Dig Dis Sci DOI 10.1007/s10620-014-3465-z

REVIEW

Hereditary and Common Familial Colorectal Cancer: Evidence for Colorectal Screening N. Jewel Samadder • Kory Jasperson Randall W. Burt

•

Received: 17 July 2014 / Accepted: 24 November 2014 Ó Springer Science+Business Media New York 2014

Abstract Colorectal cancer (CRC) is the fourth most common cancer among men and women. Between 3 and 6 % of all CRCs are attributed to well-defined inherited syndromes, including Lynch syndrome, familial adenomatous polyposis, MUTYH-associated polyposis and several hamartomatous conditions. Up to 30 % of CRC cases exhibit common familial risk, likely related to a combination of inherited factors and environment. Identification of these patients through family history and appropriate genetic testing can provide estimates of cancer risk that inform appropriate cancer screening, surveillance and/or preventative interventions. This article examines the colon cancer syndromes, their genetic basis, clinical management and evidence supporting colorectal screening. It also deals with the category of common (non-syndromic) familial risk including risk determination and screening guidelines. Keywords Colorectal cancer  Familial  Hereditary  Screening  Lynch  FAP

N. J. Samadder (&)  K. Jasperson  R. W. Burt High Risk GI Cancers Program, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112, USA e-mail: [email protected] N. J. Samadder  R. W. Burt Departments of Medicine (Gastroenterology), University of Utah, Salt Lake City, UT, USA K. Jasperson Genetic Counseling Resource, Huntsman Cancer Institute, Salt Lake City, UT, USA R. W. Burt Departments of Oncological Sciences, University of Utah, Salt Lake City, UT, USA

Introduction Colorectal cancer (CRC) is the fourth most common cancer among men and women in the USA with almost 137,000 new cases diagnosed in 2014 and over 50,000 resultant deaths [1]. Genetic alterations play a role in the development of all CRCs. Approximately 3–6 % of all CRC cases are associated with highly penetrant hereditary gastrointestinal (GI) cancer syndromes that are now well characterized. Another 25–30 % of individuals with CRC report having one or more relatives diagnosed with CRC; we have used the term common familial CRC for this group. Whereas the inherited syndromes are associated with lifetime CRC risk that may approach 70–90 %, common familial CRC is associated with a twofold to threefold increase in the individual’s risk of CRC. Early identification and intervention in each of these settings is accomplished with effective cancer prevention modalities including colonoscopy with polypectomy and/or appropriate surgery. The risk of cancer in these patient populations can be dramatically reduced with timely screening and treatment. For families with common familial CRC, earlier and more intensive screening is recommended. Genetic testing together with clinical findings is useful for diagnosis of the various syndromes among persons with a strong family history of CRC. When a disease-causing mutation is found in an index case, at-risk relatives can undergo predictive mutation-specific genetic testing and then initiation of screening, based on results, to effectively prevent the development of cancer. An understanding of the genetics of inherited CRCs is important for identifying at-risk individuals, improving the precision of cancer surveillance strategies and developing better diagnostic and therapeutic approaches. In this paper, we will review the genetics, clinical features, diagnosis and

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management of the well-defined hereditary GI cancer syndromes [including Lynch syndrome, familial adenomatous polyposis (FAP), MUTYH-associated polyposis (MAP) and several hamartomatous conditions] as well as summarizing these issues for common familial CRC. We will also focus on the evidence supporting the use of colonoscopy with polypectomy for the reduction in CRC in these high-risk populations. Cancer prevention for all of the syndromes is not confined to the colon or even the GI tract. We recommend that patients with hereditary syndromes be referred to and managed with the input from clinicians and genetic counselors who have expertise in this area.

Lynch Syndrome Overview Lynch syndrome, historically referred to as hereditary nonpolyposis colorectal cancer (HNPCC), is the most common form of hereditary CRC, accounting for approximately 2–4 % of all colorectal and endometrial cancers [2]. In addition to these two cancer types, individuals with LS are predisposed to a number of other cancers (see Table 1) [3]. Lifetime CRC risk is estimated to be as high as 50–80 %, while that of endometrial cancer is up to 40–60 % [4–8]. But actual cancer risks are likely lower than these estimates, as initial studies came from syndrome registries, consisting of highly penetrant Lynch syndrome families. The families in such registries also included a predominance of MLH1 and MSH2 gene mutation carriers. Persons and families with mutations in these two genes have the highest cancer risks of all the five genes related to Lynch syndrome. Genetics Lynch syndrome is inherited in an autosomal dominant fashion, resulting from germ line mutations in a class of genes involved in DNA mismatch repair (MMR), including MSH2, MLH1, MSH6 and PMS2. The MMR system is necessary for maintaining genomic fidelity by correcting single-base mismatches and insertion–deletion loops that form during DNA replication [9]. Mutations in MSH2 and MLH1 account for up to 70 % of Lynch syndrome cases, mutations in MSH6 account for approximately 14 %, and mutations in PMS2 are detected in 15 % of cases [10–14]. Differences in cancer risks have been reported among the MMR genes, including MSH6 and PMS2 where colon cancer risk is lower compared with MSH2 and MLH1 carriers [14, 15]. These various risks have now been incorporated into some surveillance guidelines. A fifth germ line cause of Lynch syndrome has been recently

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described with deletions in the epithelial cell adhesion molecule (EPCAM) gene which results in a EPCAM– MSH2 fusion transcripts and lack of MSH2 expression. But estimates suggest that EPCAM deletions account for only 1–3 % of Lynch syndrome cases [16–20]. Diagnosis Early recognition and diagnosis of patients at risk of Lynch syndrome is important for cancer prevention. Several tools, including analysis of family histories, tumor testing, mutation prediction models and genetic testing, are available to assist in the diagnosis. A detailed personal and family history incorporating at least three generations detailing family relationships and cancer type and age of diagnosis is important as a first step [21]. A number of models have been developed to use this information to assist in the diagnosis of Lynch syndrome. These models include, but are not limited to, PREMM(1,2,6) [22], MMRpro [23] and MMRpredict. The models utilize personal and family histories to estimate the probability that an individual carries an MLH1, MSH2 and/or MSH6 mutation [24]. These models have been validated in CRC cases, but also perform well when using endometrial cancer cases [25–27]. The Amsterdam criteria [8] and revised Bethesda guidelines [28] are used in clinical practice to identify individuals at risk of Lynch syndrome who require further evaluation. Commercial genetic testing is available for all five genes described above. Another approach identifies CRC patients who need genetic testing for Lynch syndrome by examining tumor tissues from all CRC and endometrial cancers (i.e., universal tumor testing). This approach has been shown to be cost-effective and is increasingly being incorporated as a Lynch syndrome screening method [29, 30]. Various tumor testing strategies exist, most of which begin with microsatellite instability (MSI) and/or immunohistochemistry (IHC) analysis of colorectal tumors. The approach with MSI is very sensitive since approximately 90 % of LS-associated CRCs will have MSI-High. Specificity is much lower, however, as 15 % of sporadic CRCs also exhibit this feature. IHC uses four antibodies specific for MLH1, MSH2, MSH6 and PMS2 proteins to evaluate tumors for MMR deficiency. Though the sensitivity of IHC is comparable to that of MSI analysis, IHC has the benefit of being able to direct germ line genetic testing to the appropriate MMR gene/s when loss of specific MMR protein expression is identified in a tumor. Tumor testing in endometrial cancers has also proven to be as effective at evaluating individuals for Lynch syndrome similar to CRC tissue testing. Despite the benefits, there are many hospitals across the USA that are not performing universal tumor testing for Lynch

Dig Dis Sci Table 1 Cancer risks, genes associated and recommendations for management of hereditary CRC syndromes Syndrome

Gene(s)

Lifetime cancer risks

%

Screening/surveillance

Preventative surgery

Lynch syndrome

MLH1

Colorectum

50–80

Colonoscopy every 1–2 years starting at age 20–25 years

Consider prophylactic hysterectomy once child bearing complete

MSH2

Endometrium

40–60

Consider upper endoscopy every 3–5 years, starting at age 30–35 years

MSH6

Stomach

11–19

Consider endometrial cancer screening

PMS2

Ovary

9–12

EPCAM

FAP: classic

FAP: attenuated

APC

APC

MAP

MUTYH

PJS

STK11

JPS

Hepatobiliary

2–7

Upper urinary tract

4–5

Pancreas

3–4

Small bowel

1–4

CNS (Glioblastoma)

1–5

Colorectum

100

Colonoscopy every 1–2 years starting at age 10–12 years

Duodenum/ periampullary

4–12

Upper endoscopy every 1–3 years starting at age 18–25 years

Stomach

\1

Consider thyroid ultrasound

Pancreas

2

Thyroid

1–2

Liver (hepatoblastoma)

1–2

CNS (medulloblastoma)

\1

Colorectum

70

Colonoscopy every 1–2 years, starting at age 20–25 years

Duodenum/ periampullary

4–12

Upper endoscopy every 1–3 years

Thyroid

1–2

Consider thyroid ultrasound

Colorectum

80

Colonoscopy every 1–2 years, starting at age 20–25 years

Duodenum

4

Breast

54

Upper endoscopy every 2–3 years starting in late teens

Colorectum

39

Small bowel screening (CT/MR enterography, small bowel follow-through, capsule endoscopy) every 1–3 years starting at 8–10 years

Pancreas

11–36

Colonoscopy every 2–3 year, starting in late teens

Stomach

29

Pancreas screening (MRCP or EUS) every 1–2 years, starting at age 25–30 years

Ovary

21

Mammogram and breast MRI yearly, starting at age 25 years

Lung

15

Testicular examination/ultrasound yearly, starting age 10 years

Small bowel

13

Transvaginal ultrasound, yearly, starting at age 18 years

Uterine/cervix

98

Testicle

\1

SMAD4

Colorectum

39

Upper endoscopy every 1–3 years starting at age 15 years

BMPR1A

Stomach, pancreas and small bowel

21

Colonoscopy every 1–3 years starting at age 15 years

Consideration for colectomy when polyp burden too great for endoscopic control

Consideration for colectomy when polyp burden too great for endoscopic control

Consideration for colectomy when polyp burden too great for endoscopic control

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syndrome. The Lynch Syndrome Screening Network was developed to help assist institutions with implementing universal testing [31]. The ultimate objectives of these endeavors are to increase Lynch syndrome identification. Colorectal Surveillance and Management Since adenomas are thought to be the precursors to CRC in families with Lynch syndrome, guidelines have recommended colonoscopic surveillance in these families. Ten studies have compared CRC incidence and/or mortality between screened and unscreened patients with LS [32– 41]. All ten studies showed that surveillance led to the detection of CRC at an earlier stage compared with the stage in the historical controls. The only prospective controlled trial from Finland found that surveillance led to a marked reduction in both CRC incidence and mortality [37]. This study reported on 15 years of prospective follow-up of 252 first-degree relative (133 screened and 119 declined screening). It demonstrated a 63 % reduction in CRC incidence with surveillance [6.0 vs 16.0 %, relative risk (RR) 0.38] and 65.6 % reduction in overall mortality (7.5 vs 21.8 %). There were also no CRC deaths among patients receiving surveillance, versus 7.6 % in the unscreened group [37]. Another study of long-term surveillance among LS families within the Dutch registry found a decreased CRC-related mortality, improved 5-year survival (87 % for screened patient vs 63 % of symptomatic controls) and an earlier stage of diagnosis than in controls [34]. Stupart et al. [42] presented data on surveillance colonoscopy in 178 MLH1 mutation carriers (129 screened and 49 declined screening). Surveillance in this group was associated with lower CRC incidence (10.9 vs 27 %, p = 0.019), diagnosis at an earlier stage and lower CRC-related mortality (2.3 vs 12 %, p = 0.021). A more recent study from 2005 compared outcomes from 554 LS individuals (from 290 LS families) undergoing surveillance over a 16-year period [41]. They reported a significantly decreased risk of incident CRC and CRC-related morality compared with expected values using sex- and age-specific rates from the population. All studies have shown a consistent reduction in CRC-related mortality with surveillance, and three have suggested complete prevention of CRC during surveillance. Thus, studies consistently demonstrate that periodic colonoscopic examination in Lynch syndrome results in the reduction in CRC occurrence and mortality. In addition, most studies have shown high rates of colonoscopic adherence in Lynch syndrome-positive individuals [43]. Though randomized control trials are the gold standard for evidence-based medicine, their completion at this stage is unlikely due to the ethics of randomizing a high-risk patient to colonoscopy versus no screening.

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The recommended age for initiation of colorectal surveillance in Lynch syndrome (as early as 20–25 years) is based on the finding that the risk of developing CRC before the age of 25 years is very low [4, 5, 44, 45]. A large Lynch syndrome registry (Dutch HNPCC registry) found only two patients (0.8 %) who developed CRC before the age of 20 years [46]. Current surveillance guidelines recommend an interval between colonoscopies of 1 or 2 years. This is partly based on data suggesting that the adenoma–carcinoma sequence is accelerated in Lynch syndrome. No studies have directly compared various intervals between colonoscopy, though several observational studies have suggested that cancers, even advanced stage, can occur within a 3-year interval [40, 47]. The second Finnish study reported that 21 CRCs were diagnosed after a prior negative colonoscopy, with half being diagnosed within a 3-year interval [38]. The above observations for interval tumors using a 3-year surveillance regimen, together with a recent study that found a reduction in CRC risk from 10 to 6 % after increasing the frequency of surveillance colonoscopy examinations from 3 to 1–2 years [48], support an aggressive strategy using a surveillance interval of 1–2 years. Data are currently limited on whether new endoscopic techniques, such as narrowband imaging (NBI), autofluorescence endoscopy (AFE) or chromoendoscopy (CE), are superior to white light endoscopy (WLE) at polyp detection in individuals with Lynch syndrome. Only one study has evaluated AFE compared with WLE in Lynch syndrome [49]. This study included individuals with either Lynch syndrome or familial CRC and found that 32 % more adenomas were detected using AFE than WLE. Results from three studies suggest that CE detects more adenomas than WLE or NBI [50–52]. However, the results from these studies may be influenced by their back-to-back (WLE followed by CE) study designs. Stoffel et al. [53] also used a back-to-back study design; however, it was randomized (WLE followed by either CE or WLE) and therefore represented an improved study design compared with the previous three studies. In this study, more polyps were found using CE than WLE (15 vs 8), but the difference was due to the detection of hyperplastic rather than adenomatous polyps; CE detected fewer adenomas than WLE (5 vs 7); therefore, adenoma detection in CE was not increased in this small study [53]. Overall, there is still not conclusive evidence to support that CE is superior to standard colonoscopy in Lynch syndrome. Screening for extra-colonic cancer sites (i.e., endometrium, upper GI tract) will not be addressed in depth in this section, but can be reviewed in the National Comprehensive Cancer Network (NCCN) guidelines [3]. Prophylactic hysterectomy and bilateral salpingo-oophorectomy reduces

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the incidence of endometrial and ovarian cancer in patients with Lynch syndrome and should be discussed as an option with women after completion of childbearing [54, 55]. Screening for these cancer sites is felt to be less effective. Cost-effectiveness analysis supports annual surveillance of these organs starting at age 30 years followed by prophylactic surgery at age 40 years [56]. Finally, the cancer prevention project 2 (CAPP2) showed that long-term aspirin use (600 mg/day) can decrease CRC incidence by about 63 % in Lynch syndrome [57], and the CAPP3 optimal dose finding study is underway [58].

Familial Adenomatous Polyposis (FAP) Classic and Attenuated Overview FAP is the second most common hereditary CRC syndrome, with a prevalence of about one in 10,000 live births. Men and women are equally affected, but only a small fraction (*1 %) of all CRCs are due to FAP. This is in part because many CRC cases are now prevented as a substantial fraction of persons and families with FAP are now undergoing colonoscopic surveillance and prophylactic colectomy. FAP is an autosomal dominantly inherited disorder. It typically presents in early adolescence with the development of hundreds to thousands of colonic adenomas and inevitable CRC if left untreated. The average age of CRC diagnosis without intervention is 39 years, with 95 % developing CRC by age 50. Attenuated FAP (AFAP) is a less-severe form of the disease. Nonetheless, there is a nearly 70 % lifetime risk of CRC, but a later age of CRC development, a lower polyp burden (average of 30 colon adenomatous polyps with a range of 0–100?) and tendency to develop more proximal colon neoplasms [59]. Genetics and Diagnosis FAP and AFAP are caused by germ line mutations in the APC gene, which encodes a tumor-suppressor protein that is part of the WNT signaling pathway [60]. Genetic testing of APC is often recommended when greater than 10 cumulative adenomatous colon polyps are found. Detection rate of APC mutations is significantly associated with polyp numbers [61]. Other findings associated with APC mutations include family history of colonic polyposis and/ or cancer, younger age of polyposis onset and extra-colonic findings [62]. Approximately 30 % of newly recognized FAP cases not belonging to a known FAP family are due to new or de novo APC mutations. Some studies have suggested a genotype–phenotype correlation, where the

location of the mutation within the APC gene is associated with the severity of colonic polyposis and the presence of extra-intestinal features [such as desmoids and congenital hypertrophy of the retinal pigment epithelium (CHRPE)] [63]. There are no formal recommendations on the use of genotype–phenotype correlations in the management of patients with germ line APC mutations. A genetic diagnosis of FAP and AFAP depends on finding a disease-causing mutation in the APC gene. Greater than 100 colonic adenomas is often used as the cutoff for determining the ‘‘classic’’ form of FAP. The attenuated form of FAP (AFAP) is often suspected when \100 adenomas are found in a person with an APC mutation, though no precise definition for AFAP or FAP exists. AFAP can overlap with classic FAP and with MUTYH-associated polyposis (MAP) [64]. Therefore, genetic testing is critical in order to make a genetic diagnosis and to differentiate AFAP and FAP from MAP as the tumor risks and inheritance patterns are different. Colorectal Surveillance and Management Due to the nearly 100 % lifetime risk of CRC in classic FAP, early diagnosis and screening are essential. Several studies have compared the incidence of CRC in screened versus symptomatic groups of FAP patients as part of national polyposis registries [65–68]. All of these studies have shown that the incidence of CRC was much higher among symptomatic FAP cases (50–70 %) compared with those in a registry-based surveillance program (3–10 %). Four groups from the UK have examined the results of registry-based screening programs for FAP [69–72]. The largest of these British studies by Gibbons et al. [71] summarized data on 439 patients with FAP and found that screening reduced CRC incidence from 33.6 to 5.1 % and prolonged survival by 4 years. Another study from the UK found that screening was associated with a delayed development of CRC by 15 years and diagnosis at an earlier stage [70]. A more recent study from the Dutch registry found a decrease in CRC incidence from over 65 to 2.7 % associated with screening [73]. Similar results were demonstrated by other large European, Australian and North American polyposis registries, including the Finnish registry [67, 74], Danish registry [68], Swedish registry [65], Australian FAP registry [75] and a Canadian registry [75, 76]. There is thus little question that colonoscopic surveillance by its ability to identify patients who should have prophylactic colectomy dramatically reduces CRC development and associated mortality in FAP. Surprisingly, colonoscopy adherence in FAP and AFAP is low [77]. The age for initiation of colorectal surveillance in FAP (between 10 and 12 years old) is based on the finding that the risk of developing CRC before the age of 20 years is

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very low [78] based on large case series of FAP families from the 1970s and 1980s. Colon polyps with high-grade dysplasia and cancer are rare prior to age 10 years in FAP, though a small number of cases have been described [79– 81]. Colonoscopy is the preferred option for screening, since attenuated forms of FAP may have rectal and distal colon sparing and a propensity for proximal colon polyps. Thus, a sigmoidoscopy in a patient with AFAP (which often cannot be distinguished prior to colonoscopy) may inappropriately judge their risk of cancer to be low based on visualization limited to the rectosigmoid colon. Individual colon adenomas in patients with FAP are endoscopically and histologically identical to sporadic adenomatous polyps and do not seem to have an accelerated or increased malignant potential. Thus, the adenoma to carcinoma timeline will be on average 10–15 years for any one individual adenoma. The increased cancer risk arises from the large number of adenomas that form in this condition. These findings support the current recommendation that the colonoscopy interval be every 1–2 years initially and then increased to annual surveillance once adenomatous polyps emerge. The management of AFAP can be largely extrapolated based on the above findings in classic FAP. Since the mean age of CRC diagnosis is older in AFAP compared with classic FAP (54 years old vs 39 years), a lower polyp density (median of 25 colorectal adenomas) and no cases of CRC below the age of 29 in our large Utah kindred of AFAP [59], experts have recommended initiating colonoscopy in their late teens (*18 years old) and an interval of 1–2 years. Given the proximal colonic affinity of polyps in AFAP, colonoscopy should always be used for screening and surveillance. Approximately 33 % of patients with AFAP can be managed long term with colonoscopy and polypectomy because of the lower polyp number, thus preventing the need for colectomy. Consideration of surgical management should begin early in the course of FAP, when [20 adenomas develop, when adenomas[1 cm in size are found or when advanced histology (villous or high-grade dysplasia) appears. The two main surgical options are colectomy with ileorectal anastomosis (IRA) or proctocolectomy with ileal pouch– anal anastomosis (IPAA). IPAA is the treatment of choice for those with numerous rectal adenomas. If an IRA is selected, annual (or more frequent) endoscopic surveillance must continue to ensure that cancer does not develop in the remaining rectal segment. The NSAID, sulindac, is another treatment option that can be used to effectively regress polyps in the remaining rectum, making surveillance easier [82–84]. A meta-analysis by Aziz et al. [85] compared the adverse effects, functional outcome and quality of life between IRA and IPAA. They found that quality of life

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issues were significantly less in the IRA group, though fecal urgency was reduced with a pouch (IPAA), no significant differences between the two techniques were found for sexual dysfunction or postoperative complications and rectal cancer only occurred in the IRA group [85]. Screening for extra-colonic cancer sites (i.e., duodenum and thyroid) will not be reviewed in depth in this section, but can be reviewed in the NCCN guidelines [3]. Duodenal adenomas eventually form in [50 % of FAP patients. The Spigelman staging criteria can assist physicians in determining the risk of duodenal malignancy, interval for endoscopic follow-up and need for future therapeutic endoscopy or surgical management of duodenal and ampullary adenomas. In general, upper gastrointestinal (GI) endoscopy, including side-viewing endoscopy, should be performed every 1–3 years for patient with FAP or AFAP, starting at age 25–30 years. Annual thyroid examination and/or ultrasound is also offered to AFAP/FAP patients due to the increased risk of thyroid cancer.

MUTYH-Associated Polyposis Overview MUTYH-associated polyposis (MAP) is associated with an autosomal-recessive pattern of inheritance. Biallelic mutations in the MUTYH gene may account for up to 30 % of families with multiple adenomas (15–100) who do not exhibit the classic autosomal dominant inheritance pattern associated with FAP [86, 87]. The colonic phenotype of MAP can overlap with AFAP with most cases showing fever than 100 adenomas [88, 89]. Though adenomatous polyps predominate in MAP, unlike AFAP and FAP, both hyperplastic and sessile serrated polyps can also occur at increased frequency compared with the general population [90]. Genetics and Diagnosis The MUTYH gene (previously known as MYH) is a DNA base excision repair gene involved in the repair of oxidative DNA damage. The MUTYH protein functionally prevents G:C to T:A transversions caused by oxidative stress. The Y179C and G396D mutations are the two most common pathogenic alterations in MUTYH in individuals of western European ancestry. Though biallelic MUTYH gene mutation carriers have a 28-fold increased risk of developing CRC compared with the general population [91, 92], recent studies support no or minimal increased CRC risk in monoallelic carriers [93]. Siblings of individuals with biallelic MUTYH mutations only have a 25 % chance of having MAP, compared with 50 % for an autosomal disorder such as FAP/AFAP.

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Genetic testing criteria for MAP are similar to FAP/ AFAP; however, current recommendations also include serrated polyps as indications for testing of MUTYH [94]. In a recent study of 405 patients with at least 10 colorectal polyps of any histology, 6.7 % were found to have biallelic MUTYH mutations [95]. Genetic testing for MAP is indicated in individuals with [10 colorectal adenomas and no detectable mutation in APC. Along with testing for the most common mutations (Y179C and G396D) in those of western European ancestry, full gene analysis (sequencing and large rearrangements) is also now recommended. Colorectal Surveillance and Disease Management Since MAP patients have a propensity to develop proximal colon neoplasia, colonoscopy is the preferred option for surveillance [88]. CRC due to biallelic MUTYH mutations before the age of 30 has rarely been reported [96]. Initiation of surveillance with colonoscopy in the mid-1920s has thus been advocated. The recommended interval for colonoscopy is every 1–2 years, similar to AFAP, and due to the lower polyp density compared with classic FAP. Upper endoscopy is also advised starting between age 25–30 years due to increased risk of duodenal cancer which has been estimated to be similar to AFAP/FAP [97]. Because of the lower polyp density and ability to remove them at colonoscopy, surgery may not be required. However, if surgery is required due to increasing polyp density, size, high-grade dysplasia or inability to effectively screen the colon, consideration for IRA or IPAA is appropriate.

Hamartomatous Polyposis Syndromes Overview The hamartomatous polyposis syndromes are a group of very rare autosomal dominantly inherited disorders that present with various numbers and types of hamartomatous polyps in the gastrointestinal tract. Together they account for less than 0.5 % of all CRCs. Peutz–Jeghers syndrome (PJS) and juvenile polyposis syndrome (JPS) are both associated with an increased risk of colorectal and extraintestinal malignancies. The other hamartomatous polyposis conditions are very rare and confer a much lower CRC risk than the other syndromes described in this review and will not be discussed in detail. PJS is characterized by childhood onset of multiple gastrointestinal hamartomatous polyps (most commonly in the small bowel) and distinctive mucocutaneous pigmentation typically presenting on the lips, buccal mucosa and periorbital area. It is associated with a high lifetime risk of any cancer (85–90 %), GI cancers (70 % lifetime risk),

pancreatic cancer (11–36 % lifetime risk) and breast cancer (50 % lifetime risk) [98]. Classic presentation of PJS is in the early teens with small bowel obstruction, intussusceptions and GI bleeding resulting in anemia. A clinical diagnosis of PJS can be made when an individual has two or more of the following features: (1) C2 Peutz–Jegherstype hamartomatous polyps of the small intestine; (2) typical mucocutaneous hyperpigmentation; and (3) a family history of PJS [99]. JPS is characterized by multiple (C3–5) juvenile polyps but no obvious physical findings to facilitate diagnosis. The juvenile polyps are most prominent in the colon, but also occur in the stomach, duodenum and small bowel. These patients are at a markedly increased lifetime risk of CRC (39 %) and gastric cancer (21 %), but can also develop pancreatic and small bowel cancer [100, 101]. Congenital abnormalities such as cardiac valvular disease and/or atrial and ventricular septal defects can be seen in approximately 15 % of JPS cases. A subset of JPS patients will also have overlapping features with hereditary hemorrhagic telangiectasia [102] and can present with GI arteriovenous malformations and pulmonary arteriovenous malformations, often with prominent clubbing of the nails, in addition to other vascular lesions. Genetics and Diagnosis Mutations in the serine threonine kinase 11 (STK11 also known as LKB1) tumor-suppressor gene have been found in approximately 50–70 % of PJS patients [103]. Though genetic testing can be confirmatory, some patients with a clinical diagnosis of PJS do not have informative genetic testing. Mutations in SMAD4 and BMPR1A genes are found in approximately 50 % of individuals with a clinical diagnosis of JPS [104]. As with PJS, many patients who meet clinical criteria for a diagnosis of JPS have uninformative genetic testing. Certain features seen in JPS such as gastric polyposis and vascular lesions associated with hereditary hemorrhagic telangiectasia have only been associated with SMAD4 mutations and not BMPR1A. Colorectal Surveillance and Management PJS Patients with PJS require frequent endoscopic surveillance for removal of polyps throughout the GI tract as well as screening for many extra-colonic cancers, including pancreas and breast. The evidence for surveillance endoscopy in PJS is scarce. Screening and surveillance is thus based on expert opinion considering the cancer risks and ages of onset. One study from Giardiello

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et al. [105] found an age range for CRC in PJS patients between 27 and 71 years, with an overall risk of 39 % and predisposition toward male gender. CRC accounted for the majority of GI cancers with a risk up to 39 % by age 70 years in a study from Hearle et al. [106]. The detection and removal of large polyps from PJS patients is based largely on referral center case series studies. A recent study summarizing the endoscopy findings in a series of 63 patients with PJS found that 17 of them had developed significant gastroduodenal or colonic polyps. There were 39 colon polyps and 20 large ([1 cm) gastroduodenal polyps detected in these patients [107]. Based on these studies, both colonoscopy and esophagogastroduodenoscopy with polypectomy are indicated in patients with PJS to reduce the occurrence of gastrointestinal cancers and also benign complications resulting from polyps such as intestinal blockage, intussusception and anemia. The NCCN guidelines recommend starting upper endoscopy and colonoscopy in late teens and repeating every 2–3 years [3]. Some European guidelines suggest starting at age 8 years to identify children with polyps which may cause obstruction in early adolescence and then have repeat investigations at age 18 years in those without significant polyp load [108]. Screening for extra-colonic cancer sites (i.e., breast, pancreas, small bowel) will not be reviewed in depth in this section, are also based mostly on expert opinion and can be reviewed in the NCCN guidelines [3]. In brief, patients with PJS are recommended to undergo small bowel visualization (e.g., capsule endoscopy, CT/MR enterography, small-bowel follow-through) every 1–3 years starting at age 8–10 years; pancreas screening (MRCP or EUS) every 1–2 years starting at 25–30 years; mammogram and breast MRI annually starting at age 25 years; testicular examination/ultrasound annually starting at age 10 years; and transvaginal ultrasound annually starting age 18 years. JPS CRC is the most common cause of mortality in patients with JPS. In one large case series of JPS patients, 16 of 29 (55 %) developed gastrointestinal cancer, 11 (38 %) had CRC, and 6 (21 %) had upper GI cancers [101]. JPS patients are risk of colorectal, gastric and duodenal cancers with an overall risk of any gastrointestinal malignancy exceeding 50 %. The NCCN recommends that individuals with JPS should begin upper and lower endoscopy starting at age 15 years and repeated every 1–3 years [3]. All large colonic polyps should be removed endoscopically if possible, but if too large or numerous, patients should be referred for surgical evaluation for prophylactic colectomy. No recommendations exist regarding small bowel or pancreatic surveillance.

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Serrated Polyposis Syndrome Serrated polyposis syndrome will be discussed in another paper in this special issue.

Common Familial CRC Overview Though germ line mutations in known cancer causing genes are only implicated in 5 % of CRC cases, approximately 30 % of all CRC patients report having a family history of CRC in one or more relatives [109]. Pivotal studies from our group since the 1980s have shown an elevated risk of CRC in both close and distant relatives (first degree out to third-degree relatives) of index CRC patients [110–115]. These findings of elevated familial CRC risk have been confirmed in other studies, including a large genealogy database from Sweden [116] and a prospective cohort study of healthcare workers [117]. Having one first-degree relative with CRC before age 45 years or having two first-degree relatives affected with CRC confers a threefold to sixfold CRC risk compared with the general population. However, it is important to note that the risk is not only limited to relatives of a young onset CRC case. Several studies, including a recent meta-analysis, support at least a twofold elevated familial risk even when the index CRC case is diagnosed over the age of 50 or 60 years [118]. Diagnosis The genetic basis of common familial CRC is not well understood, but studies to date have suggested a number of different, lower-penetrance susceptibility genes are involved. Both linkage analysis and large population-based genome-wide association studies have identified a number of potential loci, including 9q22, 8q23, 8q24, 9p24, 11q23 and 18q21 [119, 120]. Most of these appear to be associated with relatively small effect sizes with relative risks

Table 2 National Comprehensive Cancer Network criteria for further genetic risk evaluation Individuals meeting the revised Bethesda guidelines Individuals with a family history that meets Amsterdam criteria Individuals with [10 colorectal adenomas Individuals with multiple gastrointestinal hamartomatous polyps or serrated polyposis syndrome Individuals from a family with a known hereditary syndrome associated with CRC with or without a known mutation Individuals with a desmoid tumor

Colonoscopy every 5 years beginning at age 40 years, or 10 years before youngest affected relative

Colonoscopy every 5 years beginning at age 40 years, or 10 years before youngest affected relative

Colonoscopy every 5 years beginning at age 40 years, or 10 years before youngest affected relative

American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology [123]

American College of Gastroenterology [122]

American College of physicians [124] NSA

Colonoscopy every 5 years beginning at age 40 years, or 10 years before youngest affected relative

Colonoscopy every 5 years beginning at age 40 years, or 10 years before the youngest case in the immediate family

NSA

Adenomatous polyps \60 years in first-degree relative or in second- or more first-degree relatives

NSA

Colonoscopy every 5 years start at age 40, or 10 years 10 years before youngest affected relative

NSA

NSA

Advanced adenoma \60 years in firstdegree relative

Advanced adenoma: C1 cm in size or with high-grade dysplasia or villous elements

NSA = not specifically addressed, or screening as per average risk

Colonoscopy every 3–5 years beginning at age 40 years, or 10 years before youngest affected relative

National Comprehensive Cancer Network 2014 [126] (www.NCCN.org)

CRC \60 years in first-degree relative or CRC any age in second- or more firstdegree relatives

Table 3 National colorectal cancer screening guidelines based on family history

NSA

NSA

NSA

Colonoscopy every 5 years beginning at age 50 years or at age of onset of adenoma in relative, whichever is first

Advanced adenoma any age in first-degree relative

NSA

Use average-risk screening modality and interval starting at age 40

Use average-risk screening modality and interval starting at age 40

NSA

Either CRC or adenomatous polyps C60 in a first-degree relative or in seconddegree relatives

NSA

NSA

NSA

Colonoscopy every 5 years beginning at age 50 years

CRC C60 years in first-degree relative

NSA

NSA

NSA

Colonoscopy every 5 years beginning at age 50 years

CRC \50 years in seconddegree relative

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ranging from 1.1 to 1.26. It is most likely that much of the common familial CRC risk is due to additive effects of these lower-penetrance alleles and gene–environment interaction. For most individuals with a simple family history of CRC in one or more relatives, but lacking a phenotype associated with one of the known hereditary CRC syndromes, testing for mutations in genes known to confer to CRC risk is uninformative. The NCCN has proposed guidelines for identifying individuals at increased risk of CRC who may be candidates for further risk evaluation and possible genetic testing (Table 2). A similar tool has been validated to identify individuals at open-access colonoscopy who are at higher risk of CRC and need genetics evaluation [121]. Although most common familial CRC families do not meet clinical criteria for genetic testing at this time, members of these families are at increased risk and many warrant more aggressive CRC screening than recommended for individuals without a family history of CRC. Colorectal Surveillance and Management Screening and surveillance recommendations in this group are empirically determined, since there is no specific genetic marker to allow for a uniform diagnosis. The recommendations differ slightly among the various health policy organizations (see Table 3) [94, 122–126]. In brief, screening recommendations based on a family history are as follows: (1) patients with a single first-degree relative older than age 60 years with CRC should receive CRC screening starting at age 50 years and repeating every 5 years with colonoscopy; (2) patients who have one relative with CRC before 60 years or two first-degree relatives with CRC at any age should be screened every 5 years with colonoscopy, starting at 40 years or at an age 10 years younger than the earliest case in the family; and (3) patients with only second- or third-degree relatives with CRC should receive average-risk CRC screening with colonoscopy or stool-based tests starting at age 50 years and repeating at least every 10 years. Several randomized controlled trials (RCTs) have demonstrated that screening for CRC by fecal occult blood test (FOBT) or flexible sigmoidoscopy reduces the incidence and mortality due to CRC in the average-risk population [127–129]. Although several RCTs have been initiated recently to determine the efficacy of colonoscopy for CRC screening, observational studies support the use of colonoscopy for CRC screening [130–133]. These studies (FOBT, sigmoidoscopy and colonoscopy) have been performed in the average-risk population and have not specifically examined the effectiveness of screening in those with a strong family history of CRC (common familial CRC).

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Expert opinion suggests that a greater effectiveness of colonoscopy screening in those with common familial CRC would be due to the elevated risk seen in this population (i.e., a greater burden of colorectal neoplasia or a shorter interval for development). Thus, current guidelines suggest starting colonoscopy earlier and repeating more frequently than in average-risk populations. A study of familial CRC risk from our group showed that approximately 10 % of first-degree relatives of young onset CRC cases developed CRC below the age of 50 years, as compared to only 3 % of first-degree relatives of CRC cases over age 60 years [134]. This finding supports the earlier initiation of colonoscopy in first-degree relatives of young onset (\60 years old) CRC cases. In a recent study by Nishihara et al. using a large prospective cohort of nurse and health professionals, they determined in subgroup analysis that the protective effect of colonoscopy in those with a family history of CRC was no longer observed beyond 5 years from the colonoscopy (HR 0.91; 95 % CI 0.55–1.52). This was compared to a sustained protective effect beyond 5 years seen in those persons without a family history of CRC (HR 0.43; 95 % CI 0.32–0.58). However, this analysis was confounded by all the limitations of subgroup analysis, along with a small sample size for those with a family history of CRC. Even though the etiology of common familial CRC remains unclear, it is the largest high-risk group that physicians in practice are likely to encounter. A strong family history of cancer and/or CRC diagnosis at a young age is red flags that should prompt consideration for genetic counseling referral. Earlier and more intensive screening is recommended in members of these high-risk families and substantial room for improvement in appropriate colonoscopic screening in this group exits.

Conclusion Analysis of CRC risk has now become ‘‘primetime’’ and needs to become more integrated into mainstream clinical practice. The discovery of novel genetic factors associated with familial CRC will provide expanded opportunity in the future for genetic evaluation, testing and risk assessment beyond the known syndromes described above. A growing awareness of the role of family history and genetics in cancer development, along with direct to consumer marketing of genetic evaluation, has increased the public’s awareness of this area. Unfortunately, the majority of individuals at risk of a hereditary CRC syndrome remain unaccounted for and hence the need to improve in this area. Increasing numbers of patients will seek input regarding their genetic and familial predisposition to cancer and opportunities for cancer surveillance and prevention. It is

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now expected that not only genetic counselors, but other health care providers (gastroenterologists, colorectal surgeons, gynecologists, oncologists, primary care providers and nurses) need to possess information regarding the diagnosis and management of patients at risk of hereditary cancer syndromes and work cohesively to provide continuity of care. Regardless of new technologies for genetic testing, clinicians need to emphasize the basics of clinical care and continue to ask patients for a comprehensive personal and family (three generation) history of cancer. Referral to cancer genetics using the simple red flags (outlined in Table 2) will likely result in improved identification of high-risk families. Together these approaches will allow us to stratify patients in terms of cancer risk and provide tailored recommendations for screening, surveillance and chemoprevention, which is the goal of personalized medicine. Acknowledgments The study was funded by the National Cancer Institute, American College of Gastroenterology, American Society for Gastrointestinal Endoscopy and the Huntsman Cancer Foundation. The funding sources did not play a role in the design, conduct or reporting of the study or in the decision to submit the manuscript for publication. Conflict of interest RWB is a consultant for Myriad Genetics and NJS is a consultant for Cook Medical. No other authors have a conflict of interest to disclose. Funding Support for this project was provided by NCI grants P01CA073992 (RWB), R01-CA040641 (RWB), an Endoscopic Research Award from the American Society for Gastrointestinal Endoscopy (NJS) and a Junior Faculty Career Development Award from the American College of Gastroenterology (NJS). Partial support for the Utah Population Database and this project was provided by the Huntsman Cancer Institute Cancer Center Support Grant P30CA042014 from the National Cancer institute and the Huntsman Cancer Foundation. Support for the Utah Cancer Registry is provided by Contract #HHSN 261201000026C from the National Cancer Institute with additional support from the Utah Department of Health and the University of Utah.

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