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From Bench to Bedside . . . but When? Charis Eng1

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From Bench to Bedside . . . but When? Charis Eng1 Downloaded from genome.cshlp.org on September 23, 2021 - Published by Cold Spring Harbor Laboratory Press Insight/Outlook From Bench to Bedside . But When? Charis Eng1 Department of Adult Oncology, Human Cancer Genetics Unit, Program in Population Sciences, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA and Cancer Research Campaign, Human Cancer Genetics Research Group, University of Cambridge, Cambridge, UK But mousy, thou art no’ thy ’lane findings into clinical practice: the he- quence analysis, differential restriction In proving foresight might be vain reditary breast cancer (HBC) syndromes digestion, single-strand conformation The best laid schemes o’ mice and men gang and multiple endocrine neoplasia type 2 polymorphism (SSCP) with heterodu- aft agley (MEN 2). As highlighted in a Lancet plex analysis, and denaturing gradient And leave us nought but grief and pain Grand Round convened at the Royal gel electrophoresis (DGGE) are equally For promised joy Marsden Hospital, Sutton, UK (Eng et al. accurate and user friendly with a high Robert Burns 1994), the differences between these throughput and reasonable cost (Marsh syndromes were obvious even before the et al. 1994; Mulligan et al. 1994; Borst et Prior to September 1994, we physi- identification of BRCA1. al. 1995; Kambouris et al. 1996). cians in Cancer Family Clinic sat in BRCA1 and BRCA2 together have a total of 49 exons. Unlike RET in MEN 2, front of patients who had family histo- The Syndromes: MEN 2 vs. HBC ries of breast cancer, prophesying, albeit germ-line mutations associated with cautiously, that we would be practicing MEN 2 is an inherited cancer syn- HBC are scattered along the full length clinical cancer genetics differently once drome characterized by medullary thy- of these genes (Breast Cancer Informa- the first breast cancer susceptibility roid carcinoma (MTC) (the most com- tion Core, http://www.nhgri.nih.gov/ gene, BRCA1 was cloned. In the autumn mon fatal complication), pheochromo- Intramural research/Lab transfer/Bic). of 1994, BRCA1 was delivered into an cytoma (PC), and hyperparathyroidism Thus, various mutation scanning tech- expectant world of scientists, clinical (HPT). Depending on the tissues in- nologies are employed instead of the cancer geneticists, patients, and curious volved and their combination of fea- gold standard of nucleotide sequencing onlookers (Miki et al. 1994). In rapid tures, this syndrome is subdivided fur- (Eng and Vijg 1997). The tradeoff of ac- succession, thanks to the Human Ge- ther into MEN 2A, MEN 2B, and familial curacy for high throughput is germane, nome Project and its fallout technology medullary thyroid carcinoma (FMTC). as the entire discussion about mutation and information, the second breast can- Prior to genetic testing, annual bio- frequency, penetrance, and risk (below) cer susceptiblity gene BRCA2 was chemical screening for all individuals at can be obviated if the techniques used in mapped and isolated (Wooster et al. risk started at age 6 for MEN 2A and these molecular epidemiologic studies 1994, 1995); other genes that may lend FMTC, and younger for MEN 2B. Like all have senstivities or specificities well be- susceptiblity to breast cancer, ATM indirect screening tests, false positives low 100%. Some may fear, for example, (ataxia-telangiectasia) and PTEN and false negatives occurred. that pure heteroduplex analysis used in (Cowden syndrome), ensued (Savitsky et HBC comprises a group of autosomal the recent study by Couch et al. (1997) al. 1995; Nelen et al. 1996; Liaw et al. dominantly inherited cancer syn- has a low sensitivity. However, it is com- 1997). The era of molecular oncology dromes, including site-specific breast forting to note that the mutation fre- had arrived. cancer, breast–ovarian cancer syn- quencies obtained in comparable studies But what makes cutting-edge genetic drome, and site-specific ovarian cancer were identical using heteroduplex findings of today clinical practice to- syndrome. To complicate matters, other analysis (Couch et al. 1997) and DGGE morrow? The most important criterion HBC syndromes do exist (Table 2), but (Stoppa-Lyonnet et al. 1997), a tech- is benefit or potential benefit to the pa- for purposes of this discussion, only nique with virtually 100% accuracy (Eng tient—that genetic tests result in altered these three will be considered. and Vijg 1997). clinical management. Other criteria A RET–MEN 2-like situation, how- (Table 1) include ease of mutation detec- ever, does exist for HBC in the Ash- Ease of Mutation Detection: RET vs. kenazi Jewish population, a genetically tion, the majority of people with a spe- BRCA1 and BRCA2 cific inherited cancer syndrome contain distinct popluation of Jews, whose an- mutations within the same gene, the The RET proto-oncogene, encoding a cestors lived in central and eastern Eu- mutation analysis allows prediction of receptor tyrosine kinase, is the suscepti- rope (for review, see Tonin et al. 1996; cancer risk, and effective surveillance or bility gene for MEN 2 (Eng 1996). Al- Streuewing et al. 1997). Three ancient effective prophylactic procedures are though RET has 21 exons (Myers et al. mutations, c.185delAG and c.5382InsC available. Two inherited cancer syn- 1995), germ-line mutations in only one in BRCA1 and c.6174delT in BRCA2, are dromes illustrate the agony and ec- of eight codons encompassed within commonly found in Ashkenazi HBC stasy—apologies to Michelangelo—of five exons have thus far been associated families. It is relatively easy to test a translating the latest molecular genetic with MEN 2 (Eng et al. 1996). Direct se- panel of these mutations by any detec- 7:669–672 ©1997 by Cold Spring Harbor Laboratory Press ISSN 1054-9803/97 $5.00 GENOME RESEARCH 669 Downloaded from genome.cshlp.org on September 23, 2021 - Published by Cold Spring Harbor Laboratory Press Insight/Outlook tion technique; in the Research Molecu- 17q. More often than not, these do not though, doubtless, such analyses are in lar Diagnostics Laboratories of the Dana- represent the patient population in our progress. However, extrapolating from Farber Cancer Institute, these are the cancer genetics clinics. More recently, the BRCA1 experience, clinical cancer only BRCA1 and BRCA2 mutations that taking ‘‘all comers’’ with familial breast geneticists suspect that the BRCA2 fig- are tested. cancer, with or without ovarian cancer, ures will also be lower. Although the detection technology two centers (one in France and the other Overall, unlike MEN 2, HBC is geneti- choice is a nonissue in MEN 2, it impacts in the U.S.) found ∼15% had germ-line cally heterogeneous. Thus, more predis- greatly on HBC genetic testing. Hope- BRCA1 mutations (Couch et al. 1997; position genes can be expected, and re- fully, in the not too distant future, cost- Stoppa-Lyonnet et al. 1997). cent data support such expectations. efficient mutation scanning of several Can we predict which families repre- Paradoxically, however, when practic- genes in parallel will help (Eng and Vijg sent the 15% with germ-line BRCA1 mu- ing clinical cancer genetics, familiality 1997). tations, raising the possibility of imple- can still be presumed in all HBC as a menting practical genetic testing for whole. Bayesian calculations are still these families? The presence of ovarian used to predict inheritance and cancer Germ-Line Mutation Frequencies in cancer seems to increase the chances risk. MEN 2 and HBC Susceptibility Genes that there is a BRCA1 mutation (Couch Germ-line mutations in RET occur in et al. 1997; Stoppa-Lyonnet et al. 1997), Cancer Risk in Mutation-Positive >92% of all MEN 2 cases (Eng et al. bearing out predictions based on link- Individuals 1996). Res ipsa loquitur (That which is age, although not to that great an ex- obvious or self-evident). Unlike RET test- tent. Instead of the 90% predicted, Both MEN 2 and HBC are believed to ing in MEN 2, 3 years after BRCA1 isola- ∼40%–45% of breast–ovarian cancer have age-related penetrance (Ponder et tion and 2 years after BRCA2 cloning—a families have these mutations. Unlike al. 1988; Easton et al. 1993). Based on long time in molecular genetic terms— linkage-based estimates using large clinical presentation only, 70% of pre- we still sit in front of our HBC patients families, only 7% of the clinic families sumed RET mutation carriers will de- in Cancer Genetics Clinic, but we most with breast cancer alone carried a BRCA1 velop a sign or symptom by the age of 70 certainly cannot offer them BRCA(X) mutation (Couch et al. 1997). Interest- (Easton et al. 1989). Biochemical screen- testing as a routine clinical service. ingly, the absolute number of family ing increases the penetrance figures to Initially, based on linkage analysis members affected with breast cancer is 95% by the age of 35 (Easton et al. with 17q markers flanking the BRCA1 not independently predictive of the 1989). Hence, in general, carriers of locus in ‘‘large’’ families with breast and presence of BRCA1 mutation. germ-line RET mutations have a high ovarian cancer, BRCA1 mutations were Partially reflecting the 2% prevalence risk of developing MTC, PC, or HPT. predicted to account for the majority of of the three ancient mutations in the Based on the original linkage studies HBC families, even as high as 90% (Eas- Ashkenazi Jewish population, the clinic- in large, exaggerated families with HBC, ton et al. 1993). Similarly, ∼50% of large based study by Couch et al. (1997) re- risk estimates for breast and/or ovarian site-specific breast cancer families ap- vealed that belonging to the Ashken- cancer reached 85%–90% by the age of peared to be linked to this locus (Hall et azim increased the probability of detect- 70 and 50% by the age of 50 (Easton et al. 1990; Easton et al. 1993).
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