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CDKN2A founder mutation in pancreatic ductal adenocarcinoma patients without cutaneous features of Familial… Cremin, Carol; Howard, Sarah; Le, Lyly; Karsan, Aly; Schaeffer, David F; Renouf, Daniel; Schrader, Kasmintan A Mar 7, 2018

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CASE REPORT Open AccessCDKN2A founder mutation in pancreaticductal adenocarcinoma patients withoutcutaneous features of Familial AtypicalMultiple Mole Melanoma (FAMMM)syndromeCarol Cremin1,2,6*, Sarah Howard2,6, Lyly Le3, Aly Karsan4,5, David F. Schaeffer6,7, Daniel Renouf6,8and Kasmintan A. Schrader1,2,6,9*AbstractBackground: Approximately 5% to 10% of pancreatic ductal adenocarcinoma (PDAC) has a hereditary basis.In most of these defined hereditary cancer syndromes, PDAC is not the predominant cancer type. Traditionalcriteria for publicly funded genetic testing typically require the presence of a set combination of the predominantsyndrome-associated cancer types in the family history.We report the identification of a CDKN2A pathogenic variant in a PDAC-prone family without the cutaneousfeatures of multiple moles or melanoma that are characteristic of the Familial Atypical Multiple Mole Melanoma(FAMMM) Syndrome identified in a universal testing algorithm for inherited mutations in pancreatic cancer patients.Case presentation: We present the case of two brothers of English ancestry diagnosed with PDAC within thesame 12 month period, at the respective ages of 63 and 64 years of age. Neither brother reported a personalhistory of multiple moles or melanoma. Family history was positive for two second-degree relatives diagnosedwith PDAC but was negative for other cancers or multiple moles in first- and second-degree relatives. Due tothe absence of melanoma, this family did not meet provincial criteria for publicly funded genetic testing.Clinical genetic testing offered through a research grant identified a pathogenic variant in the CDKN2A genec.377 T > A (p.Val126Asp). This variant is a North American founder mutation believed to pre-date colonization.Conclusions: This case reminds clinicians to consider the possibility of a germline CDKN2A mutation in families with ahigh prevalence of PDAC, even in the absence of moles or melanoma. This case supports recent guidelines publishedby the American College of Medical Genetics and Genomics (ACMG) that genetics referrals are indicated in familieswith three or more cases of PDAC regardless of other cancer types in the family. A multi-gene panel approach is ofparticular benefit in diagnosing inherited cancer susceptibility in PDAC-only families.Keywords: Pancreatic cancer, CDKN2A, Familial atypical multiple mole melanoma syndrome, FAMMM, Melanoma* Correspondence:; ischrader@bccancer.bc.ca1Department of Medical Genetics, University of British Columbia, Vancouver,British Columbia, CanadaFull list of author information is available at the end of the article© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (, which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver( applies to the data made available in this article, unless otherwise stated.Cremin et al. Hereditary Cancer in Clinical Practice  (2018) 16:7 5% to 10% of pancreatic ductal adenocar-cinoma (PDAC) has a hereditary basis with the majorgenes and syndromes identified thus far outlined inTable 1. In most of these syndromes, PDAC is not thepredominant cancer type. Traditional criteria for pub-licly funded genetic testing typically require the presenceof a set combination of the predominant syndrome-associated cancer types in the family history.The genetic heterogeneity of familial pancreatic cancer(FPC), typically defined as the occurrence of pancreaticcancer in two affected first degree relatives, has beenwell described in the past decade, with mutations inhigh-penetrance genes such as BRCA2, CDKN2A,PALB2, STK11 thought to explain only 10%–15% of thefamilial clustering [1, 2]. In 2015, Zhen et al. reported ona comprehensive analysis of BRCA1, BRCA2, PALB2,and CDKN2A in a large cohort of FPC kindreds ascer-tained via the multicenter Pancreatic Cancer GeneticEpidemiology (PACGENE) Consortium and found a mu-tation prevalence of 8% among 515 FPC patients (41mutations among the four genes analyzed) [3]. In thatstudy, 2.5% of FPC PDAC patients had a mutation in theCDKN2A gene (n = 14), which is associated with theFamilial Atypical Multiple Mole Melanoma (FAMMM)syndrome. Of note, half of the CDKN2A positive FPCkindreds did not have a family history of melanoma. Theprevalence of CDKN2A mutations increased to 7.8%among PDAC cases with any positive family history ofmelanoma (n = 77).In keeping with the finding of CDKN2A families with-out a history of melanoma, herein, we report thepresentation of a CDKN2A pathogenic variant in aPDAC-prone family without the typical cutaneousfeatures of multiple moles or melanoma that are charac-teristic of the FAMMM syndrome.CDKN2A gene and FAMMM syndromeFAMMM syndrome is an autosomal dominant inheriteddisorder with incomplete penetrance and variable ex-pressivity that results from pathogenic variants in thetumor suppressor gene, CDKN2A [4]. It is characterizedby multiple nevi (usually in the hundreds), atypical nevi,and melanomas typically diagnosed10–20 years earlierthan sporadic melanoma (Table 2). In general, patho-genic variants in the CDKN2A gene are associated witha 28% to 67% lifetime risk to age 80 for melanoma andvary by geographic region (compared to a 1.9% risk inthe general population) [5, 6]. In some families withFAMMM, the CDKN2A mutation is associated with asignificantly increased risk for PDAC, though the under-lying reasons for this remain to be elucidated [7, 8].Published recommendations for CDKN2A genetic test-ing include patients with multiple (more than 3) primarymelanomas, or families with at least one melanoma andtwo other instances of melanoma or PDAC in the familywith mutation detection rates of 20%–40% in thissetting. In the largest familial melanoma data set pub-lished, the Melanoma Genetics Consortium (GenoMEL),the presence of pancreatic cancer was strongly predictivefor an underlying CDKN2A pathogenic variant. Among466 melanoma-prone families, 185 families (40%) carriedmutations in CDKN2A. Among the mutation positivefamilies, 49 (28%) reported a family history of PDAC. OfTable 1 Hereditary pancreatic cancer genes and the 30 gene Color panel. Table listing the major genes associated with hereditarypancreatic adenocarcinoma, the name of the corresponding syndrome and additional cancer risks seen in each syndrome [27]. All ofthese genes are included in the 30 gene Color Genomics panel. Other genes also included in the 30 gene panel are MUTYH, MITF,BAP1, PTEN, CDH1, BMPR1A, SMAD4, GREM1, POLD1, POLE, CHEK2, NBN, BARD1, BRIP1, RAD51C, RAD51D [14]Gene Syndrome Associated Cancers/tumours Estimated lifetime pancreaticcancer risk (to 70–80 years)Included on the30 gene panelSTK11 Peutz Jeghers syndrome Breast, GI (pancreatic),gynecologic, nasal polyps11–32% YesPRSS1 Hereditary Pancreatitis Pancreatic 20%–40% NoCDKN2A/CDK4 Familial Melanoma(Pancreatic) SyndromeMelanoma, pancreatic 17% YesBRCA1/BRCA2 Hereditary Breast andOvarian Cancer syndromeBreast, ovarian, prostate,male breast, pancreatic2%–8% YesMLH1, MSH2, MSH6,PMS2, EPCAMLynch syndrome Colon, uterine, ovarian,pancreatic3%–4% YesAPC Familial AdenomatousPolyposisColon, small intestine,desmoidElevated, not defined YesTP53 Li Fraumeni syndrome Breast (young), sarcoma, brain,adrenocortical, leukemiaElevated, not defined YesPALB2 familial pancreatic cancer Breast, pancreatic Elevated, not defined YesATM familial pancreatic cancer Breast, pancreatic Elevated, not defined YesCremin et al. Hereditary Cancer in Clinical Practice  (2018) 16:7 Page 2 of 7the 66 melanoma families with PDAC, 49 (74%) had aCDKN2A mutation. The mutation frequency in melanoma-only families was significantly lower. Only 33% of familieswithout PDAC had a CDKN2A mutation [9].Although PDAC is the second most common canceroccurring in FAMMM syndrome after melanoma, gen-etic testing of the CDKN2A gene is rarely considered inthe absence of a family history of moles and melanoma[10]. In British Columbia, the provincial criteria forsingle-gene CDKN2A testing as of January 2017 requirethe presence of three cases of PDAC/melanoma in closerelatives, at least one of which must be melanoma [11].The recent advent of next-generation sequencing (ormassively parallel sequencing), has increased the speedand reduced the cost of genetic testing. The use ofmulti-gene panels for the assessment of cancer suscepti-bility is expanding rapidly in clinical practice such thatmultiple genes can now be assessed at the same timeand cost, regardless of whether or not the family historymeets traditional criteria for a particular hereditary can-cer syndrome [12, 13].Case presentationA 63 year-old male patient diagnosed with PDAC wasreferred to the BC Cancer Agency’s Hereditary CancerProgram for hereditary cancer syndrome assessment dueto a strong family history of PDAC (Fig. 1). As the start-ing point for the genetic study of a family, this patient isconsidered the proband. The family history was note-worthy for the occurrence of PDAC in the proband andhis brother, as well as an aunt and uncle on the maternalside. Diagnoses occurred between the ages of 63 and 69.Ancestry was reported as English on both sides.The proband presented with a three-month history ofweight loss and epigastric discomfort. A computerizedtomography (CT) scan showed a 2.9 cm lesion in thehead of the pancreas. He was deemed to have locally ad-vanced unresectable PDAC and began treatment with acombination of 5-fluorouracil, irinotecan, and oxaliplatin(FOLFIRINOX). His medical history included type 2diabetes, hypertension, osteoarthritis, gout and hyperlip-idemia. He reported being a non-smoker who consumes6–8 alcoholic drinks per day.The proband’s brother presented with left upper quadrantpain and underwent an ultrasound as well as a CT scanwhich revealed the presence of a mass in the pancreaticTable 2 FAMMM Diagnostic criteria for Familial AtypicalMultiple Mole Melanoma syndrome [29]1. Malignant melanoma in one or more first- or second-degree relatives2. High total body nevi count (often >50) including some of which areclinically atypical (asymmetric, raised, color variegation present, ofvariable sizes)3. Nevi with certain histologic features on microscopy**architectural disorder with asymmetry, subepidermal fibroplasia, andlentiginous melanocytic hyperplasia with spindle or epithelioid melanocytes;variable dermal lymphocyte infiltration and the “shouldering" phenomenon.All three criteria are needed to make a diagnosisFig. 1 Pedigree. Family history of cancer as reported by the proband (denoted by the arrow), and his brotherCremin et al. Hereditary Cancer in Clinical Practice  (2018) 16:7 Page 3 of 7head and uncinate process. He was deemed to have resect-able PDAC and underwent a pancreaticoduodenectomy(Whipple) procedure. Pathology confirmed a 3.5 cm mod-erately differentiated PDAC. Margins were negative. Hewas treated with adjuvant gemcitabine for six months. Hereported being a non-smoker, rarely consuming alcohol. Hedenied a significant prior medical history.During the initial genetic consultation, the probanddenied any history of breast, ovarian, colon cancer ormelanoma in the family. There was no reported historyof pancreatitis, multiple moles, lip freckling or gastro-intestinal polyps. In this pancreatic-cancer prone family,none of the diagnoses occurred under the age of 50. Thefamily history of cancer did not meet the current provin-cial guidelines for hereditary cancer genetic testing [7].The patient was informed of the options of self-paygenetic testing through one of several genetic testingcompanies or banking DNA at the BC Cancer Agencyshould criteria change in the future. He elected to banka DNA sample and consented to future research.Genetic testingThe proband’s brother was referred to the HereditaryCancer Program six months later at which time aresearch study had opened that offered index genetictesting to unselected, newly diagnosed cases of PDACutilizing a commercial-grade genetic test provided byColor Genomics. The test is designed to assess clinicallyrelevant pathogenic variants in 30 genes associated withhereditary cancer risk, including the hereditary breastand ovarian cancer and Lynch syndrome associatedgenes. Details of their assay are published [14]. Afterreviewing the advantages and limitations of multi-genepanel testing as well as the implications of possibleresults, he consented to the research study and provideda saliva sample for genetic testing. Genetic test resultsrevealed a pathogenic missense variant in CDKN2A,c.377 T > A (p.Val126Asp). The pathogenic variant is as-sociated with FAMMM syndrome, characterized by aninherited susceptibility primarily to melanoma but alsoto PDAC. No variants were detected in the remaininggenes on the panel.Due to an inherited predisposition to cancer being di-agnosed in his brother, the proband was subsequentlyseen in follow-up, where he consented to genetic testing.His results were positive for the familial CDKN2Apathogenic variant.Discussion and conclusionsThe frequency of CDKN2A pathogenic variants in PDACfamilies without melanoma has not been well establishedbut was previously considered to be rare. Bartsch et al.(2002) investigated the frequency of CDKN2A patho-genic variants in 18 familial pancreatic cancer familiesand found no pathogenic variants in families withoutmalignant melanoma, compared to two of five familieswith a history positive for both PDAC and melanoma[15]. McWiliams et al. (2011) describe the challenges ininterpreting prevalence and penetrance of germlineCDKN2A mutations in relation to PDAC given that themutations have most commonly been described infamilies where the predominant lesion is cutaneous mel-anoma [10]. To address this, they studied an unselectedPDAC population of 1537 Caucasian patients from theUnited States and found CKDN2A mutations in nine pa-tients (0.6%). Of the 120 cases with a first-degree relativeaffected with PDAC, four (3.3%) carried mutations,which was significantly higher than in those without afamily history. However, five of the nine mutation carriersdid not have a first-degree affected relative. The authorsestimated the lifetime risk to age 80 of PDAC to be 58%among the 59 first-degree relatives of nine pathogenicvariant carriers. This is significantly higher than the 15–25% lifetime PDAC risk reported in melanoma-familystudies [16, 17]. However, the authors comment that therewas a high proportion of smokers in their study (41%) andthat the difference in cancer risk was only evident amongever-smokers. It is interesting to note that the two broth-ers in this report were non-smokers.The PACGENE study in 515 FPC kindreds found anearly five-fold higher prevalence of CDKN2A muta-tions compared to what was seen in the sporadic PDACpopulation described by McWilliams et al. (2.5%compared to 0.6%). Of note, 7 of 14 (50%) of theCDKN2A mutation associated FPC kindreds did nothave a history of melanoma [3].The specific pathogenic variant found in this family,p.Val126Asp, is a founder mutation in North Americanfamilies estimated to have originated approximately 34 to52 generations ago, pre-dating colonization [18]. Themutation does not appear at high frequency in any othercountries besides the United States and Canada. The vari-ant is absent from or extremely rare in population data-bases [19]. This mutation inhibits the catalytic activity ofthe cyclin D1/CDK4 and cyclin D1/CDK6 complexes invitro [20]. Among the seven families reported with thisfounder mutation in the GenoMEL consortium, PDACwas observed in over 40% and all seven families had ahistory of melanoma by way of ascertainment [9]. Thep.Val126Asp mutation was also described in two PDACpatients in the PACGENE study but details were not pro-vided on the family history of melanoma. In a Dutchstudy, Harinck et al. described three CDKN2A families(two with the Dutch founder mutation c.225_243del,p.Ala76fs and one with a c.19_23dup. pSer8fs mutation)without a history of melanoma and recommended thatCDKN2A testing be considered even in the absence ofreported melanomas [21].Cremin et al. Hereditary Cancer in Clinical Practice  (2018) 16:7 Page 4 of 7As the use of multi-gene panel testing in patientswith PDAC increases, it will be interesting to comparemelanoma penetrance in CDKN2A families ascertainedthrough FPC criteria compared to CDKN2A familiesascertained through FAMMM criteria. Further studiesare needed to understand what other factors, inaddition to the CDKN2A pathogenic variant, contributeto the development of PDAC as opposed to melanomain certain families.The identification of a germline CDKN2A pathogenicvariant changes the management of this family in severalways. Publicly funded carrier genetic testing for theknown familial CDKN2A pathogenic variant is nowavailable to relatives and will clarify cancer risk assess-ment and management guidelines (Table 3). Of note, thetwo remaining siblings of this sibship, neither of whomhad a personal history of cancer, presented for geneticcounseling and tested negative for the founder mutation.From a cancer treatment perspective, an active area ofresearch is the potential predictive role of CDKN2A gen-etic status in terms of estimating sensitivity to CDK4/6inhibitors [22].As with any description of a family history of cancer,one must recognize that the lack of a melanoma in closerelatives could be due to incomplete information.Furthermore, family histories are dynamic. However, theconsistent reporting from all members of the sibship re-garding the lack of any known cases of melanoma infirst-, second- or third-degree relatives is compelling andan important presentation to take note of. Indeed, afterbeing encouraged to inform family members about thepathogenic variant and to enquire about any other rela-tives with melanoma, they became aware of only onesingle case of melanoma, in a maternal second cousin(fifth-degree relative), in addition to some relatives withmoles. To the family’s knowledge, these relatives had notbeen referred for a formal dermatological assessment.In recent dermatology literature, a cautionary tone hasbeen expressed concerning the diagnostic pitfall of disre-garding family members without nevi as potential car-riers of a germline CDKN2A mutation. Indeed, this casestresses that the same diagnostic pitfall would also ariseby disregarding families without melanoma (+/− or nevi)as potential carriers [23].There is a strong need to further the evidence-base re-garding pancreatic cancer screening in high-risk families.Ideally, this is accomplished through involvement inmultidisciplinary clinical research screening programsthat are designed to evaluate the ability of both currentand new technologies to detect lesions at a stage amen-able to therapy. Relatives identified to carry theCDKN2A mutation are being invited into a pancreaticcancer screening registry.Although the two siblings reported here were non-smokers, it is important to stress that the single mostimportant modifier in the risk of PDAC appears to becigarette smoking. Smoking increases the risk of pancre-atic cancer in the general population 1.5 to 5.5-fold [24].In 2003, Rulyak and others studied pancreatic cancer-prone families and noted that pancreatic cancerdeveloped approximately 10 years earlier in smokerscompared to non-smokers [25].In conclusion, this report describing one of the mostcommon CDKN2A mutations reported in North America,in a family without cutaneous features of FAMMM syn-drome, should remind clinicians to consider the possibilityof germline CDKN2A mutations in PDAC-prone familieswithout history of moles or melanoma. This case supportsTable 3 Familial Atypical Multiple Mole Melanoma (FAMMM) Syndrome Risks and Management. Table listing lifetime cancer risksand management recommendationsCancer Type Lifetime Risk Management [28, 29]Melanoma 58% - 92% by age 80* [6] From age 10 or in late adolescence as per family history:- Baseline total body skin examination including scalp, oral mucosa,genital area, and nail, as family members may develop melanomain their early teens. This screening should also be offered to all first-and some second-degree relatives. Nevi should be examined for ABCDEfeatures of melanoma.**- Total body photography and sequential digital dermoscopy imaging canbe useful tools.Examination every 3–6 months initially to ensure nevi stability, then annually.- Thorough total monthly body self-examination should be performedby the patient with assistance from a friend or family member- Routine sun protective behaviors should be reinforced.Pancreas 17% - 25% [16, 17] - Avoid smoking- lack of evidence-based data to support pancreatic cancer screening- families should be referred for consideration of clinical researchscreening programs*varies with geography**ABCDE characteristics of the nevus: asymmetric shape, border irregularity, color variegation, diameter greater than 6 mm and elevation or evolutionCremin et al. Hereditary Cancer in Clinical Practice  (2018) 16:7 Page 5 of 7recent guidelines published by American College ofMedical Genetics and Genomics (ACMG) that geneticsreferrals are indicated in families with three or morepancreatic cancers, even in the absence of breast, colonand melanoma cancers [26]. Furthermore, in light of theknown genetic heterogeneity, a multi-gene panel approachis of particular benefit in diagnosing inherited cancersusceptibility in PDAC-only families (Table 4).AbbreviationsACMG: American College of Medical Genetics and Genomics;CT: computerized tomography; FAMMM: Familial Atypical Multiple MoleMelanoma; FOLFIRINOX: leucovorin, 5- fluorouracil, irinotecan and oxaliplatin;GenoMEL: Melanoma Genetics Consortium; PDAC: pancreatic ductaladenocarcinomaAcknowledgementsWe thank the individuals in this family who participated in this investigation.Ongoing research support is received from the Bob and Judy Hager FamilyFund, VGH Hospital Foundation, BC Cancer Foundation, Michael SmithFoundation, Canadian Institutes of Health Research.FundingCanadian Institutes of Health Research, BC Cancer Foundation, Michael SmithFoundation for Health Research, Pancreas Centre BC, VGH Foundation.Availability of data and materialsnot applicableAuthor’s contributionsAll authors contributed equally to this report, read and approved the finalmanuscript.Ethics approval and consent to participateThis report was conducted under ethics approval H16–02124 with approvalby the Research Ethics Board of the BC Cancer Agency.Consent for publicationThe patients reported provided consent for publication.Competing interestsThe authors declare that they have no competing interests.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Author details1Department of Medical Genetics, University of British Columbia, Vancouver,British Columbia, Canada. 2Hereditary Cancer Program, BC Cancer, Vancouver,British Columbia, Canada. 3Department of Medical Oncology, BC Cancer –Surrey, Surrey, British Columbia, Canada. 4Centre for Clinical Genomics,Genome Sciences Centre, BC Cancer Research Centre, Vancouver, BritishColumbia, Canada. 5Department of Pathology & Laboratory Medicine,University of British Columbia, Vancouver, British Columbia, Canada.6Pancreas Centre BC, Vancouver, British Columbia, Canada. 7Division ofAnatomical Pathology, Vancouver General Hospital, Vancouver, BritishColumbia, Canada. 8Division of Medical Oncology, BC Cancer, Vancouver,British Columbia, Canada. 9Department of Molecular Oncology, BC CancerResearch Centre, Vancouver, British Columbia, Canada.Received: 15 November 2017 Accepted: 5 February 2018References1. Klein AP. Genetic susceptibility to pancreatic cancer. Mol Carcinog. 2012;51(1):14–24.2. Petersen GM. Familial pancreatic cancer. Semin Oncol. 2016;43(5):548–53.3. Zhen DB, Rabe KG, Gallinger S, Syngal S, Schwartz AG, Goggins MG, et al.BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer:a PACGENE study. Genet Med. 2015;17(7):569–77.4. Cannon-Albright LA, Goldgar DE, Meyer LJ, Lewis CM, Anderson DE,Fountain JW, et al. Assignment of a locus for familial melanoma, MLM, tochromosome 9p13-p22. Science. 1992;258(5085):1148–52.5. Begg CB, Orlow I, Hummer AJ, Armstrong BK, Kricker A, Marrett LD, et al.Lifetime risk of melanoma in CDKN2A mutation carriers in a population-based sample. J Natl Cancer Inst. 2005;97(20):1507–15.6. Bishop DT, Demenais F, Goldstein AM, Bergman W, Bishop JN, Bressac-dePaillerets B, et al. Geographical variation in the penetrance of CDKN2Amutations for melanoma. J Natl Cancer Inst. 2002;94(12):894–903.7. 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Pancreatic cancer diagnosed at any age, if any of the followingcriteria are met.(i) ≥2 cases of pancreatic cancer in close relatives(ii) ≥2 cases of breast, ovarian, and/or aggressive prostate cancerin close relatives(iii) Ashkenazi Jewish ancestryB. Pancreatic cancer and ≥1 Peutz Jeghers type polyp in the samepersonC. Pancreatic cancer and two additional cases of any LynchSyndrome associated cancer in the same person or in close relativesD. ≥3 cases of pancreatic cancer and/or melanoma in close relativesE. Pancreatic cancer and melanoma in the same personF. Unaffected but with a family history of:(i) Ashkenazi Jewish ancestry and pancreatic cancer at any age ina close relative(ii) three or more cases of breast, ovarian, pancreatic and/oraggressive prostate cancer in close relatives(iii) three or more cases of pancreatic cancer and/or melanoma.Cremin et al. Hereditary Cancer in Clinical Practice  (2018) 16:7 Page 6 of 717. 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Ipenburg NA, Gruis NA, Bergman W, van Kester MS. The absence of multipleatypical nevi in germline CDKN2A mutations: comment on "hereditarymelanoma: update on syndromes and management: genetics of familialatypical multiple mole melanoma syndrome". J Am Acad Dermatol. 2016;75(4):e157.24. Fuchs CS, Colditz GA, Stampfer MJ, Giovannucci EL, Hunter DJ, Rimm EB,et al. A prospective study of cigarette smoking and the risk of pancreaticcancer. Arch Intern Med. 1996;156(19):2255–60.25. Rulyak SJ, Lowenfels AB, Maisonneuve P, Brentnall TA. Risk factors for thedevelopment of pancreatic cancer in familial pancreatic cancer kindreds.Gastroenterology. 2003;124(5):1292–9.26. Hampel H, Bennett RL, Buchanan A, Pearlman R, Wiesner GL, GuidelineDevelopment Group, American College of Medical Genetics and GenomicsProfessional Practice and guidelines committee and National Society ofgenetic counselors practice guidelines committee. A practice guidelinefrom the American College of Medical Genetics and Genomics and theNational Society of genetic counselors: referral indications for cancerpredisposition assessment. Genet Med. 2015;17(1):70–87.27. McKay S, Humphris J, Johns A, Gill A, Inherited Pancreatic TK. Cancer. CancerForum. 2016;40(1):2.28. Parker JF, Florell SR, Alexander A, DiSario JA, Shami PJ, Leachman SA.Pancreatic carcinoma surveillance in patients with familial melanoma. ArchDermatol. 2003;139(8):1019–25.29. Soura E, Eliades PJ, Shannon K, Stratigos AJ, Tsao H. Hereditary melanoma:update on syndromes and management: genetics of familial atypicalmultiple mole melanoma syndrome. J Am Acad Dermatol. 2016;74(3):395.•  We accept pre-submission inquiries •  Our selector tool helps you to find the most relevant journal•  We provide round the clock customer support •  Convenient online submission•  Thorough peer review•  Inclusion in PubMed and all major indexing services •  Maximum visibility for your researchSubmit your manuscript your next manuscript to BioMed Central and we will help you at every step:Cremin et al. Hereditary Cancer in Clinical Practice  (2018) 16:7 Page 7 of 7


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