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6 Sex-limited, Sex-influenced, and Parent of Origin Effects (Parental Imprinting and Uniparental Disomy)

6 Sex-limited, Sex-influenced, and Parent of Origin Effects (Parental Imprinting and Uniparental Disomy)

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198



USING A PEDIGREE TO RECOGNIZE INDIVIDUALS WITH AN INCREASED SUSCEPTIBILITY



there is a duplication of 11p15 that occurs on the chromosome inherited from the

unaffected father. Less commonly, a child with BWS inherits both copies of chromosome 11 from his or her father (uniparental disomy) (Santiago et al., 2008).



5.7 ENVIRONMENTAL AND OCCUPATIONAL RISK FACTORS FOR

CANCER

Potential environmental and occupational risk factors should be recorded in a cancer

family history (Table 5.7). For example, lung cancer in a 70-year-old person with

a 50 pack-year history of smoking is not surprising, but lung cancer in a 30-yearold nonsmoker is remarkable. Pack years are calculated by dividing the number of

cigarettes smoked per day by 20 (the number of cigarettes in a pack) and multiplying

this figure by the number of years a person has smoked. For example, a person who

smokes 40 cigarettes a day and has smoked for 10 years would have a 20 pack-year

smoking history (40 cigarettes per day ữ 20 cigarettes per pack = 2; 2 ì 10 years

of smoking = 20 pack-year history). Excessive tobacco and alcohol use remain the

most common environmental exposures linked to increase risk for cancer (National

Institute Environment Health Services, 2003).

Increasingly, viruses and bacterial infections are being linked to human cancer

(Goon et al., 2009; National Institute Environment Health Services, 2003):

r Human papilloma virus with cervical, anal, and head and neck carcinomas

r Hepatitis B and C with liver carcinoma

r HTLV (human lymphotrophic virus 1) with adult T-cell leukemia, non-Hodgkin

lymphoma

r Epstein Barr virus with nasopharyngeal carcinoma, Burkitt lymphoma, and

posttransplantation polycolonal lymphomas, Kaposi sarcoma, and lymphomas

r HIV infection with Kaposi sarcoma and non-Hodgkin lymphoma

r Kaposi sarcoma–associated herpesvirus (KSHV)/human herpesvirus 8 (HHV-8)

and Kaposi sarcoma

r Helicobacter pylori infection and stomach carcinoma

r Possible association with H. pylori infection with MALT lymphoma and pancreatic cancer

r Schistosomiasis (parasitic infection) and bladder, liver and intestinal carcinoma

In persons with relatives from Asia, particularly Korea and Japan, there is an

epidemic of stomach cancer related to H. pylori infections. A family history that

suggests a dominantly inherited gastric cancer may be primarily environmental.

It is interesting that there may be an emerging “epidemic” of gastric fundic gland

polypsis related to treatment of acid reflux with chronic acid suppression therapy

with proton pump inhibitors (Freeman, 2008). Traditionally fundic gland polyposis

has been considered a possible manifestation of familial adenomatous polyposis coli



ENVIRONMENTAL AND OCCUPATIONAL RISK FACTORS



TABLE 5.7



199



Lifestyle and Occupational Risk Factors for Cancer



Exposures



Related Cancer



Tobacco (cigarettes, pipe smoking, cigar)



Mouth, throat, nasal cavity, larynx, lung,

esophagus, stomach, pancreas, kidney,

colon, lip, bladder, cervix, liver, leukemia,

vulva

Lung

Breast, mouth, pharynx, larynx, esophagus,

liver, possibly colon

Possible association with colon, prostate, lung,

breast

Breast, endometrial, kidney, gallbladder, colon,

esophagus

Colon, possibly endometrial

Colon

Lung



Secondhand smoke

Alcohol (2 drinks daily, particularly with

tobacco use)

Dietary fats

Obesity

Red meat consumption

Betel nut chewing

Beryllium (aerospace and defense

industries, X-ray tubes, nuclear weapons,

aircraft, brakes, rocket fuel, ceramic

manufacturing)

Diethylstilbestrol (DES) exposure in utero

Estrogen replacement

Alkylating agents (chemotherapy)

Sun exposure, tanning beds

Multiple sexual partners (risk of human

papilloma virus)

Daily perineal talcum powder use (from

silicate particles)

Arsenic (mining, copper smelting,

pesticides, glass making, wood

preservatives)

Asbestos (shipyard, mining, cement, millers,

textile, pipe insulation, building

demolition)

Aromatic amines (dyes)

Benzene (varnishes, other industrial uses)

Bis-ether

Shoe (manufacturing)

Chromium (metal plating)

Hardwood manufacturing

Hermatite mining

Isopropyl alcohol manufacturing

Mustard gas

Pesticides (high doses)

Nickel refining

Rubber industry (benzidine, napathylamine)

Silica dust (coal mines, mills, granite quarry,

sandblasting)

Soot, tars, oils

Vinyl chloride (PVC)

Wood dust (sanding, furniture manufacture)



Cervix, vagina (clear-cell)

Uterus, breast

Leukemia

Skin

Cervix

Possible ovarian

Lung, liver, skin, bladder, kidney



Lung, larynx, mesothelioma



Bladder

Leukemia

Lung

Nasal cavity

Lung

Nasal cavity

Lung

Para-nasal sinuses

Lung, pharynx, larynx

Lymphoma, leukemia, lip, stomach, lung, brain,

prostate, melanoma, skin, kidney

Lung, nasal sinuses

Leukemia, bladder

Lung

Skin, lung, bladder

Liver (angiosarcoma)

Nasal cavities and sinuses



200



USING A PEDIGREE TO RECOGNIZE INDIVIDUALS WITH AN INCREASED SUSCEPTIBILITY



TABLE 5.7



(Continued )



Exposures



Related Cancer



Uranium

Radon (uranium mining, natural exposures)

Radiation (atomic bomb fallout, nuclear

accident)



Lung

Lung

Oral cavity, esophagus, stomach, colon, liver,

lung, non-melanoma skin, breast, ovary,

bladder, nervous system, and thyroid

(papillary)

Thyroid



Ionizing radiation (used to treat acne, ring

worm)



Sources: Bravi et al. 2008; Hamatani et al. 2008; Muscat and Huncharek 2008; National Cancer Institute 2008;

National Institute Environment Health Services 2003; Pelucci et al. 2006; Preston et al. 2007.



(FAP); therefore, a medication history has growing importance when considering

candidates for genetic testing and consideration of further screening for gastrointestinal cancers.



5.8 BE CAUTIOUS IN ASSUMING A CANCER IS SPORADIC OR A

NEW MUTATION IF THE CANCER IS DIAGNOSED AT A YOUNG AGE

OR IS UNCOMMON

When cancer is diagnosed at a young age or at a younger age than typical, the family

history is more likely to be unremarkable for a history of cancer because the person’s

first- and second-degree relatives are also young and are less likely to have developed

cancer. For example, a person diagnosed with colon cancer in his or her 20s and 30s

may have siblings and parents who are all under the age of 50. A small family size

may also hide a familial cancer syndrome (Weitzel et al., 2007). In these situations it is

better to err on the side of caution and offer genetic testing then to miss a diagnosis of

an inherited cancer syndrome. This approach is important for the person with cancer

who is being evaluated because many inherited cancer syndromes are associated with

risks for other cancers, and thus the person would have different cancer surveillance

than typical. Also, close relatives (i.e., first- or second-degree relatives) might be

offered cancer surveillance at a younger age than usual.

Most cancer genetic testing does not identify all of the possible mutations in a

gene, so a negative genetic test in the proband will reduce, but not entirely eliminate,

the possibility of an inherited cancer syndrome. Table 5.8 lists some of the cancers for

which it is reasonable to consider genetic testing in the setting of a noncontributory

family history of cancer based on the age at diagnosis and particularly if the type of

cancer is uncommon. Further clinical evaluation may also be warranted preceeding or

in conjunction with gene mutation analysis. For example, a diagnosis of cribriformmorular variant of papillary thyroid cancer may be a sign of familial adenomatous

polyposis (FAP) (Tomoda et al., 2004), and endometrial cancer diagnosed before age

50 suggests the possibility of Lynch syndrome (Walsh et al., 2008); in both cases,

colonoscopy screening should be considered. (Walsh et al., 2008).



201



Dysplastic gangliocytoma of

the cerebellum

(Lhermitte-Duclos disease

or LDD)

Breast cancer, female

(premenopausal)c



PTCH /NBCCS



Primitive neuroectodermal

tumors (PNET) (< age 3 y)



7–13% (higher if ancestry is

associated with founder

mutations such as

Ashkenazi)

Similar to BRCA1



Unknown



BRCA2 /HBOC2



PTEN /CS



Considered pathognomonic in

adults



Rare cancer, but several

reports in LFS; study by

Gonzalez et al., suggests

likelihood of identifying

mutation may approach

100%

Unknown, examine for clinical

features

Unknown but high yield if

suggestive IHC



Estimate of Likelihood of

Finding a Mutation, in

Absence of Family historyb



BRCA1/HBOC1



Biallelic and

homozygosity for

Lynch mutations

CCMR–D

PTEN /Cowden



TP53 /LFS



Gene/Syndromea



Choroid plexus carcinoma

(childhood)



Tumors, Tumor Site and Clues

from Age at Diagnosis



Triple negative

(estrogen receptor

neg/progesterone

receptor and

neg./Her2/Neu neg)

More likely to be high

grade, estrogen

receptor positive

Consider if concurrent

macrocephaly



Generally desmoplastic

subtype

Consider MSI and IHC

for MLH1, MSH2 ,

MSH6 , and PMS2



Pathology Clues



(Continued)



Buxbaum et al. (2007);

Lachlan et al. (2007);

Pilarski (2009)



Diaz et al. (2007); Lakhani

et al. (2005)



Pilarski (2009)



Wimmer and Etzler (2008)



Evans and Farndon (2008)



Gonzalez et al. (2009);

Krutilokova et al., (2005);

Russell-Swetek et al. (2008)



References



TABLE 5.8 Examples of Solid Tumors and Tumor Sites Where Genetic Testing Should Be Considered Even if the Family History of Cancer

Seems Unremarkable



202



(Continued )



Endometrial cancer (<50 y)



MLH1, MSH2 , MSH6,

PMS2, TACSTD1/

Lynch



BRCA1/HBOC1

BRCA2 /HBOC2

BRCA1/HBOC1

BRCA2 /HBOC2



Primary peritoneal cancer



Fallopian tube cancer (any

age)



BRCA1/HBOC1

BRCA2 /HBOC2



PTEN /Cowden



BRCA1/HBOC1

BRCA2 /HBOC2



Gene/Syndromea



Ovarian cancer (any age)



Breast cancer, male



Tumors, Tumor Site and Clues

from Age at Diagnosis



TABLE 5.8



3–11% (founder mutations in

BRCA2: 40% likelihood of

identifying 995del5 if

affected male Icelandic;

∼13% if affected male

Ashkenazi)

Case reports in Cowden

syndrome; look for

dermatological findings,

and might consider if

macrocephaly

10–15% if Northern

Europeans, ∼30% if

Ashkenazi

Similar frequency to those

with ovarian cancer

Slightly higher frequency than

observed with ovarian

cancer

9–20% in unselected families

(do MSI/IHC on uterine

tissue if available before

germline testing)



Estimate of Likelihood of

Finding a Mutation, in

Absence of Family historyb



Often poorly

differentiated, FIGO

stage II,

tumor-infiltrating

lymphocytes, higher

mitotic rates; if

possible do MSI and

IHC on tumor tissue

before germline

testing



Often distal/fibria



Primarily papillary

serous



Pathology Clues



Hampel et al. (2006); Kovacs

et al. (2009); Lu et al.

(2007); Umar et al. (2004);

Walsh et al. (2008)



Medeiros et al. (2006)



Menczer et al. (2003)



Brozek et al. (2008); Chetrit

et al. (2008)



Pilarski, (2009)



Thorlacius et al. (2007);

Chodick et al. (2008)



References



203



Unknown



Unknown



Unknown

Unknown

Unknown; the incidence of

gastric cancer varies widely

in different populations.

Threshold for testing would

be lower in populations

where gastric cancer rare;

may even consider in

persons < 50 with DGC if

from low-risk population



MLH1, MSH2, MSH6,

PMS2, TACSTD1/

Lynch



MLH1, MSH2, MSH6,

PMS2, TACSTD1/

Lynch



MYH /MAP, APC /FAP



PTEN /CS, STK11/PJS



CDH1/HDGC



Colon cancer (<50 y)



Colon cancer, synchronous or

metachronous Lynch

syndrome related tumorsc

(any age)

Polyposis, >10 adenomatous

polyps

Hyperplastic polyps/mixed

polyposis

Diffuse gastric cancer (DGC)

(<35 y)



Often right sided,

poorly differentiated,

mucinous/signet-ring

cell differentiation

and densely

infiltrated by

lymphocytes; if

possible do MSI and

IHC on tumor tissue

before germline

testing

If possible, do MSI and

IHC on tumor tissue

before germline

testing



Suriano et al. (2005)



(Continued)



Jass (2000); Lefevre et al.

(2006)

Sweet et al. (2005)



Umar et al. (2004)c



Jass (2000; 2008); Kovacs

et al., (2009); Umar et al.

(2004)



204

Unknown



Unknown

Unknown



May be as high as 25%



May be as high as 25%

>80%

Unknown



10%

22–30%

∼30% of head and neck

paragangliomas



CDH1/HDGC



VHL



FLCN /BHD



APC /FAP



RET /MEN2A, MEN2B,

FMTC

TP53 /LFS



PKAR1A/CNC



APC /FAP



VHL, SDHB, RET,

SDHD /PGL1,

SDHAF2 /PGL2,

SDHC /PGL3,

SDHB /PGL4



Papillary thyroid cancer

(cribriform-morular variant

or CMV)



Medullary thyroid cancer



Primary pigmented nodular

adrenocortical dysplasia

(PPNAD)

Hepatoblastoma, <15 y

(usually 6 mo.– 3 y)

Pheochromocytoma

Paraganglioma



Adrenal cortical cancer <18 y



Diffuse gastric cancer,

synchronous/metachronous

lobular breast cancer (any

age)

Clear cell renal cancer,

bilateral

Renal tumors, more than one

morphology



Tumors, Tumor Site and Clues

from Age at Diagnosis



Gene/Syndromea



(Continued )

Estimate of Likelihood of

Finding a Mutation, in

Absence of Family historyb



TABLE 5.8



Particularly

chromosome and

oncocytoma

Predominantly females

and young age at

diagnosis; consider

screening for

polyposis



Pathology Clues



Dahia (2006)

Boedeker et al. (2007); Dahia

(2006)



Aretz et al. (2006)



Gonzalez et al. (2009); Varley

et al. (2003)

Lindor et al. (2008)



Richards (2009)



Tomoda et al. (2004)



Suriano et al. (2005)



References



205



Pathognomonic for Cowden

syndrome

Unknown

Unknown



PTEN /Cowden



STK11/PJS



PRKAR1A/Carney

complex

STK11 (LKB1)/PJS



Trichilemmomas



Sertoli-cell tumors



Unknown but probably high

yield to testing



Calcifying sertoli tumor

(LCCSCT)d

Calcifying sertoli tumor

(LCCSCT)

Bilateral, multifocal,

small



Consider MSI and IHC

for MLH1, MSH2,

MSH6 and PMS2 ;

more likely on trunk

(as compared to

head/neck); more

often adenoma than

carcinoma;

keratoacanthomalike



Amos et al. (2007)



Young (2005)



Stratakis et al. (2001)



Amos et al. (2007)



Pilarski (2009)



Chhibber et al. (2008); Singh

et al. (2008)



Ferolla et al. (2007)



b Few



to Table 5.4a and b for syndrome abbreviations.

large studies are available to estimate the likelihood of finding a mutation in association with a particularly pathology. Disorders are included in this table where the

likelihood of a mutation-positive test is reasonable, particularly given the importance of identification of the familial cancer syndrome and the opportunity to provide cancer

screening and cancer risk reduction to the identified individual.

c Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC) related cancers include colorectal, small bowel, endometrial, stomach, ovarian, pancreas, ureter

and renal pelvis, biliary tract, brain tumors (usually glioblastoma as seen in Turcot syndrome), sebaceous gland adenomas, and keratoacanthomas in Muir–Torre syndrome.

d LCCSCT = large cell calcifying Sertoli cell tumors.



a Refer



Ovarian SCTAT (sex cord

tumors with annular tubules)

Adenoma malignum of the

cervix



STK11 (LKB1)/ PJS



Unclear how often Lynch

syndrome would be

identified by this pathology

without other clinical

features of Lynch,c but at

least make sure a good

family history is taken and

consider IHC and MSI



MLH1, MSH2, MSH6,

PMS2, TACSTD1/

Lynch



50% or higher



Unknown



MEN1/MEN1



Thymic neuroendocrine

carcinoma (carcinoid)

Sebaceous

adenoma/carcinoma



206



USING A PEDIGREE TO RECOGNIZE INDIVIDUALS WITH AN INCREASED SUSCEPTIBILITY



5.9 FAMILY ANCESTRY IS IMPORTANT FOR CANCER RISK

ASSESSMENT

It is important to record the ethnicity of each grandparent because a number of

founder mutations have been identified for various cancer syndromes. For example,

the 999del5 mutation in BRCA2 accounts for 40% of inherited breast cancer risk

in Iceland (Thorlacius, 1997), and in individuals of Ashkenazi Jewish ancestry the

founder mutations in BRCA1 (185delAG and 5382insC) and BRCA2 (6174delT) are

common. The likelihood of identifying a BRCA1 or BRCA2 mutation in a man or

woman of Ashkenazi ancestry with a family history of breast and/or ovarian cancer

is higher than for a non-Ashkenazi person with a similar family history. For example,

a Caucasian woman with ovarian cancer and no family history of breast or ovarian

cancer has about a 13% probability of having a BRCA1 or BRCA2 mutation as

compared to a 22–35% likelihood of testing positive for a mutation if the woman is

Ashkenazi Jewish (Myriad Genetics Laboratories, 2006). Also, the son or daughter

of a parent with one of the BRCA Ashkenazi Jewish founder mutations is offered

screening for all three BRCA mutations if the other parent is Ashkenazi Jewish, given

the high frequency of these BRCA founder mutations in that population (Berliner

and Fay, 2007; Rubenstein, 2004)

Another example of the importance of noting a client’s ethnicity in cancer risk

assessment is in genetic evaluation of the hereditary polyposis syndromes. The autosomal recessive MYH-associated polyposis or MAP syndrome is associated with two

common MYH mutations in the northern European population, Y16C and G282D;

therefore, targeted genetic testing is often the approach; gene sequencing would be

required for a person of non-European ancestry as there are other mutations that could

be responsible (Lefevre et al., 2006).

The likelihood of identifying a genetic sequence variant of uncertain significance

varies in different populations. For example, the probability of finding a variant of

unknown significance of the BRCA1 or BRCA2 gene is about 7% in a person of

northern or central European ancestry, but 21% in a person of African American

ancestry, 14% in person of Asian ancestry, and 8% in a person of Native American

ancestry (Myriad Genetics, personal correspondence, July 2006). Persons undergoing

cancer genetic counseling should be advised of this possibility before they undergo

genetic testing (Trepanier et al., 2004).



5.10 CONSANGUINITY AND CANCER RISK ASSESSMENT

The offspring of closely related individuals are at higher risk to have inherited the

same autosomal recessive gene mutations from a common ancestor (autozygosity)

(Bennett et al., 2002). Some of the autosomal recessive conditions associated with

cancer are listed in Table 5.6. MYH-associated polyposis or MAP is a fairly common

cause of increased risk for colon cancer and is inherited in an autosomal recessive

pattern. For individuals with MAP, evaluation of the partner would be particularly



CONSANGUINITY AND CANCER RISK ASSESSMENT



207



important if the couple is consanguineous because the partner may be heterozygous

for the same recessive mutation. Therefore their children would be at 50% risk to

be homozygous for the MYH mutation, and thus at potential risk to be affected

with multiple adenomatous colon polyps associated with increased risk for colon

cancer.

Fumaric aciduria (fumarase deficiency) is a severe inborn error of metabolism in

homozygous or compound heterozygotes for mutations in FH; monoallelic carriers

of mutations in FH may have manifestations HLRCC (hereditary leiomyomatosis

with multiple cutaneous and uterine leiomyomas and renal cell carcinoma) (Alam

et al., 2005; Wei et al., 2006). Although this is a rare condition, it is a condition

to consider in relation to consanguinity if the diagnosis is made in a heterozygous

adult with leiomyomatosis and/or renal cell cancer, or in a child with fumarase

deficiency.

The role of consanguinity in relation to autosomal dominant cancer syndromes has

not been well studied (Bennett et al., 2002). There is the potential risk of inheriting

the mutant allele from both parents related through a common ancestor. Having

two BRCA1 gene mutations (biallelic) is considered an embryonic lethal, whereas

individuals who have two parents who each have a BRCA2 mutation are at 25% risk

to be biallelic for the BRCA2 mutation that causes Fanconi anemia group D1 (Alter

et al., 2007). There is a suggestion of embryonic lethality inheritance with certain

biallelic BRCA2 mutations as well (Rahman and Scott, 2007).

Having two mutations (homozygosity or compound heterozygosity) in the Lynch

syndrome mismatch repair genes (MLH1, MSH2, MSH6, PMS2, TACSTD1) is associated with a condition called constitutional mismatch repair deficiency (CMMR-D),

which first appeared in the literature as the syndrome CoLoN: colon tumors or/and

leukemia/lymphoma or/and neurofibromatosis type 1 features (Bandipalliam, 2005;

Gallinger et al., 2004; Hedge et al., 2005; Will et al., 2007). The cancers have been primarily identified in childhood, with the predominance of cancers being brain, colon,

and hematological, and the children have neurofibromatosis features (such as caf´e au

lait spots, axillary freckling, macrocephaly). Although each parent carries a mutation

in one of the Lynch syndrome genes, the child may not have a family history of the

typical cancers seen in Lynch syndrome (Senter et al., 2008; Wimmer and Etzler

2008). This may be particularly true with PMS2 mutations for which the penetrance

of cancer seems to be significantly lower than with the other Lynch syndrome mutations (Senter et al., 2008, Wimmer and Etzler, 2008). Many of the children affected

with CMMR-D have had consanguineous parents (Poley et al., 2007; Wimmer and

Etzler, 2008).

Traditionally, genetic counseling for couples who are consanguineous has focused on risks that their offspring will have severe autosomal recessive disorders

that present in the first few years of life; hence forward, more attention should

be paid to noting a family history of common adult-onset disorders, particularly

cancer.

Biallelic mutations in the cancer susceptibility gemes PALB2/FACN and BR1P1

also cause Fanconi anemia (Seal et al., 2006; Schindler et al., 2007).



208



USING A PEDIGREE TO RECOGNIZE INDIVIDUALS WITH AN INCREASED SUSCEPTIBILITY



5.11 CANCER WORRY: THE PEDIGREE AS A PSYCHOSOCIAL TOOL

Coyote’s Call

For Ron, July 30, 2002

We are sitting on top of the porch stairs side by side, Chaco and I listening to the quiet,

Watching the small wind-driven waves slowly make their way across the clear plate

glass, until reflections ripple—each in our own private worlds.

I am thinking of you,

80 miles south in your bed,

Connected to all those lines

With “Your Paddy” spending the night—a one of a kind sleep over.

It starts—one, two and then a serenade of strange, wild yips

Inspired by the last days of the full moon.

Chaco startles and heads down the stairs.

I summon him back

“Those are just your ancestors calling,” I reassure.

Then it occurs to me that ours have voices not yet audible

And they are calling you.

I don’t want either of you to leave me . . . even to join them.

I can hold onto Chaco, I cannot do that for you.

There is a call—stronger, more powerful than mine.

It wants you there;

I, and we, want you here.

Please, turn off your silent voices!

It is morning now, the moon is fading;

We hold on for another day.

Coda:

2004

Now they are calling me too.

I do not want to go. I know you did not either.

I intend to fight as long as I possibly can.

Then I too will join you.

2005

Now it is time.

—Dona Boyd-MacDonald (1944–2006, printed with permission of Steve Boyd,

Seattle)



Reviewing a pedigree is not only the major tool for providing cancer risk assessment but is also an obvious reference to the experience of cancer in the family. Have

people in the family survived their cancer? Were several people in the family diagnosed with cancer over a short time span? Did available cancer surveillance methods



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