THE INHERITANCE BEHAVIOR OF CANCER AS
A SIMPLE MENDELIAN RECESSIVE
STUDIES IN THE NATURE AND INHERITABILITY OF
SPONTANEOUS CANCER IN MICE
TWENTY-FIRST REPORT
MAUD SLYE
(From the Cancer Laboratory of the Otho S. A . Sprague Memorial Institute and thc
University of Chicago)
The study of the inheritance behavior of cancer susceptibility
and cancer resistance is difficult, because we are not dealing with
a superficial character, but instead with a type of organic
response to a stimulus. This pathologic response, moreover,
usually does not occur until middle life or later. It is particularly difficult to study the inheritance behavior of internal
cancer, because we have here the additional handicap that
certain diagnosis is not possible until necropsy. This makes the
selection of double parentage carrying the same type and location of internal neoplasm a matter of great labor and infinite
pains in the mating and the carrying until death of very large
numbers of mice and their offspring, whose ancestry showed the
location and type of neoplasm desired for testing.
On the other hand there is an important objection to using
breast cancer only in these heredity studies; that is, breast
cancer is uncommon in males. Outside of this stock I know of
no spontaneous breast cancers reported in male mice.
Practically all other studies in cancer heredity dealing either
with spontaneous or with experimentally produced tumors have
been carried on with breast cancer only. This has probably been
due to the fact that other stocks have yielded very few internal
tumors. Nearly all the mouse tumors reported in the literature
are mammary gland carcinomas. This in itself is a very strong
argument for the inheritability of specific types and specific
locations of neoplasms.
15
16
MAUD SLYE
The original stock which furnished the ancestry for nearly all
the internal tumors which have appeared in this laboratory for
sixteen years was a stock of piebald, white-footed mice secured
from Japan, strain 90. This strain and its inbred and hybrid
derivatives have produced nearly every type and location of
neoplasm known in human pathology.
The other stocks used in these studies were from several
sources. The forebears of a large part of the self-colored and
the albino mice were secured in 1909 from the breeding establishment of Abbie Lathrop of Granby, Mass., who was at that time
breeding mice for the market, and who supplied the basis for
most of the stocks used in this country by students of cancer
heredity. It is very interesting that my stocks secured from
this source showed exactly the same types and locations of
neoplasms shown by stocks from the same source which were in
use in other laboratories. These were mainly carcinoma of the
mammary gland, some lung tumors, a few thymus and a very
few ovarian tumors.
Since all other types and locations of neoplasms except breast
cancer occur in practically equal numbers in males and females
in my strains, it has been possible to secure as many cases of
double cancerous parentage as was necessary for the work. It
has also been possible, in hybrid crosses, to test the method of
heredity where the male carried the neoplasm and the female
wm cancer free, as well as where the female was the cancerous
member. This has not, to my knowledge, been done in studies
carried on elsewhere.
Over three hundred crosses have been made in this laboratory
between a cancerous individual as one parent and an analyzed,
absolutely non-cancerous individual as the other parent. In
these hybridizations with analyzed material, cancer has never
in any instance appeared in the first hybrid generation. In
every case where it has been possible to carry the young to
cancer age in sufficient numbers to make a test, cancer has
appeared in the second hybrid generation.
It must not be assumed, as has been done by Lynch of the
Rockefeller Institute, that no tests have been made except those
INHERITANCE BEHAVIOR O F CANCER
17
shown in the charts which have been published to date. These
are only a few typical results selected to show what has been
true of all, and the statement has invariably been made in my
publications that hundreds of such tests have been made and
that the results of all were parallel.
Number in which Cancer
Number of Crosses Made between
Cancer and Analyzed Non-cancer
Behaved as a Recessive
300...................................300
Out of these hundreds of tests, a few typical ones have been
selected and charted here to show both the exact method of
procedure and the exact results obtained. Note how closely
these results follow the mendelian expectation in heredity for
the given type of cross, and how rigid is the method of analysis
by which the mice are classified in regard to their cancer tendency. Chart 1 shows strain 145. I n this strain the parent
female was 168. She was the daughter of parents neither of
which had cancer. Her mother, female 499, died in old age of
Bright’s disease, and her father, male 250, died of pulmonary
infection. Female 168 herself died of uncertain causes but had
no tumor. She had therefore been selected for this cross as
she apparently was an extracted non-tumorous mouse.
The parent, male 274, died of carcinoma of the lung. He
came of a family which showed at necropsy 100 per cent of
cancer, strain 139. His mother, 158, died of carcinoma of the
mammary gland with metastases in the lungs; his father, 193,
with primary carcinoma of the lung. He was therefore used in
this cross because he was an analyzed, extracted, cancerous individual, both of whose parents had lung carcinoma and who
himself had lung carcinoma.
We have here a typical mendelian cross between the presence and the absence of a character; that is, male 274 with
the cancer-resistant tendency absent, and female 168 with the
cancer-resistant tendency present. Note that this is a cross
where the male carried the neoplasm and the female waa canoer
free.
The first hybrid generation showed no cancer whatever, which
is the typical behavior in hybridization for a mendelian recessive.
2
CAERT
1
A MATING BETWfEN AN AUALYL€D UON-TUMOROUS
WITH A ' T U M O k O U S
MENDELIAN RESULTS ,SHOWING CANCER BEHAVING ,A5 AQ1MPi-E MENDELIAN
RECESSIVE
8 GIVING PERFECT
INHERITANCE BEHAVI0.R OF CANCER
19
The cancer-resistant tendency, then, was dominant over the
cancer-susceptible tendency in this cross, just as pigmentation
is dominant over the absence of pigmentation in the standard
mendelian cross.
When two of these first generation hybrid non-cancerous
mice were mated (female 434 who died with edema of the lungs
without cancer and male 946 who died of pulmonary hemorrhage
without cancer), the resulting offspring showed nearly perfect
mendelian ratio of 4 dominant non-cancer to 6 hybrid noncancer to 3 recessive cancer. The cancer representatives were
females 1483 and 2426 with carcinoma of the mammary gland
and male 4920 with a carcinoma of the lung.
Female 2672 in the second generation, who died of subacute
ascending nephritis, was analyzed to determine whether she was
dominant non-cancer or hybrid non-cancer, by being mated
with male 4920 with carcinoma of the lung. Cancer appeared
in her immediate offspring: female 4794 with carcinoma of the
lung and female 3383 with two primary carcinomas of the
mammary gland.
Female 2672 was thus shown to be a hybrid non-cancerous
mouse capable of transmitting the disease, though not herself
frankly showing it. This mating also demonstrated the fact
that when hybrid non-cancer is mated with recessive cancer,
cancer appears in the immediate offspring just as recessive
albinism appears in the immediate offspring in the standard
mendelian cross.
I n the effort to derive an analyzed extracted dominant noncancerous mouse, two others of the offspring of the same first
generation hybrid carriers were selected, female 3387 who died
of chronic nephritis without cancer and male 3257 who died of
wounds without cancer. Their son, male 3904, shown in this
chart and who died of a mesenteric abscess without tumor,
appeared to be an extracted dominant non-cancerous mouse.
As necropsy is performed upon all mice dying in this laboratory,
and as every suspicious tissue is examined microscopically, it is
absolutely known which mice have and which have not any
form of neoplasm.
20
MAUD SLYE
By this cross then there was obtained an analyzed cancerous
female 3383 and an analyzed extracted non-cancerous male 3904
for further testing. Note that the types of tumors which appeared in this strain 145, and the organs in which they were
located, were identical with those bred in, namely, cancer of the
mammary gland from ancestral female 158 and carcinoma of
the lung from ancestral male 193 and parent male 274. Moreover, no other types or locations of neoplasms occurred in this
family except those bred in. Just so in the standard mendelian
cross, it is the same color which is bred in (gray) which appears
in the pigmented offspring.
Ancestral male 193 had one daughter in strain 139 (from
which he was derived) with sarcoma of the mammary gland.
Sarcoma of the mammary gland came out later in strain 145,
as shown in chart 4, thus proving male 193 a hybrid carrier of
sarcoma of the mammary gland as well as carcinoma of the
mammary gland, though not himself frankly showing either, as
he died with carcinoma of the lung only. It is thus shown to be
possible for a cancerous individual with one type and location of
neoplasm to be a hybrid carrier of other types and locations of
neoplasms which they do not frankly show, and to transmit
these types to their offspring. This is one of the difficulties in
analyzing out an individual or a strain, so that it neither frankly
shows nor transmits more than one type and location of neoplasm
and it is one of the facts which inevitably confuse the results
when studies in the inheritability of spontaneous cancer are
attempted with unanalyzed materials.
The inheritance behavior, then, of the cancer-resistant and
and the cancer-susceptible tendencies are here identical with the
pigmentation and the non-pigmentation tendencies. The cancerresistant tendency, like the pigmentation tendency, behaved
like a mendelian dominant ; and the cancer-susceptible tendency,
like the non-pigmentation tendency, behaved like a recessive.
Also, just as the type of color bred in is the one which appears
in the offspring,so the types and locations of neoplasms bred in
are the ones which occurred in the offspring.
Chart 2 shows the inbreeding test which was given male 3904
3059
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1986
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L U N G A.BSCCS5
PROVING HIM NON-TUMOQ2US
SEPTICLMIA
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8 390%
CHART
2
NO FRATERNITY IN THIS BKANCH OF T H E FAMILY €VL\PKODUCEDA
NEOPLASM E I T H E & M A L I C N A N T OR BENIGN
VAUNT
INBRED ANALYSIS OF
PART OF STRAIN 145
s
=s
INF
CHART
3
NO FRATERNITY IN THIS FAMILY EVER PRODUCED
O K BENIGN
UUI
A TUMOR M A L I G N A N T
%-
'
&
I
4
c
=3
L
t
5M
m
INHERITANCE BEHAVIOR OF CANCER
23
to prove whether he was certainly an extracted dominant
non-cancerous mouse. He was mated with his sister, female
3903 (also shown in chart 1). She died of suppurative nephritis
without tumor, and appeared also to be an extracted dominant
non-cancerous mouse, as did all other mice in this branch. No
fraternity of this branch of strain 145 has ever shown a neoplasm,
either malignant or benign, although the strain still persists in
the laboratory and has been in existence for fifteen years, the
original cross having been made in October 1910. We have
here, then, analyzed dominant non-cancerous mice for hybridization testing.
To further test male 3904 as an extracted dominant noncancerous mouse, he was hybridized with absolutely unrelated
female 711, who was an analyzed non-cancerous member of
strain 71 and who died in old age of an aortic rupture, without
tumor. No fraternity of this strain 224 ever showed a neoplasm
malignant or benign, although it persisted in the laboratory for
five years.
This is the method by which are analyzed all mice appearing
in these studies. They are not chance mice picked up in the
market or in the laboratory and mated by chance. They are
analyzed individuals whose ancestry and inheritance potentialities are known factors and they therefore can be manipulated
with a certain outcome. No mouse is ever assumed to be
cancerous, hybrid carrier, or cancer free. Only after complete
analysis i s his cancer potentiality classified.
Chart 4 shows a part of strain 150 which resulted from the
cross of analyzed cancerous female 3383 and analyzed extracted
dominant non-cancerous male 3904 whose analysis is shown in
the foregoing charts.
The first hybrid generation from this cross was all noncancerous; that is, again the non-cancer tendency was dominant
over the cancer tendency, but cancer appeared in the second
generation in female 9778 with a carcinoma of the mammary
gland and male 5695 with a sarcoma of the mammary gland.
Again when cancerous male 5695 was mated with non-cancerous
female 5786, no cancer appeared in the next generation. I n
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INHERITANCE BEHAVIOgf OF CANCER
25
both tests then shown in this chart, the non-cancer tendency
was dominant over the cancer tendency.
This chart shows also the origins of branches I, 11, 111, and
IV of this strain. Branch I is made by the crossing of two
first generation hybrids, female 6488 and male 5426. Branch I1
is derived from mating two other Jirst generation hybrids, female
10852 and male 8035. Branch I11 is made by mating two
hybrid non-cancerous mice of the second generation, female
12148 and male 11246. Branch IV is derived by mating two
second generation extracted dominant non-cancerous mice,
female 10911 and male 11346. Note how in every case the
cancer inheritance behavior is in exact accord with the standard
mendelian expectation for a simple recessive; that is, (1) The
mating of a cancerous and an analyzed dominant non-cancerous
mouse gives hybrid non-cancerous mice, with cancer appearing
in the second generation. (2) The mating of two hybrid noncancerous mice gives the standard three types, dominant noncancer, hybrid non-cancer, and recessive cancer. (3) The mating
of two dominant non-cancerous mice gives dominant non-cancer
only, no cancer ever appearing again in such branches, as, for
example, in the non-tumorous branch IV of strain 145, which
has now been carried through more than fifty generations without a neoplasm.
Chart 5 gives Branch I and shows the result of mating
analyzed dominant non-tumorous female 5786 with her cancerous brother 5695, both of the second generation shown in chart 4.
None of their immediate offspping ever showed tumors of any
nature. Cancer thus again behaved like a recessive. Note
that four branches of this family were made by mating four
pairs of these hybrid non-cancerous mice, and in every case some
cancer appeared in the next generation (generation 4 in the
chart). The non-cancerous members of these branches are not
here shown for lack of space. Hybrid carrier female 16273
produced cancer in her immediate offspring, both when tested
with male 17451 and with male 16350. This is another hybridization where the male carried the cancer (of the mammary
gland) and the female was cancer free.
PART OF STRAIN 150
BR.1
CHART 5
A c3loss BETWIEN A GOON-TUfiORpUS -FE?'lALL AND ATUMO-US MALI. SHOWING HOW C A N C m A P P L A U D IN THE.
GENERATIONrRL)M EVERY TESTING OF FIRST GENERATION H Y B R I D - W W L R S IN LINES A . D . C , A N D D
CONTINUED ANALYSIS OF MATING OF CANCERI)US W I T H NON-CANCEROU6 M I C E
SLCOND HYBRlD
Y
=4
U N K . INF.
CARC. M . G L .
METAS. ,LUNGS
9
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0 T.
U N Y . INF
CONTINUATION O F B U N C H I
PART OF STRAlN 150
y
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11219
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d
M t T A 5 . LUNGS
CARC.
11444
N.T.
W N K 1ND
28
MAUD SLYE
Throughout these charts the only tumors both primary and
secondary which occurred were tumors of the mammary gland
and of the lung, like the ancestral tumors of the strain shown in
chart 1.
Chart 6 gives the continuation of branch I of this same strain.
Two third generation hybrid non-cancerous mice, female 17214
mated with male 17327,. also gave the standard three types in
their immediate offspring : dominant non-cancer, hybrid noncancer, and recessive cancer. Female 17214 is also the parent
in line c shown in chart 5.
This demonstrates that, parallel to the pigment cross, wherever
these hybrid carriers occur, whether in the first, the second, the
third, or the nth generation, when mated with similar hybrid
mice they give the mendelian standard three types: dominant
non-cancer, hybrid non-cancer, and recessive cancer. When
these hybrid carriers are mated with dominant non-cancer they
give the standard results for such a cross, that is, dominant noncancer and hybrid carriers as shown in a later chart (chart 13).
Note, then, that by the successive mating of dominant noncancer with hybrid carriers, cancer could be held off indefinitely
but would still be present potentially, transmitted by the hybrid
carriers through generation after generation, but never frankly
shown as long as dominant non-cancer is mated with hybrid
carriers. But when, in any generation, the 2d, the 3d or the
nth, two hybrid non-cancerous mice are mated, cancer will
appear in the next generation in almost mendelian ratio.
In these studies cancer has repeatedly been held off for twentyfive or more generations by persistently mating analyzed
dominant non-cancer with hybrid carriers through successive
generations. But when eventually two of these hybrid carriers
were mated, cancer has appeared in the next generation in every
case.
An illustration of the holding off of cancer until the thirteenth
generation, by the continued mating of analyzed dominant noncancer with hybrid carriers, wm given in chart 5 of strain 84,
branch C, published in 1922 (1). Here, by the mating in the
twelfth generation, of two hybrid carriers of lung tumors
INHERITANCE BEHAVIOR OF CANCER
v"
WV
L1-
We
L;
0
2
29
30
MAUD SLYE
(female 22781 and male 22986, both without frank tumor of any
kind) an adenoma of the lung occurred in their daughter, female
30908 of the thirteenth hybrid generation. In the same report
(the 18th in this series) another similar instance was given, in
branch I11 of strain 164. Here, in the seventh hybrid generation, two hybrid carriers of osteosarcoma were mated, female
12689 and male 12853, neither of which had frank tumor of any
kind. Their daughter, female 21189, of the eighth hybrid
generation, died of osteosarcoma of the leg and spine.
It is this possibility of transmitting cancer through successive
generations by the right selective mating, without its frank
appearance, which explains in human statistics the seemingly
erratic occurrence of cancer sometimes in families when there
has been no previous known case. Our human statistics however cover at best only two ancestral generations and the diagnoses in these were rarely based upon autopsy.
Chart 7 shows branch I1 with two extracted dominant noncancerous lines A and B, derived from the two hybrid noncancerous mice of the first generation shown in chart 4, male
8035 and female 10852. Nowhere in these branches of the
family was there ever a neoplasm of any sort.
These two branches, as well as hundreds of other families in
these studies, demonstrate how immediately and how completely
cancer can be bred out of a family by the right selective mating:
thus showing that we already have a possible and perfect
cancer preventive.
Line C shows another mating between cancer and non-cancer :
female 18243 and male 17704. The continuation of this line
is given in chart 9.
Chart 8 shows a part of the continuation of line B of strain
150, branch 11,whose origin was given in chart 7. This is one of
the analyzed non-tumorous lines extracted from the original
cross shown in chart 4 between cancer and non-cancer. This
line has been in my hands for over fifteen years, has also been
carried through over fifty generations, has been subjected to
every possible analytic test, and has never yielded a neoplasm.
Chart 9 shows the continuation of line C of strain 150, branch
E
G,-
C
4
=3
U N Y . INF-
'I
1NF.
ENDING. L400R
INT.
INC.
2N?.67
UNK
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CHART
U N Y . LNC.
PLCITONITI S
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LINE B
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N.7-
35060
II
8
CHSLNEPU
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STRAIN 150 BRR
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STWN 150 0m
=4
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STRAIN 150 B R . ~
34
M A U D SLYE
11, whose origin is given in chart 7. This cross between tumorous female 18243 and analyzed dominant non-tumorous male
17704 yielded no tumor in the first hybrid generation; but
cancer appeared, as invariably happens in these studies, in the
second generation, female 25898 with a carcinoma of the
mammary gland and an adenoma of the lung. This female
25898 was tested with analyzed non-tumorous male 27767 and
again cancer did not appear in the immediate offspring, but did
appear in the second generation from every pair of hybrid
carriers tested. Note the appearance here of pseudoleukemia
and leukemia, closely allied to the thymus lymphosarcoma of
parent female 18243, and which occurred in the ancestry of this
strain. The facts of the incidence and the inheritance behavior
of these diseases will be given in a later article.
Chart 10 gives part of branch I11 of strain 150 whose origin
was shown in chart 4. Here again the result of mating a hybrid
non-cancerous male 15783 with a recessive cancerous female
24817, both of the third hybrid generation, gives the typical
results. Cancer appears in their immediate offspring.
Chart 11 shows branch IV of strain 150 whose origins were
given in charts 4 and 6. This is another of the extracted noncancerous families from the original hybrid cross.
Chart 12 shows one of the 100 per cent tumorous branches of
strain 150 derived from double tumorous parentage: female
9778 and male 5695.
Note the three generations of cancerous and precancerous
eyelids and muzzle skin in this branch, derived apparently from
hybrid carriers, as this type of tumor occurred several generations
back in the ancestry of this strain. This chart emphasizes
again the fact that tumorous individuals frankly showing one
type of neoplasm may also be hybrid carriers of other types and
locations of tumors. It is thus possible, aa in this chart, to
derive 100 per cent strains of a type of neoplasm not shown by
either parent or any grandparent; but lying even many generations back in the ancestry, transmitted by hybrid carriers
through generation after generation, until finally two hybrid
carriers of this concealed type of neoplasm are mated. The
INHERITANCE BEHAVIOR O F CANCER
I
35
9
INHERITANCE BEHAVIOR OF CANCER
37
next generation then frankly shows it, and from this single
appearance it is possible, by the right selective mating, to derive
100 per cent strains of this rare tumor type. This behavior
is identical with that of albinism when it is similarly manipulated.
It is by this intensive, persistent analysis of individuals and
strains in this laboratory, and thus taking advantage of a single
appearance of types of neoplasms not elsewhere reported in the
literature of mouse cancer, that it has been possible to derive
considerable numbers of nearly every type of neoplasm known
in human pathology.
I wish to reemphasize a t this point the rigid criteria which
have been used in the diagnoses of all neoplasms reported in
these studies. No growth concerning which there was the
slightest question as to its neoplastic nature has ever been
classified among the neoplasms throughout this work, and no
diagnosis more certain than that of “precancerous lesion ” has
ever been used in these questionable cases. To make clear the
classification “precancerous eyelids and muzzle skin” used in
chart 12, I quote from H. G. Wells: “The epithelium of the
surface and hair follicles shows a marked overgrowth, much
beyond a simple hyperplasia in response to chronic irritations,
with deviations from the normal character of such hyperplasias
sufficient to warrant suspicion of a neoplastic character of growth,
but without the actual infiltrative growth of unquestionably
malignant character.”
Without this infiltrative growth of unquestionably malignant
character, the diagnosis of cancer is never made in the study of
these mice. It is probable that many of the so-called “precancerous lesions ” mentioned in these reports are actually
early carcinomas, especially since it has not as yet been possible
to study all such lesions by serial sections, which might in some
instances reveal areas of unquestioned malignancy not revealed
in the few sections so far studied. In fact in many cases lesions
have been diagnosed as non-malignant, from the first sections
made; but upon more careful study of more sections, have
proved to be definitely malignant.
S U N 1 6 4 - W I r ~PARTIAL
ANCESTRY
INHERITANCE BEHAVIOR OF CANCER
39
All the foregoing charts are concerned with the analysis of
parts of a single strain. This selection of charts, to be here
shown, has been made in order to make clear the infinite care
which has been taken and the thorough analysis which has been
made, before the cancer potentiality of any mouse has been
announced, and before any statement has been made concerning
the inheritance behavior of cancer resistance and cancer
susceptibility.
It is obviously impossible within the limits of a few relatively
brief reports to give the results obtained in all tests in this
laboratory. But I have uniformly made the statement that
the charts published, which give only a small fraction of all the
studies, are typical of all. This “all” means over 5000 neoplasms. In every test made, involving over 5000 neoplasms,
every neoplasm has occurred in accordance with mendelian
expectation for a simple recessive. This is true ,whether two
cancerous mice have been mated; or two analysed non-cancerous mice; or cancer with hybrid non-cancer; or hybrid noncancer with analyzed cancer-free mice; or cancer with analyzed
cancer-free mice.
When it has been possible to complete all the multiform and
intricate studies of spontaneous cancer which this stock, now
built up, is yielding, the full genealogy of every mouse and every
strain used in these studies will be finished, charted and published.
Chart 13 gives part of strain 164 with partial ancestry. The
parent female 1236 was a first generation hybrid carrier, derived
from the mating of cancerous female 529 with hybrid carrier
242. The parent male was an analyzed non-cancerous house
mouse belonging to an analyzed strain in my hands many years
without the occurrence of any neoplasms. He himself died of
uncertain causes but had no tumor.
The first generation showed one half dominant non-cancer,
branches I and 11, which never yielded any tumor; and one half
hybrid non-cancer, branches I11 and IV, which gave neoplasms
in the second hybrid generation. This is the typical mendelian
result from the crossing of dominant non-cancer with hybrid
carrier.
acAkc
M GL
i
CHART
14
7 C d t c M G L . ADPNOMA
A D L N O M A LUNG
L1vElc
U l E r U N E F18XOo1D
-2
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meTALt
I=CL*C=D
01
ZCAILC M GI.
LIVEKNEARLI
5
INHERITANCE BEHAVIOR O F CANCER
41
Chart 14 shows another 100 per cent cancer strain of entirely
different derivation, that is, part of strain 338, branch V. This
family was derived from a double cancerous parentage, female
8619 with two carcinomas of the mammary gland and male
8751 with an adenoma of the liver. The ancestry behind this
strain has been published previously (2). It is here omitted in
order to get the chart within the necessary size limits. The
ancestry while in my hands carried sarcomas, carcinomas and
adenomas in most of the organs here represented.
Note the large number of liver tumors, both sarcomas and
adenomas, there being eleven cases of liver tumor primary and
secondary among twenty-four individuals, or nearly 50 per cent.
This is very noteworthy, because outside of this laboratory there
have been only two spontaneous liver tumors in mice reported
in all the literature, one by the Imperial Cancer Research
Laboratory of England (3) and one from the Cancer Laboratory
of Harvard University (4).
The liver tumors in this strain 338 were deliberately bred for,
in the effort to show that the occurrence of the uncommon internal tumors, as well as the more common mammary gland
tumors, unquestionably was determined by heredity.
I n line A note female 8865 with an osteoid sarcoma of the
mammary gland, metastasizing in the liver, succeeded by her
grandson male 16370 with an osteosarcoma of the subcutaneous
tissues of the leg, matastasizing in the liver. In line B, female
22263 with a secondary sarcoma of the uterine wall is succeeded
by her granddaughter female 30469 with a uterine fibroid.
Note the very frequent occurrence in this strain of multiple
tumors, particularly females 9741, 12261, 22263, 30469 and
30501. The latter two mice had more neoplastic than normal
tissues at the time of their death.
I n this strain there is also one case of pseudoleukemia, a
disease which occurred in the ancestry of the strain. In this
laboratory chronic leukemia, pseudoleukemia, lymphosarcoma
and kindred diseases have uniformly occurred in cancer strains
only, and have followed the laws of heredity as surely as have
neoplastic diseases. Their behavior in this laboratory would
42
MAUD SLYE
indicate that they are neoplastic diseases. The standards for
classification, and photomicrographs showing typical structures,
are shown in a recently published article by J. P. Simonds ( 5 ) .
Chart 15 shows part of another 100 per cent cancer family,
branch VI of the same strain 338. Note the occurrence of lung
tumors, primary or secondary, in every member of the family,
from parent female 11560 with secondary carcinoma of the lungs,
and parent male 9783 with primary carcinoma of the lungs.
The comparison of this chart with chart 14 from the same ancestry shows how these different types and locations of neoplasms segregate out, some branches of the strain showing one
type and location of cancer, and other branches showing entirely
different locations, and emphasizing different types of tumors,
where all were derived from the same ancestry which yielded all
these types and locations of tumors. In this branch also of
strain 338, there occurred another uterine fibroid, female 15190.
This occurrence of three uterine tumors within the few members of these two branches of the same strain is noteworthy;
because outside of these studies I know of no report of uterine
tumors in mice. This strain 338 is one of the hybrid derivatives
of strain 90, which carried uterine tumors, as well as many other
internal neoplasms.
These charts are typical. Whenever in this laboratory two
cancerous mice have been mated, it has always been possible
to secure 100 per cent cancerous families except for those mice
that die in infancy or which are swept off by infections earlier in
life than the normal age for the type of cancer to which they are
predisposed, and the age at which they are predisposed to develop the disease. Occasionally a mouse in one of these 100
per cent strains, derived from double cancerous parentage, will
develop a cancer when only two weeks old, although six months
is an early cancer age in mice, and is approximately the equivalent of 32 years, an early cancer age in man.
In the hybridization test, also, cancer has uniformly proved
itself to be inheritable. It has followed almost with exactness
the standard expectation for a typical simple mendelian recessive so that the standard mendelian diagrams have proved to be
r l . G ~ .
9
CnpC. M . C L
LUNGS XlDDLED
MITA5
LUNG
X'IETAS. LUNGS
15190
T
CHART
15
2 CARC. M.CL
IXULT. METAS. LUNGS
UTERJNL F l B q O M A
ADENOMA
I
OR.=
5 CAUC. M . G L
MULT. W f A 5 . LUNGS
CARC. LUNGS
3.cAgt. M . G L
PIULT. META5. LUNGS
CAPC.
PARTS OF STRAIN 338
M
ci
44
MAUD SLYE
exactly duplicated by the behavior of the cancer tendency and
the non-cancer tendency in heredity.
It is this hybridization test which proves beyond dispute the
inheritability of any character, for nothing but heredity could
explain the segregating out, and the transmission unchanged, of
characters in which the two parents are unlike, and the perfect
mendelian pattern which they uniformly follow, as for example
albinism and pigmentation, cancer susceptibility and cancer
resistance.
When both parents die of the same disease and all the later
members of the family die of the same cause, as in a 100 per cent
inbred test, we have no absolute demonstration that it is not a
case of epidemic contagion either extra or intra-uterine. But
we cannot explain by contagion the perfect mendelian pattern
shown in a hybridization test. This pattern, by every test that
can be made, the cancer and the non-cancer tendencies have
uniformly followed.
RESUM& 1. In every test, then, with thoroughly analyzed
material, and by the most rigorous criteria, the cancer-resistant
and the cancer-susceptible tendencies have proved to be inheritable.
2. By the hybridization test, the tendency to cancer resistance has proved to be dominant over the tendency to cancer
susceptibility, and both these tendencies have proved to be
unquestionably inheritable, by following with great perfection
the mendelian pattern.
3. The types of cancer, both primary and secondary, and the
locations where they are likely to occur, have also proved to be
inheritable, both by the inbreeding and by the hybridization
tests, and these characters also have closely followed the mendelian pattern.
The vital objection to using only breast cancer in heredity
studies is obvious from the foregoing charts and discussion.
Breast cancer occurs only rarely in males. None of the heredity
studies using spontaneous breast cancer only have reported
any cases of breast cancer in males. It would be impossible to
analyze the females used in cancer heredity studies, if no crosses
INHERITANCE BEHAVIOR OF CANCER
45
could be made with cancerous males. No other manipulative
measure could make possible the certain distinction of analyzed
cancer-free females from hybrid carriers, thus every mating
made with a female without frank cancer would involve the
possibility of error.
There are few problems in medical research which have occasioned so much dispute and so much disagreement as the problems of the nature and the inheritability of cancer. Observations in this laboratory, which have a marked bearing upon the
problem of the nature of cancer, will be published in a forthcoming report. The present article will concern itself only with
the problem of the inheritability of cancer.
There has been in the medical profession a reluctance to accept
the fact of the inheritability of cancer, and a preconceived and
enduring prejudice against it. This opposition has largely been
caused by fear of the effect of the knowledge of this fact upon the
mind of the public, and no amount of exact evidence has been
sufficient to change this prejudice; although all workers in the
subject have found cancer inheritable, whether they have dealt
with spontaneous tumors or with tumors experimentally produced in any one of many different ways; or even where they
have taken extensive statistics concerning the inheritability of
human cancer, such as those made by Warthin, Davenport and
others. We have, then, the amazing spectacle of scientific men,
trained in the standards of accurate thinking, accepting the
fact of the inheritability of the cancer-susceptible tendency for
mice, and rejecting the fact of its inheritability for the human
species. Such a tenet leads to the inevitable conclusion that
evolution applies up to the human species and breaks there,
leaving man unrelated to all other forms of life.
Few thorough inheritance studies have as yet been made
concerning any pathologic condition except cancer, and I know
of none which has dealt with normal health conditions. Studies
are currently being carried on in this laboratory concerning the
inheritability of various normal conditions and of pathologic
conditions other than cancer. The results of these researches
point to the conclusion that when a thorough test has been made,
46
MAUD BLYE
we shall find that heredity basically controls every item of the
normal and of the pathologic organic response, though the type
of inheritance behavior is not alike in all. These studies will be
published as fast as it is possible to complete them in sufficient
numbers to make a certain test.
What then becomes of the opposition to the idea of cancer
heredity, when we find that all tissue behavior is basically controlled by heredity? Only the Bryanic point of view remains.
Divergences in the method of the inheritance behavior of
various diseases should help to classify them as to basic etiology.
This point I hope to make clear in a later article.
Among research workers in cancer heredity, all have agreed
as to its inheritability, but there has been disagreement as to the
method of inheritability which it follows.
Little and Tyzaer (6) (7) ( S ) , who made a thorough and
extended test with grafted tumors, found that the tendency to
take a graft was inheritable; but that the method of inheritability was that of multiple factors, the most efficient of which
was a dominant, determining cancer in the first hybrid generation. This divergence of view from the results uniformly obtained in this laboratory seems to be harmonized perfectly by
the fact that a grafted tumor i s in the nature of a parasite
growing in a foreign host, Whether or not the host will accept
the graft depends upon the ability of the host tissues to regenerate normally and furnish an accessory blood supply to the
growth. Success in grafting tumors would thus depend upon
normal regeneration in the host exactly as would success in
grafting other tissues such as skin, bone, etc., thus determining
normal regeneration to be dominant over abnormal regeneration.
This is in accord with all results in this laboratory, which show
that normal regeneration is dominant and abnormal regeneration
(as in cancer) recessive.
Lathrop of Granby, Mass., and Loeb of St. Louis (9), working
together with mice that were not autopsied, also concluded that
the inheritance behavior of cancer showed multiple factors, but
differed in detail from the behavior chronicled by Little and
Tyzzer.
INHERITANCE BEHAVIOR OF CANCER
47
Other workers, such as Murray (10) of the Imperial Cancer
Research Laboratory of England, Cuenot of France, Bullock
and Curtis at Columbia working with experimentally induced
liver sarcoma in rats ( l l ) , Marsh (12) of the Gratwick
Cancer Laboratory at Buffalo, N. Y., and others, have concluded that cancer is hereditary, but have not defined its method.
Lynch (13), of the Rockefeller Institute of New York, has
recently published the results of her studies, in which she concludes that cancer is hereditary and defines its method. She
concludes that it behaves like a mendelian unit character, but
that the tendency to cancer susceptibility is dominant over the
cancer-resistent tendancy.
Lynch bases her conclusions on the mating of 15 females with
mammary gland carcinoma with 15 males without frank cancer
of any sort. These mice were derived from various sources,
and there is no evidence given in her publication that any of
them was analyzed as to cancer potentiality. The cancer
potentiality of the 15 females with breast carcinoma is of course
evident. But there is no way of determining with certainty the
difference between a pure-breeding extracted non-cancerous individual and a hybrid cancer carrier without frank cancer, except
that of such thorough analysis as has uniformly been made in
this laboratory of every mouse reported. This method is shown
and discussed in the foregoing charts.
Lynch bases her argument for the dominance of cancer susceptibility upon her opinion that among 15 unanalyzed males
without frank cancer, it is incredible that none should be purebreeding, extracted cancer-free. She therefore thinks that some
of these males must have been extracted non-cancerous, and
concludes when she finds cancer in the first hybrid generation,
that cancer susceptibility must be a dominant.
It is the experience of this laboratory, that of all the items
necessary for the analysis of the inheritance behavior of cancer,
in stocks yielding any cancer, none is so difficult to achieve
with certainty, as an extracted absolutely non-cancerous individual, male or female. It requires the most painstaking and
long-continued analysis to demonstrate beyond doubt the fact
48
MAUD SLYE
that any individual is extracted cancer-free and not a hybrid
carrier.
As I have already pointed out, this is true because cancer can
be carried for any number of generations desired, in hybrid
derivatives from matings of dominant non-cancer with hybrid
carriers; and until every analytic test has been made, the
dominant non-cancer cannot be distinguished with certainty
from the hybrid carrier. It is for this reason that the studies in
this laboratory have taken seventeen years instead of a few
months. Even the strains of wild house mice and Peromyscus
carried in this laboratory have yielded some cancer, and even
these stocks have required long analysis to be sure of the cancerfree members.
These arguments apply with equal certainty to all other
characters in heredity, as well as to cancer susceptibility. The
most potent source of error in all heredity studies would seem
to be the failure to make thorough analysis of each individual,
with the resulting use of hybrid carriers mistaken as extracts
free from the character under study. In my opinion, when
every individual used in any heredity study has been thoroughly
analyzed, there will no longer be these divergences which make
it so difficult to unify the results of scientific research.
In this controversy as to whether cancer susceptibility is
dominant or recessive in hybrid crosses, it is well to bear in mind
some of the well-known common facts.
1. Whatever may be our theory of the nature of cancer, all
agree that it is a pathologic condition, not the normal condition
typical of the species. It would quickly be subversive of racial
integrity if the abnormal were dominant over the normal in
any species. Racial integrity in the matter of the dominance
of the normal over the abnormal has consistently been maintained in this laboratory in every character under observation
for seventeen years, in every strain carried which now involves
nearly 65,000 mice, counting both living and dead members of
these strains.
2. If cancer susceptibility dominated over cancer resistance,
it would be an easy matter to secure cancerous animals for
heredity studies, as every hybrid cross between cancer and non-
INHERITANCE BEHAVIOR O F CANCER
49
cancer would yield an entire first generation of cancerous individuals and 3 cancerous to 1 non-cancerous individual in the
second generation.
Instead of this ease in securing large numbers of cancerous
mice, all workers with spontaneous cancer have found it extremely difficult to establish a large cancer-bearing stock for
such studies, and therefore many workers have been diverted from
using spontaneous cancer stock, and have used instead experimentally produced tumors. Lynch also has evidently found it
difficult to establish a large cancer-bearing stock, or she surely
would not attempt to establish the method of the inheritability
of the cancer-susceptible tendency by only fifteen crosses of
unanalyzed individuals.
I n this laboratory there has been no such ease in securing a
cancer-bearing stock. It has required the unbroken effort of
seventeen years. Moreover the conclusions published from this
laboratory have been based upon over five thousand primary
spontaneous neoplasms, including nearly every type known in
human pathology. I n every one of these five thousand neoplasms, both external and internal, the inheritance behavior of
cancer susceptibility has been that of a simple mendelian recessive.
Number of Cases in which Cancer
Has Behaved as a Recessive
Number of Neoplasms
5,000. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5,000
REFERENCES
1. SLYE:J. Cancer Res., 1922, vii, 107.
2. SLYE:J. Cancer Res., 1916, 1, 479.
3. MURRAY:Third Scientific Report of the Imperial Cancer Research Fund, 1908,
69.
J. Med. Res., 1909, xxi, 479.
4. TYZZER:
5. SIMONDS,
J. P.: J. Cancer Res., 1925, ix, 329.
6. TYZZER:
J. Med. Res., 1909, xxi, 519.
J. Cancer Res., 1916, 1, 125.
7. TYZZER:
8. LITTLE:J. Cancer Res., 1921, vi, 106.
9. LATHROP
AND LOER:J. Expcr. Mcd., 1915, xxii, 646-713; 1918, xxviii, 475.
10. MURRAY:Fourth Scientific Report of the Imperial Cancer Research Fund, 1911,
114.
11. BULLOCK
AND CURTIS:J. Cancer Res., 1924, viii, 1.
12. MARSH:J. Cancer Res., 1925, ix, 411.
13. LYNCH:J. Exper. Med., 1924, xxxix, 481.
4