesroughly 1% in certain populations (217,297,298).

Biallelic mutation of the MUTYH gene has been foundin individuals with multiple colorectal adenomas and in-creased risk for colorectal cancer, a condition designatedas MUTYH-associated polyposis, or MAP. The risk forcolorectal cancer appears to be relatively high, increasedperhaps 50- to 100-fold over the general population risk.Recent studies have shown that carriers of monoallelicMUTYH mutation may themselves have somewhat ele-vated risk for colorectal cancer (increased by perhaps afactor of 2 or 3) (299,300).

Similarly, an increased risk for cancer may affect thoseindividuals heterozygous for the alpha-1-antitrypsin PiZallele, for which the frequency of carriers, in the UnitedStates, is about 3% (301).

Studies focused on the blood relatives of ataxia telang-iectasia patients suggest that carrier females, heterozy-gous for mutation in the ATM gene, are at increased riskfor breast cancer (which may primarily affect those lessthan 50 years old) (302). Recent work confirms that,among individuals with breast cancer, there is an elevatedfrequency of ATM mutation, consistent with a relativerisk of about 2 or 3 (303,304). Hence, on the basis of es-timates that 1% of the population carries an ATM muta-tion, it appears that ATM could account for a substantialincidence of breast cancer, analogous to BRCA1 andBRCA2 (305).

Recognizing affected donors

Prior to manifesting overt malignancy, individualswith heritable predisposition to cancer may present few,if any, features suggestive of disease. There are severalreasons for this. With some genetic disorders, cancer isthe predominant manifestation and other features are mi-nor or nondiagnostic. With certain other disorders, thereis wide variability in clinical expression and featuresother than cancer are often very mild. And with yet otherdisorders, the characteristic manifestations often do notarise until later in life. Thus, the clinical features of af-fected individuals may be unremarkable. In addition,family history might fail to indicate the presence of dis-ease. With autosomal dominant disorders, family historyis often negative, both for the reasons just cited, and asa consequence of de novo mutation. And with autosomalrecessive disorders, family history is often negative, dueto the characteristics of this pattern of inheritance.

The inadequacy of clinical features for reliably identi-fying affected (or at-risk) donors, prior to the develop-ment of cancer, is a concern with many different disor-ders. For example, the symptoms of glycogen storagedisease type I often become apparent during the first yearof life, but this characteristic of the disease cannot be re-lied upon; some affected individuals do not develop man-ifestations until they are adults, but apparently they none-theless have predisposition to develop hepatocellular

carcinoma (110,111). With Fanconi anemia, the clinicalfeatures are quite heterogeneous, and the range in age atdiagnosis is very broad. It appears that there is failure todiagnose Fanconi anemia prior to the manifestation ofcancer in approximately one-quarter of those who do de-velop cancer (106). The early clinical features of Bloomsyndrome can be relatively mild, and cancer has been di-agnosed in some affected individuals prior to the recog-nition of Bloom syndrome as their underlying predis-posing condition (39). Parathyroid carcinoma that isthought to be sporadic, arising in the absence of knownfamily history, may in fact be due to germ-line HRPT2mutation (160). Medullary thyroid carcinoma that ap-pears to be sporadic may in fact be due to germ-line RETmutation (306). Hepatoblastoma that appears to be spo-radic may be due to germ-line APC mutation (63). Withvon Hippel-Lindau disease, renal cell carcinoma can bethe presenting manifestation, typically in the fifth decadeof life (270). With multiple endocrine neoplasia type 1,some affected individuals are diagnosed at an advancedage, and cancer can be the initial manifestation (190).Even with especially well-known disorders, such asLynch syndrome or hereditary breast and ovarian cancer,affected individuals may escape clinical recognition,prior to the initial development of cancer. Thus, it maybe difficult to recognize many of those who are geneti-cally predisposed to develop cancer, and it may thereforealso be difficult to exclude them from becoming donors.

Furthermore, if the donor is an embryo, and if the em-bryo does not subsequently proceed through prenatal development, the potential for clinical recognition ofgerm-line mutation is limited. The birth of a healthy in-fant would provide vital indication of the integrity of thegenome. However, at an early embryonic stage, diversemutations incompatible with development and birth of ahealthy infant may be present, but inapparent. Some ofthese mutations would likely pose risk, if transplanted toa recipient. Consider, for example, mutation of PTPN11.This gene codes for SHP-2, a protein tyrosine phospha-tase with an important role in signal transduction. Dis-tinct clinical outcomes have been associated with severalcategories of PTPN11 mutation (221,307). Germ-linemutations of PTPN11 are associated with Noonan syn-drome, and with multiple lentigines/LEOPARD syn-drome. Mutations associated with LEOPARD syndromehave been shown to have loss of catalytic activity,whereas (remarkably) gain-of-function mutations havebeen associated with Noonan syndrome. Moreover, ac-tivating PTPN11 mutations that are somatic have beenassociated with juvenile myelomonocytic leukemia(JMML) (along with other hematopoietic malignancies).Thus, JMML may occur as sporadic, nonsyndromic dis-ease with somatic PTPN11 mutation, and it also may oc-cur with Noonan syndrome and germ-line PTPN11 mu-tation. The JMML that occurs in conjunction with

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Noonan syndrome often resolves spontaneously (222).However, sporadic JMML is generally an aggressive dis-ease, with poor prognosis. The marked difference in theoutcome of sporadic as opposed to syndromic JMML ap-pears to correlate with the level of activation of SHP-2.The PTPN11 mutations found in sporadic JMML gener-ally exhibit greater SHP-2 gain of function than the mu-tations found in Noonan syndrome (307). It is remark-able that somatic PTPN11 mutations found in aggressiveJMML might not be found as germ-line mutations, andthis requires explanation. It seems plausible that germ-line PTPN11 mutations leading to markedly elevatedSHP-2 gain of function could be fatal during prenatal de-velopment (or could possibly cause some overt congen-ital disorder other than Noonan syndrome) (307). In anycase, such mutation might be entirely inapparent in anearly embryo, but yet the use of this early embryo as asource of donated cells could pose risk for hematopoieticmalignancy in the transplantation recipient.

Progression to cancer

If the donor harbors predisposing germ-line mutation,there may be recipient risk for the development of can-cer (15–17), but the magnitude of risk would be in ques-tion. Because the risk for cancer in the recipient wouldlikely relate to the risk for cancer in the donor, the mag-nitude of donor risk is of central importance.

For the individual born with germ-line mutation, the riskfor developing malignancy can be very high. Consider, forexample, multiple endocrine neoplasia type 2. This cancerpredisposition syndrome is associated with various acti-vating mutations of the RET proto-oncogene. In the ab-sence of prophylactic thyroidectomy, there is high risk foraggressive (often fatal) medullary thyroid carcinoma tomanifest at young age (194). For certain specific muta-tions, such as that in codon 918, the risk is exceptionallyhigh, with cancer as early as 9 months old (191,192).

Thus, among the predisposing disorders, the magni-tude of cancer risk can be remarkably high. To the ex-tent that an autonomous process is sufficient for the de-velopment of cancer in any of these genetic disorders, itis reasonable to suppose that the predisposition to cancercould be transmitted by transplantation, and that, as a firstapproximation, the recipient’s risk would correlate di-rectly with the donor’s risk (such that, in comparing twodisorders, the disorder with greater donor risk would tendto be the disorder with greater recipient risk). However,in fact, different predisposing disorders are associatedwith diverse pathways leading to diverse types of cancer,and numerous factors may thus have major impact on thelikelihood for cancer to develop (or not develop) in trans-plantation recipients.

An obvious factor is the limitation of increased cancerrisk in the recipient to those tissues that are predisposed

to cancer by the transplanted mutation. Thus, for exam-ple, predisposing mutation of the MET proto-oncogene,associated with hereditary papillary renal carcinoma,would be expected to pose risk in the recipient of renaltransplantation (17). Similarly, in the future, RET muta-tion could become a special concern if research to de-velop thyroid transplantation comes to fruition (308).

In addition, developmental history may be an impor-tant factor. For example, absence of the predisposing mu-tation during the prenatal development of the individualwho, subsequently, is the recipient of transplantationcould result in markedly different risk for the recipientas compared to the donor.

Furthermore, environmental factors might be impor-tant, including the recipient tissue environment intowhich transplanted cells are placed, because, ultimately,the formation and progression of a tumor may be criti-cally dependent on its stromal context (309). The studyof tumorigenesis in neurofibromatosis type 1 (NF1) pro-vides important insight. Data from a conditional modelfor NF1 in mice suggest that haploinsufficient NF1�/�

cells in the environment play an important role, allowing(possibly promoting) overt tumor formation by neoplas-tic cells (310). This could become an important consid-eration in the effort to develop allogeneic Schwann celltransplantation therapy (311). Fortunately, it appears thatSchwann cells, if inadvertently transplanted from anNF1�/� donor into an NF1�/� recipient, would likelypresent less risk for tumor formation in the recipient thanthey would in the donor. However, the degree of risk mit-igation in the recipient might depend on the extent towhich transplant derived tissue does or does not containhaploinsufficient donor cells of other histologic types,such as mast cells or fibroblasts (312). Hence, the riskmight be greater if stem cells (rather than matureSchwann cells) were transplanted, and they gave rise todiverse types of differentiated cells.

CONCLUSION: THE INTEGRITY OF THE GENOME

In this article we have focused on risk to the recipientfrom the transplantation of cells (potentially as organs ortissues) that might harbor germ-line mutation predispos-ing to cancer. The underlying theme is, however, moregeneral in nature.

Allogeneic transplantation involves transfer to the re-cipient of cells that possess a foreign genome, with diverseperturbations of that genome likely to reside within thepopulation of transplanted cells. In addition, specific ge-netic or epigenetic abnormalities of clinical significancemight be present. These abnormalities could have beenpresent in the donor germ-line; they could have arisen dur-ing the life of the donor; or they could have arisen during


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manipulation of the donated cells. The modification ofdonor cells may be designed to introduce highly advanta-geous properties, possibly including safeguards againstmalignancy (313,314). Nonetheless, it remains of concernthat manipulation (even seemingly minor manipulation)might introduce unintended genetic or epigenetic abnor-mality (or incompatibility) that could give rise to diseasein the recipient, whether cancer or other types of disease(315). Remarkably, there is potential for the introductionof abnormality, especially epigenetic abnormality, evenwith the generation of patient-specific cells, derived by so-matic cell nuclear transfer (316). The transplantation ofcells harboring epigenetic abnormality could present a risksimilar to that from genetic abnormality. For example, itappears that epimutation of either MLH1 or MSH2 maygive rise to hereditary nonpolyposis colorectal cancer(317,318). Nonetheless, the risk from epigenetic abnor-mality may have its own characteristic features, reflectingthe specific roles of epigenetic abnormality in disease pro-cesses, including cancer. For example, methylation of theCDH1 promoter occurs frequently in hereditary diffusegastric cancer as the second hit, inactivating the germ-linewild-type allele (117,119,319).

Thus, with transplantation therapy, there are funda-mental concerns that relate to the integrity of the genomeand the risk for genetic or epigenetic abnormality, of anyorigin, that might cause harm to the recipient. There isimperative to develop strategies for mitigating or elimi-nating this risk, which might include comprehensive test-ing of the genome.

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Address reprint requests to:Dr. Kenneth D. McMilin

Alabama and Central Gulf Coast RegionAmerican Red Cross Blood Services

1130 22nd Street SouthBirmingham, AL 35205

E-mail: [email protected]

Received October 12, 2006; accepted November 13,2006.


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Allogeneic Transplantation and the Risk for Transmission of Genetic Disease: The Heritable Cancer Disorders